CANTAXEL

Main information

  • Trade name:
  • CANTAXEL 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:
  • CANTAXEL Concentrate for Soln for Inf 6 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/162/001
  • Authorization date:
  • 01-09-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cantaxel6mg/mlconcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlofconcentrateforsolutionforinfusioncontains6mgpaclitaxel.

Avialof5mlcontains30mgpaclitaxel.

Avialof16.7mlcontains100mgpaclitaxel.

Avialof25mlcontains150mgpaclitaxel.

Avialof50mlcontains300mgpaclitaxel.

Excipients:

525mg/mlmacrogolglycerolricinoleate,404mg/mlethanol96%.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

Clear,colourlessorslightlyyellowviscoussolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ovariancarcinoma:

Infirstlinechemotherapyofovariancancer,paclitaxelisindicatedforthetreatmentofpatientswithadvanced

carcinomaoftheovaryorwithresidualdisease(>1cm)afterinitiallaparotamy,incombinationwithcisplatin.

Insecond-linechemotherapyofovariancancer,paclitaxelisindicatedinthetreatmentofmetastaticcarcinomaofthe

ovaryafterfailureofstandardplatinumcontainingtherapy.

Breastcarcinoma:

Intheadjuvantsetting,Paclitaxelisindicatedforthetreatmentofpatientswithnode-positivebreastcarcinoma

followinganthracyclineandcyclophosphamide(AC)therapy.AdjuvanttreatmentwithPaclitaxelshouldberegardedas

analternativetoextendedACtherapy.

Paclitaxelisindicatedfortheinitialtreatmentoflocallyadvancedormetastaticbreastcancereitherincombination

withananthracyclineinpatientsforwhomanthracyclinetherapyissuitable,orincombinationwithtrastuzumab,in

patientswhoover-expresshumanepidermalgrowthfactorreceptor2(HER-2)ata3+levelasdeterminedby

immunohistochemistryandforwhomananthracyclineisnotsuitable(seesection4.4and5.1).

Asasingleagent,Paclitaxelisindicatedforthetreatmentofmetastaticcarcinomaofthebreastinpatientswhohave

failed,orarenotcandidatesforstandard,anthracyclinecontainingtherapy.

Advancednon-smallcelllungcarcinoma:

Paclitaxel,incombinationwithcisplatin,isindicatedforthetreatmentofnon-smallcelllungcarcinoma(NSCLC)in

patientswhoarenotcandidatesforpotentiallycurativesurgeryand/orradiationtherapy.

AIDS-relatedKaposi’ssarcoma

PaclitaxelisindicatedforthetreatmentofpatientswithadvancedAIDS-relatedKaposi’ssarcoma(KS)whohave

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Limitedefficacydatasupportsthisindication,asummaryoftherelevantstudiesisshowninsection5.1.

4.2Posologyandmethodofadministration

Methodofadministration:Theconcentrateforsolutionforinfusionmustbedilutedbeforeuse(seesection6.6)and

shouldonlybeadministeredintravenously.

Paclitaxelshouldbeadministeredthroughanin-linefilterwithamicroporousmembraneof0.22µm(seesection6.6).

Allpatientsmustbepremedicatedwithcorticosteroids,antihistaminesandH

-antagonistspriortopaclitaxel,e.g.

8-20mgforKSpatients

oranequivalentantihistaminee.g.chlorphenamine

IV=intravenous

First-linechemotherapyofovariancarcinoma:

Althoughotherdosageregimensareunderinvestigation,acombinationregimenofpaclitaxelandcisplatinis

recommended.

Accordingtodurationofinfusion,twodosesofpaclitaxelarerecommendedpaclitaxel175mg/m 2

administered

intravenouslyover3hours,followedbycisplatinatadoseof75mg/m 2

everythreeweeksorpaclitaxel135mg/m 2

,in

a24-hourinfusion,followedbycisplatin75mg/m 2

,witha3-weekintervalbetweencourses(seesection5.1).

Second-linechemotherapyofovariancarcinoma:

Therecommendeddoseofpaclitaxelis175mg/m 2

administeredoveraperiodof3hours,witha3-weekinterval

betweencourses.

Adjuvantchemotherapyinbreastcarcinoma:

Therecommendeddoseofpaclitaxelis175mg/m 2

administeredoveraperiodof3hoursevery3weeksforfour

courses,followingACtherapy.

First-linechemotherapyofbreastcarcinoma:

Whenusedincombinationwithdoxorubicin(50mg/m 2

),paclitaxelshouldbeadministered24hoursafterdoxorubicin.

Therecommendeddoseofpaclitaxelis220mg/m 2

administeredintravenouslyoveraperiodof3hours,witha3-week

intervalbetweencourses(seesections4.5.and5.1).

Whenusedincombinationwithtrastuzumab,therecommendeddoseofpaclitaxelis175mg/m 2

administered

intravenouslyoveraperiodof3hours,witha3-weekintervalbetweencourses(seesection5.1).Paclitaxelinfusion

maybestartedthedayfollowingthefirstdoseoftrastuzumaborimmediatelyafterthesubsequentdosesof

trastuzumabiftheprecedingdoseoftrastuzumabwaswelltolerated(fordetailedtrastuzumabposologyseethe

SummaryofProductCharacteristicsoftrastuzumab).

Second-linechemotherapyofbreastcarcinoma:

Therecommendeddoseofpaclitaxelis175mg/m 2

administeredoveraperiodof3hours,witha3-weekinterval

betweencourses.

TreatmentofadvancedNSCLC:

Therecommendeddoseofpaclitaxelis175mg/m 2

administeredoveraperiodof3hoursfollowedbycisplatin80

mg/m 2

Drug Dose AdministrationpriortoPaclitaxel

dexamethasone 20mgoral*

orIV Fororaladministrationapproximately12and6hoursorfor

IVadministration:30to60min

diphenhydramine ** 50mgIV 30to60min

cimetidineor

ranitidine 300mgIV

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TreatmentofAIDS-relatedKS

Therecommendeddoseofpaclitaxelis100mg/m 2

administeredasa3-hourintravenousinfusioneverytwoweeks.

Subsequentdosesofpaclitaxelshouldbeadministeredaccordingtoindividualpatienttolerance.

Paclitaxelshouldnotbereadministereduntiltheneutrophilcountis1,500/mm 3

(1,000/mm 3

forKSpatients)andthe

plateletcountis100,000/mm 3

(75,000/mm 3

forKSpatients).

Patientswhoexperiencesevereneutropenia(neutrophilcount<500/mm 3

for7days)orsevereperipheralneuropathy

shouldreceiveadosereductionof20%forsubsequentcourses(25%forKSpatients)(seesection4.4).

Patientswithhepaticimpairment:

Inadequatedataareavailabletorecommenddosagealterationsinpatientswithmildtomoderatehepaticimpairments

(seesection4.4and5.2).Patientswithseverehepaticimpairmentshouldnotbetreatedwithpaclitaxel.

Paediatricuse:

Paclitaxelisnotrecommendedforuseinchildrenbelow18yearsduetolackofdataonsafetyandefficacy.

4.3Contraindications

CantaxelHypersensitivitytopaclitaxelortoanyexcipient,especiallymacrogolglycerolricinoleate(seesection4.4).

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

Paclitaxeliscontraindicatedduringlactation(seesection4.6).

InKS,Paclitaxelisalsocontraindicatedinpatientswithconcurrent,serious,uncontrolledinfections.

4.4Specialwarningsandprecautionsforuse

Paclitaxelshouldbeadministeredunderthesupervisionofaphysicianexperiencedintheuseofcancer

chemotherapeuticagents.Sincesignificanthypersensitivityreactionsmayoccur,appropriatesupportiveequipment

shouldbeavailable.

Giventhepossibilityofextravasation,itisadvisabletocloselymonitortheinfusionsiteforpossibleinfiltrationduring

drugadministration.

Patientsmustbepretreatedwithcorticosteroids,antihistaminesandH

-antagonists(seesection4.2).

Paclitaxelshouldbegivenbeforecisplatinwhenusedincombination(seesection4.5).

Significanthypersensitivityreactionscharacterisedbydyspnoeaandhypotensionrequiringtreatment,angioedema,

andgeneralisedurticariahaveoccurredin<1%ofpatientsreceivingpaclitaxelafteradequatepremedication.These

reactionsareprobablyhistamine-mediated.Inthecaseofseverehypersensitivityreactions,paclitaxelinfusionshould

bediscontinuedimmediately,symptomatictherapyshouldbeinitiatedandthepatientshouldnotberechallengedwith

themedicinalproduct.

Bonemarrowsuppression(primarilyneutropenia)isthedose-limitingtoxicity.Frequentmonitoringofbloodcounts

shouldbeinstituted.Patientsshouldnotberetreateduntilneutrophilsrecoverto1,500/mm 3

(1,000/mm 3

forKS

patients)andplateletsrecoverto100,000/mm 3

(75,000/mm 3

forKSpatients).IntheKSclinicalstudy,themajority

ofpatientswerereceivinggranulocytecolonystimulatingfactor(G-CSF).

Patientswithhepaticimpairmentmaybeatincreasedriskoftoxicity,particularlyGrade3-4myelosuppression.

Thereisnoevidencethatthetoxicityofpaclitaxelisincreasedwhengivenasa3-hourinfusiontopatientswithmildly

abnormalliverfunction.Whenpaclitaxelisgivenasalongerinfusion,increasedmyelosuppressionmaybeseenin

patientswithmoderatetoseverehepaticimpairment.Patientsshouldbemonitoredcloselyforthedevelopmentof

profoundmyelosuppression(seesection4.2).Inadequatedataareavailabletorecommenddosagealterationsinpatients

withmildtomoderatehepaticimpairments(seesection5.2).

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betreatedwithpaclitaxel.

Severecardiacconductionabnormalitieshavebeenreportedrarelywithsingleagentpaclitaxel.Ifpatientsdevelop

significantconductionabnormalitiesduringpaclitaxeladministration,appropriatetherapyshouldbeadministeredand

continuouscardiacmonitoringshouldbeperformedduringsubsequenttherapywithpaclitaxel.Hypotension,

hypertension,andbradycardiahavebeenobservedduringpaclitaxeladministration;patientsareusuallyasymptomatic

andgenerallydonotrequiretreatment.Frequentvitalsignmonitoring,particularlyduringthefirsthourofpaclitaxel

infusion,isrecommended.SeverecardiovasculareventswereobservedmorefrequentlyinpatientswithNSCLCthan

breastorovariancarcinoma.AsinglecaseofheartfailurerelatedtopaclitaxelwasseenintheAIDS-KSclinicalstudy.

Whenpaclitaxelisusedincombinationwithdoxorubicinortrastuzumabforinitialtreatmentofmetastaticbreast

cancer,attentionshouldbeplacedonthemonitoringofcardiacfunction.Whenpatientarecandidatesfortreatment

withpaclitaxelinthesecombinations,theyshouldundergobaselinecardiacassessmentincludinghistory,physical

examination,ECG,echocardiogram,and/orMultipleGatedacquisition(MUGA)scan.Cardiacfunctionshouldbe

furthermonitoredduringtreatment(e.g.everythreemonths).Monitoringmayhelptoidentifypatientswhodevelop

cardiacdysfunctionandtreatingphysiciansshouldcarefullyassessthecumulativedose(mg/m 2

)ofanthracycline

administeredwhenmakingdecisionsregardingfrequencyofventricularfunctionassessment.Whentestingindicates

deteriorationincardiacfunction,evenasymptomatic,treatingphysiciansshouldcarefullyassesstheclinicalbenefitsof

furthertherapyagainstthepotentialforproducingcardiacdamage,includingpotentialirreversibledamage.Iffurther

treatmentisadministered,monitoringofcardiacfunctionshouldbemorefrequent(e.g.every1-2cycles).Formore

detailsseeSummaryofProductCharacteristicsoftrastuzumabordoxorubicin.

Althoughtheoccurrenceofperipheralneuropathyisfrequent,thedevelopmentofseveresymptomsisrare.Insevere

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

NSCLCpatientsandinovariancancerpatientstreatedinthefirst-linesetting,theadministrationofpaclitaxelasathree

hourinfusionincombinationwithcisplatinresultedinagreaterincidenceofsevereneurotoxicitythanbothsingle

agentpaclitaxelandcyclophosphamidefollowedbycisplatin.

Specialcareshouldbetakentoavoidintra-arterialapplicationofpaclitaxel,sinceinanimalstudiestestingforlocal

toleranceseveretissuereactionswereobservedafterintra-arterialapplication.

Paclitaxelincombinationwithradiationofthelung,irrespectiveoftheirchronologicalorder,maycontributetothe

developmentofinterstitialpneumonitis.

Cantaxelcontainsethanol96%(404mg/ml),considerationshouldbegiventopossibleCNSandothereffects.

Harmfulforthosesufferingfromalcoholism.Tobetakenintoaccountinpregnantorbreast-feedingwomen,children

andhigh-riskgroupssuchaspatientswithliverdiseaseorepilepsy.

Pseudomembranouscolitishasbeenrarelyreportedincludingcasesinpatientswhohavenotbeenconcomitantly

treatedwithantibiotics.Thisreactionshouldbeconsideredinthedifferentialdiagnosisofcasesofsevereorpersistent

diarrhoeaoccurringduringorshortlyaftertreatmentwithpaclitaxel.

InKSpatients,severemucositisisrare.Ifseverereactionsoccur,thepaclitaxeldoseshouldbereducedby25%.

Cantaxelcontainsmacrogolglycerolricinoleate,whichmaycausesevereallergicreactions(seesection4.3).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Therecommendedregimenofpaclitaxeladministrationinthefirst-linechemotherapyofovariancarcinomaisfor

paclitaxeltobegivenbeforecisplatin.Whenpaclitaxelisgivenbeforecisplatin,thesafetyprofileofpaclitaxelis

consistentwiththatreportedforsingleagentuse.Whenpaclitaxelwasgivenaftercisplatin,patientsshowedamore

profoundmyelosuppressionandanapproximately20%decreaseinpaclitaxelclearance.Patientstreatedwithpaclitaxel

andcisplatinmayhaveanincreasedriskofrenalfailureascomparedtocisplatinaloneingynaecologicalcancers.

Sincetheeliminationofdoxorubicinanditsactivemetabolitescanbereducedwhenpaclitaxelanddoxorubicinare

givencloserintime,paclitaxelforinitialtreatmentofmetastaticbreastcancershouldbeadministered24hoursafter

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Themetabolismofpaclitaxeliscatalysed,inpart,bycytochromeP450isoenzymesCYP2C8andCYP3A4(seesection

5.2).ClinicalstudieshavedemonstratedthatCYP2C8-mediatedmetabolismofpaclitaxel,to6-hydroxypaclitaxel,is

themajormetabolicpathwayinhumans.Concurrentadministrationofketoconazole,aknownpotentinhibitorof

CYP3A4,doesnotinhibittheeliminationofpaclitaxelinpatients;thus,bothmedicinalproductsmaybeadministered

togetherwithoutdosageadjustment.Furtherdataonthepotentialofdruginteractionsbetweenpaclitaxelandother

CYP3A4substrates/inhibitorsarelimited.Therefore,cautionshouldbeexercisedwhenadministeringpaclitaxel

concomitantlywithmedicinesknowntoinhibit(e.g.erythromycin,fluoxetine,gemfibrozil)orinduce(e.g.rifampicin,

carbamazepine,phenytoin,phenobarbital,efavirenz,nevirapine)eitherCYP2C8orCYP3A4.

Paclitaxelclearanceisnotaffectedbycimetidinepremedication.

StudiesinKSpatients,whoweretakingmultipleconcomitantmedications,suggestthatthesystematicclearanceof

paclitaxelwassignificantlylowerinthepresenceofnelfinavirandritonavir,butnotwithindinavir.Insufficient

informationisavailableoninteractionswithotherproteaseinhibitors.Consequently,paclitaxelshouldbeadministered

withcautioninpatientsreceivingproteaseinhibitorsasconcomitanttherapy.

Theamountofalcoholinthismedicinalproductmayaltertheeffectsofothermedicines.

4.6Fertility,pregnancyandlactation

Thereisnoadequatedatafromtheuseofpaclitaxelinpregnantwomen.Paclitaxelhasbeenshowntobeboth

embryotoxicandfoetotoxicinrabbits,andtoreducefertilityinrats.Aswithothercytotoxicmedicinalproducts,

paclitaxelmaycausefoetalharmwhenadministeredtopregnantwomen.Therefore,paclitaxelshouldnotbeused

duringpregnancyunlessclearlynecessary.Womenofchildbearingpotentialreceivingpaclitaxelshouldbeadvisedto

avoidbecomingpregnant,andtoinformthetreatingphysicianimmediatelyshouldthisoccur.Femaleandmalepatients

offertileage,and/ortheirpartnersshouldusecontraceptionsforatleast6monthsaftertreatmentwithpaclitaxel.

Malepatientsshouldseekadviceregardingcryoconservationofspermpriortotreatmentwithpaclitaxelbecauseofthe

possibilityofinfertility.

Paclitaxeliscontraindicated(duringlactation(seesection4.3).Itisnotknownwhetherpaclitaxelisexcretedinhuman

milk.Breast-feedingshouldbediscontinuedforthedurationoftherapy.

4.7Effectsonabilitytodriveandusemachines

Paclitaxelhasnotbeendemonstratedtointerferewiththeabilitytodriveandusemachines.However,itshouldbe

notedthatCantaxeldoescontainalcohol(seesections4.4and6.1).

4.8Undesirableeffects

Unlessotherwisenoted,thefollowingdiscussionreferstotheoverallsafetydatabaseof812patientswithsolidtumours

treatedwithsingle-agentpaclitaxelinclinicalstudies.AstheKSpopulationisveryspecific,aspecialchapterbasedon

aclinicalstudywith107patients,ispresentedattheendofthissection.

Thefrequencyandseverityofundesirableeffects,unlessotherwisementioned,aregenerallysimilarbetweenpatients

receivingpaclitaxelforthetreatmentofovariancarcinoma,breastcarcinoma,orNSCLC.Noneoftheobserved

toxicitieswereclearlyinfluencedbyage.

Themostfrequentsignificantundesirableeffectwasbonemarrowsuppression.Severeneutropenia(<500cells/mm 3

occurredin28%ofpatients,butwasnotassociatedwithfebrileepisodes.Only1%ofpatientsexperiencedsevere

neutropeniafor7days.Thrombocytopeniawasreportedin11%ofpatients.Threepercentofpatientshadaplatelet

countnadir<50,000/mm 3

atleastoncewhileonstudy.Anaemiawasobservedin64%ofpatients,butwassevere(Hb

<5mmol/l)inonly6%ofpatients.Incidenceandseverityofanaemiaisrelatedtobaselinehaemoglobinstatus.

Neurotoxicity,mainlyperipheralneuropathy,appearedtobemorefrequentandseverewitha175mg/m 2

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

24-hourinfusion(25%peripheralneuropathy,3%

severe)whenpaclitaxelwascombinedwithcisplatin.InNSCLCpatientsandinovariancancerpatientstreatedwith

paclitaxelover3hoursfollowedbycisplatin,thereisanapparentincreaseintheincidenceofsevereneurotoxicity.

Peripheralneuropathycanoccurfollowingthefirstcourseandcanworsenwithincreasingexposuretopaclitaxel.

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.

Insomecases,theonsetoftheinjectionsitereactioneitheroccurredduringaprolongedinfusionorwasdelayedbya

weekto10days.

Thetablebelowlistsundesirableeffectsregardlessofseverityassociatedwiththeadministrationofsingleagent

paclitaxeladministeredasathreehourinfusioninthemetastaticsetting(812patientstreatedinclinicalstudies)andas

reportedinthepostmarketingsurveillance*ofpaclitaxel.

Thefrequencyofundesirableeffectslistedbelowisdefinedusingthefollowingconvention:

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

(1/10,000),notknown(frequencycannotbeestimatedfromtheavailabledata).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Infectionsand

infestations: Verycommon:Infection(mainlyurinarytractandupperrespiratory

tractinfections),withreportedcasesoffataloutcome

Uncommon:Septicshock

Rare*:Pneumonia,peritonitis,sepsis

Bloodand

lymphatic

system

disorders: Verycommon:Myelosuppression,neutropenia,anaemia,

thrombocytopenia,leucopenia,bleeding

Rare*:febrileneutropenia

Veryrare*:Acutemyeloidleukaemia,myelodysplasticsyndrome

Immunesystem

disorders: Verycommon:Minorhypersensitivityreactions(mainlyflushingand

rash)

Uncommon:Significanthypersensitivityreactionsrequiringtherapy

(e.g.,hypotension,angioneuroticoedema,respiratorydistress,

generalisedurticaria,chills,backpain,chestpain,tachycardia,

abdominalpain,paininextremities,diaphoresisandhypertension)

Rare*:Anaphylacticreactions

Veryrare*:Anaphylacticshock

Metabolismand

nutrition

disorders: Veryrare*:anorexia

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Psychiatric

disorders: Veryrare*:confusionalstage

Nervoussystem

disorders: Verycommon:Neurotoxicity(mainlyperipheralneuropathy)

Rare*:Motorneuropathy(withresultantminordistalweakness)

Veryrare*:Autonomicneuropathy(resultinginparalyticileusand

orthostatichypotension),grandmalseizures,convulsions,

encephalopathy,dizziness,headache,ataxia

Eyedisorders: Veryrare*:Opticnerveand/orvisualdisturbances(scintillating

scotomata),particularlyinpatientswhohavereceivedhigherdosesthan

recommended

Notknown*:Macularoedema,photopsia,vitreousfloaters

Earand

labyrinth

disorders: Veryrare*:ototoxicity,hearingloss,tinnitus,vertigo

Cardiac

disorders: Common:Bradycardia

Uncommon:Cardiomyopathy,asymptomaticventriculartachycardia,

tachycardiawithbigeminy,AVblockandsyncope,myocardial

infarction

Rare:Cardiacfailure

Veryrare*:Atrialfibrillation,supraventriculartachycardia

Vascular

disorders: Verycommon:Hypotension

Uncommon:Hypertension,thrombosis,thrombophlebitis

Veryrare*:Shock

Notknown*:Phlebitis

Respiratory,

thoracicand

mediastinal

disorders: Rare*:Dyspnoea,pleuraleffusion,interstitialpneumonia,lungfibrosis,

pulmonaryembolism,respiratoryfailure

Veryrare*:Cough

Gastrointestinal

disorders: Verycommon:Nausea,vomiting,diarrhoea,mucosalinflammation

Rare*:bowelobstruction,bowelperforation,ischaemiccolitis,

pancreatitis

Veryrare*:mesentericthrombosis,pseudomembranouscolitis,

oesophagitis,constipation,ascites,neutropeniccolitis

Hepatobiliary

disorders: Veryrare*:Hepaticnecrosis,hepaticencephalopathy(bothwith

reportedcasesoffataloutcome)

Skinand

subcutaneous

tissuedisorders: Verycommon:Alopecia

Common:Transientandmildnailandskinchanges

Rare*:Pruritus,rash,erythema

Veryrare*:Stevens-Johnsonsyndrome,epidermalnecrolysis,erythema

multiforme,exfoliativedermatitis,urticaria,onycholysis(patientson

therapyshouldwearsunprotectiononhandsandfeet)

Notknown*:Scleroderma

Musculoskeletal

andconnective

tissuedisorders: Verycommon:Arthralgia,myalgia

Notknown*:Systemiclupuserythematosus

General

disordersand

administration

siteconditions: Common:Injectionsitereactions(includinglocalisedoedema,pain,

erythema,induration,onoccasionextravasationcanresultincellulitis,

skinfibrosisandskinnecrosis)

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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);twophaseIIItrialsinthefirst-linetreatmentofmetastaticbreastcancer:one

investigatingthecombinationwithdoxorubicin(paclitaxel+doxorubicin:267patients),anotheroneinvestigatingthe

combinationwithtrastuzumab(plannedsubgroupanalysispaclitaxel+trastuzumab:188patients)andtwophaseIII

trialsforthetreatmentofadvancedNSCLC(paclitaxel+cisplatin:over360patients)(seesection5.1).

Whenadministeredasathreehourinfusionforthefirst-linechemotherapyofovariancancer,neurotoxicity,

arthralgia/myalgia,andhypersensitivitywerereportedasmorefrequentandseverebypatientstreatedwithpaclitaxel

followedbycisplatinthanpatientstreatedwithcyclophosphamidefollowedbycisplatin.Myelosuppressionappearedto

belessfrequentandseverewithpaclitaxelasathreehourinfusionfollowedbycisplatincomparedwith

cyclophosphamidefollowedbycisplatin.

Forthefirstlinechemotherapyofmetastaticbreastcancer,neutropenia,anaemia,peripheralneuropathy,

arthralgia/myalgia,asthenia,feveranddiarrhoeawerereportedmorefrequentlyandwithgreaterseveritywhen

paclitaxel(220mg/m 2

)wasadministeredasa3hourinfusion24hoursfollowingdoxorubicin(50mg/m 2

)when

comparedtostandardFACtherapy(5-FU500mg/m 2

,doxorubicin50mg/m 2

,cyclophosphamide500mg/m 2

).Nausea

andvomitingappearedtobelessfrequentandseverewiththepaclitaxel(220mg/m 2

)/doxorubicin(50mg/m 2

regimenascomparedtothestandardFACregimen.Theuseofcorticosteroidsmayhavecontributedtothelower

frequencyandseverityofnauseaandvomitinginthepaclitaxel/doxorubicinarm.

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%).Someofthesefrequencydifferencesmaybeduetothe

increasednumberanddurationoftreatmentswithpaclitaxel/trastuzumabcombinationvssingleagentpaclitaxel.Severe

eventswerereportedatsimilarratesforpaclitaxel/trastuzumabandsingleagentpaclitaxel.

Whendoxorubicinwasadministratedincombinationwithpaclitaxelinmetastaticbreastcancer,cardiaccontraction

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

standardFACregimen.Congestiveheartfailurewasobserved<1%inbothpaclitaxel/doxorubicinandstandardFAC

arms.

Administrationoftrastuzumabincombinationwithpaclitaxelinpatientspreviouslytreatedwithanthracyclines

resultedinanincreasedfrequencyandseverityofcardiacdysfunctionincomparisonwithpatientstreatedwith

paclitaxelsingleagent(NYHAClassI/II10%vs.0%;NYHAClassIII/IV2%vs.1%)andrarelyhasbeenassociated

withdeath(seetrastuzumabSummaryofProductCharacteristics).Inallbuttheserarecases,patientsrespondedto

appropriatemedicaltreatment.

Radiationpneumonitishasbeenreportedinpatientsreceivingconcurrentradiotherapy.

AIDS-relatedKaposi’ssarcoma

Investigations: Common:SevereelevationinAST(SGOT),severeelevationinalkaline

phosphatase

Uncommon:Severeelevationinbilirubin

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aregenerallysimilarbetweenKSpatientsandpatientstreatedwithpaclitaxelmonotherapyforothersolidtumours,

basedonaclinicalstudyincluding107patients.

Bloodandlymphaticsystemdisorders:Bonemarrowsuppressionwasthemajordose-limitingtoxicity.Neutropenia

isthemostimportanthaematologicaltoxicity.Duringthefirstcourseoftreatment,severeneutropenia(<500

cells/mm 3

)occurredin20%ofpatients.Duringtheentiretreatmentperiod,severeneutropeniawasobservedin39%of

patients.Neutropeniawaspresentfor>7daysin41%andfor30-35daysin8%ofpatients.Itresolvedwithin35days

inallpatientswhowerefollowed.TheincidenceofGrade4neutropenialasting7dayswas22%.

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.

Hepatobiliarydisorders:Amongpatients(>50%onproteaseinhibitors)withnormalbaselineliverfunction,28%,

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

parameters,theincreaseswereseverein1%ofcases.

4.9Overdose

Thereisnoknownantidoteforpaclitaxeloverdose.Incaseofoverdose,thepatientshouldbecloselymonitored.

Treatmentshouldbedirectedattheprimaryanticipatedtoxicities,whichconsistofbonemarrowsuppression,

peripheralneurotoxicityandmucositis.

Overdosesinpaediatricpatientsmaybeassociatedwithacuteethanoltoxicity.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherpeuticgroup:Antineoplasticagent/taxanes

ATCcode:L01CD01

Paclitaxelisanantimicrotubuleagentthatpromotestheassemblyofmicrotubulesfromtubulindimersandstabilises

microtubulesbypreventingdepolymerisation.Thisstabilityresultsintheinhibitionofthenormaldynamic

reorganisationofthemicrotubulenetworkthatisessentialforvitalinterphaseandmitoticcellularfunctions.In

addition,paclitaxelinducesabnormalarraysorbundlesofmicrotubulesthroughoutthecellcycleandmultipleastersof

microtubulesduringmitosis.

Infirst-linechemotherapyofovariancarcinoma,thesafetyandefficacyofpaclitaxelwereevaluatedintwomajor

randomisedcontrolled(vs.cyclophosphamide750mg/m 2

/cisplatin75mg/m 2

)clinicaltrials.IntheIntergrouptrial

(BMSCA139-209),over650patientswithstageII

,IIIorIVprimaryovariancancerreceivedamaximumof9

treatmentcoursesofpaclitaxel(175mg/m 2

over3hr)followedbycisplatin(75mg/m 2

)orcontrol.

Thesecondmajortrial(GOG111/B-MSCA139-022),evaluatedamaximumof6coursesofeitherpaclitaxel(135

mg/m 2

over24hours)followedbycisplatin(75mg/m 2

)orcontrolinover400patientswithstageIII/IVprimary

ovariancancerwitha>1cmresidualdiseaseafterstaginglaparotomy,orwithdistantmetastases.

Whilethetwodifferentpaclitaxelposologieswerenotcomparedwitheachotherdirectly,inbothtrialspatientstreated

withpaclitaxelincombinationwithcisplatinhadasignificantlyhigherresponserate,longertimetoprogressionand

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myelosuppressionwereobservedinadvancedovariancancerpatientsadministered3-hourinfusionof

paclitaxel/cisplatinascomparedtopatientswhoreceivedcyclophosphamide/cisplatin.

Intheadjuvanttreatmentofbreastcarcinoma,3121patientswithnodepositivebreastcarcinomaweretreatedwith

adjuvantpaclitaxeltherapyornochemotherapyfollowingfourcoursesofdoxorubicinandcyclophosphamide(CALGB

9344,BMSCA139-223).Medianfollow-upwas69months.Overall,paclitaxelhadasignificantreductionof18%in

theriskofdiseaserecurrencerelativetopatientsreceivingACalone(p=0.0014)andasignificantreductionof19%in

theriskofdeath(p=0.0044)relativetopatientsreceivingACalone.Retrospectiveanalysesshowbenefitinallpatient

subsets.Inpatientswithhormonereceptornegative/unknowntumours,reductioninriskofdiseaserecurrencewas28%

(95%CI:0.59-0.86).Inthepatientsubgroupwithhormonereceptorpositivetumours,theriskreductionofdisease

recurrencewas9%(95%CI:0.78-1.07).However,thedesignofthestudydidnotinvestigatetheeffectofextendedAC

therapybeyond4cycles.Itcannotbeexcludedonthebasisofthisstudyalonethattheobservedeffectscouldbepartly

duetothedifferenceindurationofchemotherapybetweenthetwoarms(AC4cycles;AC+paclitaxel8cycles).

Therefore,adjuvanttreatmentwithpaclitaxelshouldberegardedasanalternativetoextendedACtherapy.

Inasecondlargeclinicalstudyinadjuvantnodepositivebreastcancerwithasimilardesign,3060patientswere

randomizedtoreceiveornotfourcoursesofpaclitaxelatahigherdoseof225mg/m 2

followingfourcoursesofAC

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

of17%intheriskofdiseaserecurrencerelativetopatientswhoreceivedACalone(p=0.006);paclitaxeltreatmentwas

associatedwithareductionintheriskofdeathof7%(95%CI:0.78-1.12).Allsubsetanalysesfavouredthepaclitaxel

arm.Inthisstudypatientswithhormonereceptorpositivetumourhadareductionintheriskofdiseaserecurrenceof

23%(95%CI:0.6-0.92);inthepatientsubgroupwithhormonereceptornegativetumourtheriskreductionofdisease

recurrencewas10%(95%CI:0.7-1.11).

Inthefirst-linetreatmentofmetastaticbreastcancer,theefficacyandsafetyofpaclitaxelwereevaluatedintwopivotal,

fazeIII,randomised,andcontrolledopen-labeltrials.

Inthefirststudy(BMSCA139-278),thecombinationofbolusdoxorubicin(50mg/m 2

)followedafter24hoursby

paclitaxel(220mg/m 2

by3-hourinfusion)(AT),wascomparedversusstandardFACregimen(5-FU500mg/m 2

doxorubicin50mg/m 2

,cyclophosphamide500mg/m 2

)bothadministeredeverythreeweeksforeightcourses.Inthe

randomisedstudy,267patientswithmetastaticbreastcancer,whohadeitherreceivednopriorchemotherapyoronly

non-anthracyclinechemotherapyintheadjuvantsetting,wereenrolled.Resultsshowedasignificantdifferenceintime

toprogressionforpatientsreceivingATcomparedtothosereceivingFAC(8.2vs.6.2months;p=0.029).Themedian

survivalwasinfavourofpaclitaxel/doxorubicinvs.FAC(23.0vs.18.3months;p=0.004).IntheATandFAC

treatmentarm44%and48%,respectively,receivedfollow-upchemotherapywhichincludedtaxanesin7%and50%,

respectively.TheoverallresponseratewasalsosignificantlyhigherintheATarmcomparedtotheFACarm(68%vs.

55%).Completeresponseswereseenin19%ofthepaclitaxel/doxorubicinarmpatientsvs.8%oftheFACarm

patients.Allefficacyresultshavebeensubsequentlyconfirmedbyablindedindependentreview.

Inthesecondpivotalstudy,theefficacyandsafetyofthepaclitaxelandtrastuzumabcombinationwasevaluatedina

plannedsubgroupanalysis(metastaticbreastcancerpatientswhoformerlyreceivedadjuvantanthracyclines)ofthe

studyHO648g.Theefficacyoftrastuzumabincombinationwithpaclitaxelinpatientswhodidnotreceiveprior

adjuvantanthracyclineshasnotbeenproven.Thecombinationoftrastuzumab(4mg/kgloadingdosethen2mg/kg

weekly)andpaclitaxel(175mg/m²)3-hourinfusion,everythreeweekswascomparedtosingleagentpaclitaxel(175

mg/m²)3-hourinfusion,everythreeweeksin188patientswithmetastaticbreastcanceroverexpressingHER2(2+or

3+asmeasuredbyimmunohistochemistry),whohadpreviouslybeentreatedwithanthracyclines.Paclitaxelwas

administeredeverythreeweeksforatleastsixcourseswhiletrastuzumabwasgivenweeklyuntildiseaseprogression.

Thestudyshowedasignificantbenefitforthepaclitaxel/trastuzumabcombinationintermsoftimetoprogression(6.9

vs.3.0months),responserate(41%vs.17%),anddurationofresponse(10.5vs.4.5months)whencomparedto

paclitaxelalone.Themostsignificanttoxicityobservedwiththepaclitaxel/trastuzumabcombinationwascardiac

dysfunction(seesection4.8).

InthetreatmentofadvancedNSCLCpaclitaxel175mg/m 2

followedbycisplatin80mg/m 2

hasbeenevaluatedintwo

phaseIIItrials(367patientsonpaclitaxelcontainingregimens).Bothwererandomised.Trials,onecomparedto

treatmentwithcisplatin100mg/m 2

,theotherusedteniposide100mg/m 2

followedbycisplatin80mg/m 2

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Fortheprimaryoutcomeofmortality,therewasnosignificantdifferencesbetweenthepaclitaxelcontainingregimen

andthecomparator(mediansurvivaltimes8.1and9.5monthsonpaclitaxelcontainingregimens,8.6and9.9months

oncomparators).Similarly,forprogression-freesurvivaltherewasnosignificantdifferencesbetweentreatments.There

wasasignificantbenefitintermsofclinicalresponserate.Qualityofliferesultsaresuggestiveofabenefiton

paclitaxelcontainingregimensintermsofappetitelossandprovideclearevidenceoftheinferiorityofpaclitaxel

containingregimensintermsofperipheralneuropathy(p<0.008).

InthetreatmentofAIDS-relatedKS,theefficacyandsafetyofpaclitaxelwereinvestigatedinanon-comparativestudy

inpatientswithadvancedKS,previouslytreatedwithsystemicchemotherapy.Theprimaryendpointwasbesttumour

response.Ofthe107patients,63wereconsideredresistanttoliposomalanthracyclines.Thissubgroupisconsideredto

constitutethecoreefficacypopulation.Theoverallsuccessrate(complete/partialresponse)after15cyclesoftreatment

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

first3cycles.Inliposomalanthracycline-resistantpatients,theresponserateswerecomparableforpatientswhohad

neverreceivedaproteaseinhibitor(55.6%)andthosewhoreceivedoneatleast2monthspriortotreatmentwith

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

survivalcouldnotbecomputed,butthelower95%boundwas617daysincorepatients.

5.2Pharmacokineticproperties

Followingintravenousadministration,paclitaxelexhibitsabiphasicdeclineinplasmaconcentrations.

Thepharmacokineticsofpaclitaxelweredeterminedfollowing3-and24-hourinfusionsatdosesof135and175

mg/m 2

.Meanterminalhalf-lifeestimatesrangedfrom3.0and52.7hours,andmean,non-compartmentallyderived,

valuesfortotalbodyclearancerangedfrom11.6to24.0l/hr/m 2

;totalbodyclearanceappearedtodecreasewithhigher

plasmaconcentrationsofpaclitaxel.Meansteady-statevolumeofdistributionrangedfrom198to688l/m 2

,indicating

extensiveextravasculardistributionand/ortissuebinding.Withthe3-hourinfusion,increasingdosesresultinnon-

linearpharmacokinetics.Forthe30%increaseindosefrom135mg/m 2

to175mg/m 2

,theC

andAUC

values

increased75%and81%,respectively.

Followinganintravenousdoseof100mg/m 2

givenasa3-hourinfusionto19KSpatients,themeanC

was1,530

ng/ml(range761-2,860ng/ml)andthemeanAUC5,619ng.hr/ml(range2,609-9,428ng.hr/ml).Clearancewas20.6

l/h/m 2

(range11-38)andthevolumeofdistributionwas291l/m 2

(range121-638).Theterminaleliminationhalf-life

averaged23.7hours(range12-33).

Intrapatientvariabilityinsystemicpaclitaxelexposurewasminimal.Therewasnoevidenceforaccumulationof

paclitaxelwithmultipletreatmentcourses.

Invitrostudiesofbindingtohumanserumproteinsindicatethat89-98%ofdrugisbound.Thepresenceofcimetidine,

ranitidine,dexamethasoneordiphenhydraminedidnotaffectproteinbindingofpaclitaxel.

Thedispositionofpaclitaxelhasnotyetbeenfullyelucidatedinhumans.Meanvaluesforcumulativeurinaryrecovery

ofunchangeddrughaverangedfrom1.3%to12.6%ofthedose,indicatingextensivenon-renalclearance.

Hepaticmetabolismandbiliaryclearancemaybetheprincipalmechanismsfordispositionofpaclitaxel.

PaclitaxelappearstobemetabolisedprimarilybycytochromeP450enzymes.Followingadministrationofa

radiolabelledpaclitaxel,anaverageof26,2and6%oftheradioactivitywasexcretedinthefaecesas6-

hydroxypaclitaxel,3’p-dihydroxypaclitaxeland6-3’p-dihydroxypaclitaxel,respectively.Theformationofthese

hydroxylatedmetabolitesiscatalysedbyCYP2C8,CYP3A4andbothCYP2C8andCYP3A4,respectively.

Theeffectofrenalorhepaticdysfunctiononthedispositionofpaclitaxelfollowinga3-hourinfusionhasnotbeen

investigatedformally.Thepharmacokineticparametersobtainedfromonepatientundergoinghaemodialysiswho

receiveda3-hourinfusionofpaclitaxel135mg/m 2

werewithintherangeofthosedefinedinnon-dialysispatients.

Inclinicaltrialswherepaclitaxelanddoxorubicinwereadministeredconcomitantlythedistributionandeliminationof

doxorubicinanditsmetaboliteswereprolonged.Totalplasmaexposuretodoxorubicinwas30%higherwhenpaclitaxel

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ForuseofPaclitaxelincombinationwithothertherapies,pleaseconsulttheSummaryofProductCharacteristicsof

cisplatin,doxorubicinortrastuzumabforinformationontheuseofthesemedicinalproducts.

5.3Preclinicalsafetydata

Paclitaxelhasbeenshowntobeembryotoxicandfoetotoxicinrabbits,andtodecreasefertilityinrats.

Thecarcinogenicpotentialofpaclitaxelhasnotbeenstudied.However,paclitaxelisapotentialcarcinogenicand

genotoxicagentbaseduponitspharmacodynamicmechanismofaction.Paclitaxelhasbeenshowntobemutagenicin

bothinvitroandinvivomammaliantestsystems.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Macrogolglycerolricinoleate

Ethanol96%

Citricacid,anhydrous(E330)for(pH-adjustment)

6.2Incompatibilities

MacrogolglycerolricinoleatecanresultinDEHP[di-(2-ethylhexyl)phthalate]leachingfromplasticizedpolyvinyl

chloride(PVC)containers,atlevelswhichincreasewithtimeandconcentration.Consequently,thepreparation,storage

andadministrationofdilutedCantaxelsolutionsshouldbecarriedoutusingnon-PVC-containingequipment.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Shelflifebeforeopening

2years.

Shelflifeafteropening

Themedicinalproductshouldbedilutedimmediatelyafteropening.

Shelflifeafterdilution:

Chemicalandphysicalin-usestabilityofthesolutionpreparedforinfusionhasbeendemonstrated:

for27hoursat25°Candambientlightingconditions,whendilutedin0.9%sodiumchloridesolutionforinfusion,or

5%glucosesolutionforinfusion

for24hoursat25°Candambientlightingconditions,whendilutedinamixtureof0.9%sodiumchloridesolution

forinfusionand5%glucosesolutionforinfusion,orRinger’ssolutionforinfusioncontaining5%glucose.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuser,unlessdilutionhastakenplaceincontrolledand

validatedasepticconditions.

6.4Specialprecautionsforstorage

Donotfreeze.

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6.5Natureandcontentsofcontainer

CleartypeIglassvialswithfluoropolymercoatedchlorobutylrubberstopper.

Packsizes:1vialwith5ml,16.7ml,25mland50mlconcentrateforsolutionforinfusion.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Themedicinalproductisforsingleuseonly(seesection6.3).Anyunusedsolutionshouldbediscarded.

Handling:

Aswithallantineoplasticagents,cautionshouldbeexercisedwhenhandlingthismedicinalproduct.Dilutionshouldbe

carriedoutunderasepticconditionsbytrainedpersonnelinadesignatedarea.Adequateprotectiveglovesshouldbe

worn.Precautionsshouldbetakentoavoidcontactwiththeskinandmucousmembranes.Intheeventofcontactwith

theskin,theareashouldbewashedwithsoapandwater.Followingtopicalexposure,tingling,burningandredness

havebeenobserved.Intheeventofcontactwiththemucousmembranes,theseshouldbeflushedthoroughlywith

water.Uponinhalation,dyspnoea,chestpain,burningthroatandnauseahavebeenreported.

Ifunopenedvialsarerefrigeratedorfrozen,aprecipitatemayformthatredissolveswithlittleornoagitationupon

reachingroomtemperature.Productqualityisnotaffected.Ifthesolutionremainscloudyorifaninsolubleprecipitate

isnoted,thevialshouldbediscarded.

TheChemo-DispensingPindeviceorsimilardeviceswithspikesshouldnotbeused,sincetheycancausethevial

stoppertocollapse,resultinginthelossofsterileintegrity.

Preparationforintravenousadministration:

Priortoinfusion,thismedicinalproductmustbedilutedusingaseptictechniquesin0.9%sodiumchloridesolutionfor

infusion,or5%glucosesolutionforinfusion,oramixtureof0.9%sodiumchloridesolutionforinfusionand5%

glucosesolutionforinfusion,orRinger’ssolutionforinfusioncontaining5%glucose,toafinalconcentrationof0.3to

1.2mg/ml.

Onlyclearsolutionspracticallyfreefromparticlesshouldbeused.

Formicrobial,chemicalandphysicalin-usestabilityofthedilutedsolutionsseesection6.3.

Uponpreparation,solutionsmayshowsomehaziness,whichisattributedtotheformulationvehicleandisnotremoved

byfiltration.Thismedicinalproductshouldbeadministeredthroughanin-linefilterwithamicroporousmembrane

0.22µm.Nosignificantlossesinpotencyhavebeennotedfollowingsimulateddeliveryofthesolutionthrough

intravenoustubingcontaininganin-linefilter.

TherehavebeenrarereportsofprecipitationduringPaclitaxelinfusions,usuallytowardstheendofa24hourinfusion

period.Althoughthecauseofthisprecipitationhasnotbeenelucidated,itisprobablylinkedtothesupersaturationof

thedilutedsolution.Toreducetheprecipitationrisk,thismedicinalproductshouldbeusedassoonaspossibleafter

dilution,andexcessiveagitation,vibrationorshakingshouldbeavoided.Theinfusionsetsshouldbeflushed

thoroughlybeforeuse.Duringinfusion,theappearanceofthesolutionshouldberegularlyinspectedandtheinfusion

shouldbestoppedifprecipitationispresent.

TominimizepatientexposuretoDEHPwhichmaybeleachedfromplasticizedPVCinfusionbags,sets,orother

medicalinstruments,dilutedsolutionsofthismedicinalproductshouldbestoredinnon-PVCbottles(glass,

polypropylene)orplasticbags(polypropylene,polyolefin)andadministeredthroughpolyethylene-linedadministration

sets.Theuseoffilterdevices(e.g.IVEX-2 ®

)whichincorporateshortinletand/oroutletplasticizedPVCtubinghasnot

resultedinanysignificantleachingofDEHP.

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Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirementsforcytotoxic

compounds.

7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLtd

WaterfordRoad

Clonmel

Co.Tipperary

8MARKETINGAUTHORISATIONNUMBER

PA126/162/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1 st

September2006

Dateoflastrenewal:23 rd

June2010

10DATEOFREVISIONOFTHETEXT

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