DOCETAXEL EBEWE

Main information

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

Documents

Localization

  • Available in:
  • DOCETAXEL EBEWE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/017/001
  • Authorization date:
  • 16-07-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DocetaxelEbewe10mg/mlConcentrateforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onemloftheconcentrateforsolutionforinfusioncontains10mgdocetaxel.

Eachvialof2mlcontains20mgdocetaxelanhydrous(10mg/ml).

Eachvialof8mlcontains80mgdocetaxelanhydrous(10mg/ml).

Eachvialof16mlcontains160mgdocetaxelandhydrous(10mg/ml).

Excipient:Eachsingle-dosevialofconcentrateforsolutioncontains27%(w/w)ethanol96%.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

Clear,colourlesstopale,yellowsolution;pH3.0–4.5

4CLINICALPARTICULARS

4.1TherapeuticIndications

Breastcancer

DOCETAXELEBEWEincombinationwithdoxorubicinandcyclophosphamideisindicatedfortheadjuvanttreatment

ofpatientswith

operablenode-positivebreastcancer

operablenode-negativebreastcancer

Forpatientswithoperablenode-negativebreastcancer,adjuvanttreatmentshouldberestrictedtopatientseligibletoreceive

chemotherapyaccordingtointernationallyestablishedcriteriaforprimarytherapyofearlybreastcancer(seesection5.1).

DOCETAXELEBEWEincombinationwithdoxorubicinisindicatedforthetreatmentofpatientswithlocally

advancedormetastaticbreastcancerwhohavenotpreviouslyreceivedcytotoxictherapyforthiscondition.

DOCETAXELEBEWEmonotherapyisindicatedforthetreatmentofpatientswithlocallyadvancedormetastatic

breastcancerafterfailureofcytotoxictherapy.Previouschemotherapyshouldhaveincludedananthracyclineoran

alkylatingagent.

DOCETAXELEBEWEincombinationwithtrastuzumabisindicatedforthetreatmentofpatientswithmetastatic

breastcancerwhosetumorsoverexpressHER2andwhopreviouslyhavenotreceivedchemotherapyformetastatic

disease.

DOCETAXELEBEWEincombinationwithcapecitabineisindicatedforthetreatmentofpatientswithlocally

advancedormetastaticbreastcancerafterfailureofcytotoxicchemotherapy.Previoustherapyshouldhaveincludedan

anthracycline.

Non-smallcelllungcancer

DOCETAXELEBEWEisindicatedforthetreatmentofpatientswithlocallyadvancedormetastaticnon-smallcell

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DOCETAXELEBEWEincombinationwithcisplatinisindicatedforthetreatmentofpatientswithunresectable,

locallyadvancedormetastaticnon-smallcelllungcancer,inpatientswhohavenotpreviouslyreceivedchemotherapy

forthiscondition.

Prostatecancer

DOCETAXELEBEWEincombinationwithprednisoneorprednisoloneisindicatedforthetreatmentofpatientswith

hormonerefractorymetastaticprostatecancer.

Gastricadenocarcinoma

DOCETAXELEBEWEincombinationwithcisplatinand5-fluorouracilisindicatedforthetreatmentofpatientswith

metastaticgastricadenocarcinoma,includingadenocarcinomaofthegastroesophagealjunction,whohavenotreceived

priorchemotherapyformetastaticdisease.

Headandneckcancer

DOCETAXELEBEWEincombinationwithcisplatinand5-fluorouracilisindicatedfortheinductiontreatmentof

patientswithlocallyadvancedsquamouscellcarcinomaoftheheadandneck.

4.2Posologyandmethodofadministration

Theuseofdocetaxelshouldbeconfinedtounitsspecialisedintheadministrationofcytotoxicchemotherapyandit

shouldonlybeadministeredunderthesupervisionofaphysicianqualifiedintheuseofanticancerchemotherapy(see

section6.6).

Recommendeddose

Forbreast,non-smallcelllung,gastric,andheadandneckcancers,premedicationconsistingofanoralcorticosteroid,

suchasdexamethasone16mgperday(e.g.8mgBID)for3daysstarting1daypriortoDocetaxelEbewe

administration,unlesscontraindicated,canbeused(seesection4.4).ProphylacticG-CSFmaybeusedtomitigatethe

riskofhematologicaltoxicities.

Forprostatecancer,giventheconcurrentuseofprednisoneorprednisolonetherecommendedpremedicationregimenis

oraldexamethasone8mg,12hours,3hoursand1hourbeforetheDocetaxelEbeweinfusion(seesection4.4).

DocetaxelEbeweisadministeredasaone-hourinfusioneverythreeweeks.Seesection6.6forfurtherdetailson

preparationofinfusionsolution.

Careshouldbetakenofadministrationoftheinfusiontoavoidextravasation.

Breastcancer

Intheadjuvanttreatmentofoperablenode-positiveandnode-negativebreastcancer,therecommendeddoseof

DocetaxelEbeweis75mg/m 2

administered1-hourafterdoxorubicin50mg/m 2

andcyclophosphamide500mg/m 2

every3weeksfor6cycles(seealsoDoseadjustmentsduringtreatment).

Forthetreatmentofpatientswithlocallyadvancedormetastaticbreastcancer,therecommendeddoseofDocetaxel

Ebeweis100mg/m 2

inmonotherapy.Infirst-linetreatment,DocetaxelEbewe75mg/m 2

isgivenincombination

therapywithdoxorubicin(50mg/m 2

IncombinationwithtrastuzumabtherecommendeddoseofDocetaxelEbeweis100mg/m 2

everythreeweeks,with

trastuzumabadministeredweekly.Inthepivotaltrialtheinitialdocetaxelinfusionwasstartedthedayfollowingthe

firstdoseoftrastuzumab.Thesubsequentdocetaxeldoseswereadministeredimmediatelyaftercompletionofthe

trastuzumabinfusion,iftheprecedingdoseoftrastuzumabwaswelltolerated.Fortrastuzumabdoseand

administration,seetrastuzumabsummaryofproductcharacteristics.

Incombinationwithcapecitabine,therecommendeddoseofDocetaxelEbeweis75mg/m 2

everythreeweeks,

combinedwithcapecitabineat1250mg/m 2

twicedaily(within30minutesafterameal)for2weeksfollowedby1-

weekrestperiod.Forcapecitabinedosecalculationaccordingtobodysurfacearea,seecapecitabinesummaryof

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Non-smallcelllungcancer

Inchemotherapynaïvepatientstreatedfornon-smallcelllungcancer,therecommendeddoseregimenisDocetaxel

Ebewe75mg/m 2

immediatelyfollowedbycisplatin75mg/m 2

over30-60minutes.Fortreatmentafterfailureofprior

platinum-basedchemotherapy,therecommendeddoseis75mg/m²asasingleagent.

Prostatecancer

TherecommendeddoseofDocetaxelEbeweis75mg/m 2

.Prednisoneorprednisolone5mgorallytwicedailyis

administeredcontinuously(seesection5.1).

Gastricadenocarcinoma

TherecommendeddoseofDocetaxelEbeweis75mg/m 2

asa1hourinfusion,followedbycisplatin75mg/m 2

,asa1

to3hourinfusion(bothonday1only),followedby5-fluorouracil750mg/m 2

perdaygivenasa24-hourcontinuous

infusionfor5days,startingattheendofthecisplatininfusion.Treatmentisrepeatedeverythreeweeks.Patientsmust

receivepremedicationwithantiemeticsandappropriatehydrationforcisplatinadministration.ProphylacticG-CSF

shouldbeusedtomitigatetheriskofhematologicaltoxicities(seealsoDoseadjustmentsduringtreatment).

Headandneckcancer

Patientsmustreceivepremedicationwithantiemeticsandappropriatehydration(priortoandaftercisplatin

administration).ProphylacticG-CSFmaybeusedtomitigatetheriskofhematologicaltoxicities.Allpatientsonthe

docetaxel-containingarmoftheTAX323andTAX324studies,receivedprophylacticantibiotics.

Inductionchemotherapyfollowedbyradiotherapy(TAX323)

Fortheinductiontreatmentofinoperablelocallyadvancedsquamouscellcarcinomaoftheheadandneck

(SCCHN),therecommendeddoseofdocetaxelis75mg/m 2

asa1hourinfusionfollowedbycisplatin75mg/m 2

over1hour,ondayone,followedby5-fluorouracilasacontinuousinfusionat750mg/m 2

perdayforfivedays.

Thisregimenisadministeredevery3weeksfor4cycles.Followingchemotherapy,patientsshouldreceive

radiotherapy.

Inductionchemotherapyfollowedbychemoradiotherapy(TAX324)

Fortheinductiontreatmentofpatientswithlocallyadvanced(technicallyunresectable,lowprobabilityof

surgicalcure,andaimingatorganpreservation)squamouscellcarcinomaoftheheadandneck(SCCHN),the

recommendeddoseofdocetaxelis75mg/m 2

asa1hourintravenousinfusiononday1,followedbycisplatin

100mg/m 2

administeredasa30-minuteto3hourinfusion,followedby5-fluorouracil1000mg/m 2

/dayasa

continuousinfusionfromday1today4.Thisregimenisadministeredevery3weeksfor3cycles.Following

chemotherapy,patientsshouldreceivechemoradiotherapy.

Forcisplatinand5-fluorouracildosemodifications,seethecorrespondingsummaryofproductcharacteristics.

Doseadjustmentsduringtreatment

General

DocetaxelEbeweshouldbeadministeredwhentheneutrophilcountis 1,500cells/mm 3

.Inpatientswhoexperienced

eitherfebrileneutropenia,neutrophil<500cells/mm 3

formorethanoneweek,severeorcumulativecutaneous

reactionsorsevereperipheralneuropathyduringDocetaxelEbewetherapy,thedoseofDocetaxelEbeweshouldbe

reducedfrom100mg/m 2

to75mg/m 2

and/orfrom75to60mg/m².Ifthepatientcontinuestoexperiencethese

reactionsat60mg/m²,thetreatmentshouldbediscontinued.

Adjuvanttherapyforbreastcancer

Inthepivotaltrialinpatientswhoreceivedadjuvanttherapyforbreastcancerandwhoexperiencedcomplicated

neutropenia(includingprolongedneutropenia,febrileneutropenia,orinfection),itwasrecommendedtouseG-CSFto

provideprophylacticcoverage(eg,day4to11)inallsubsequentcycles.Patientswhocontinuedtoexperiencethis

reactionshouldremainonG-CSFandhavetheirdocetaxeldosereducedto60mg/m².

However,inclinicalpracticeneutropeniacouldoccurearlier.ThustheuseofG-CSFshouldbeconsideredfunctionof

theneutropenicriskofthepatientandcurrentrecommendations.PatientswhoexperienceGrade3or4stomatitis

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Incombinationwithcisplatin

ForpatientswhoaredosedinitiallyatDocetaxelEbewe75mg/m 2

incombinationwithcisplatinandwhosenadirof

plateletcountduringthepreviouscourseoftherapyis<25,000cells/mm 3

,orinpatientswhoexperiencefebrile

neutropenia,orinpatientswithseriousnon-hematologictoxicities,theDocetaxelEbewedoseinsubsequentcycles

shouldbereducedto65mg/m 2

.Forcisplatindoseadjustments,seethecorrespondingsummaryofproduct

characteristics.

Incombinationwithcapecitabine

Forcapecitabinedosemodifications,seecapecitabinesummaryofproductcharacteristics.

ForpatientsdevelopingthefirstappearanceofaGrade2toxicity,whichpersistsatthetimeofthenext

DocetaxelEbewe/capecitabinetreatment,delaytreatmentuntilresolvedtoGrade0-1,andresumeat100%ofthe

originaldose.

ForpatientsdevelopingthesecondappearanceofaGrade2toxicity,orthefirstappearanceofaGrade3toxicity,

atanytimeduringthetreatmentcycle,delaytreatmentuntilresolvedtoGrade0-1,thenresumetreatmentwith

DocetaxelEbewe55mg/m².

Foranysubsequentappearancesoftoxicities,oranyGrade4toxicities,discontinuetheDocetaxelEbewedose.

Fortrastuzumabdosemodifications,seetrastuzumabsummaryofproductcharacteristics.

Incombinationwithcisplatinand5-fluorouracil

Ifanepisodeoffebrileneutropenia,prolongedneutropeniaorneutropenicinfectionoccursdespiteG-CSFuse,the

DocetaxelEbewedoseshouldbereducedfrom75to60mg/m 2

.Ifsubsequentepisodesofcomplicatedneutropenia

occurtheDocetaxelEbewedoseshouldbereducedfrom60to45mg/m 2

.IncaseofGrade4thrombocytopeniathe

DocetaxelEbewedoseshouldbereducedfrom75to60mg/m 2

.Patientsshouldnotberetreatedwithsubsequentcycles

ofDocetaxelEbeweuntilneutrophilsrecovertoalevel>1,500cells/mm 3

andplateletsrecovertoalevel>100,000

cells/mm 3

.Discontinuetreatmentifthesetoxicitiespersist.(Seesection4.4).

RecommendeddosemodificationsfortoxicitiesinpatientstreatedwithDocetaxelEbeweincombinationwithcisplatin

and5-fluorouracil(5-FU):

Forcisplatinand5-fluorouracildoseadjustments,seethecorrespondingsummaryofproductcharacteristics.

InthepivotalSCCHNtrialspatientswhoexperiencedcomplicatedneutropenia(includingprolongedneutropenia,

febrileneutropenia,orinfection),itwasrecommendedtouseG-CSFtoprovideprophylacticcoverage(eg,day6-15)in

allsubsequentcycles.

Specialpopulations:

Patientswithhepaticimpairment

Basedonpharmacokineticdatawithdocetaxelat100mg/m²assingleagent,patientswhohavebothelevationsof

transaminase(ALTand/orAST)greaterthan1.5timestheupperlimitofthenormalrange(ULN)andalkaline

phosphatasegreaterthan2.5timestheULN,therecommendeddoseofdocetaxelis75mg/m 2

(seesections4.4and

Toxicity Doseadjustment

Diarrheagrade3 Firstepisode:reduce5-FUdoseby20%.

Secondepisode:thenreduceDocetaxelEbewedoseby20%.

Diarrheagrade4 Firstepisode:reduceDocetaxelEbeweand5-FUdosesby20%.

Secondepisode:discontinuetreatment.

Stomatitis/mucositis

grade3 Firstepisode:reduce5-FUdoseby20%.

Secondepisode:stop5-FUonly,atallsubsequentcycles.

Thirdepisode:reduceDocetaxelEbewedoseby20%.

Stomatitis/mucositis

grade4 Firstepisode:stop5-FUonly,atallsubsequentcycles.

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Forthosepatientswithserumbilirubin>ULNand/orALTandAST>3.5timestheULNassociatedwithalkaline

phosphatase>6timestheULN,nodosereductioncanberecommendedanddocetaxelshouldnotbeusedunless

strictlyindicated.Incombinationwithcisplatinand5-fluorouracilforthetreatmentofpatientswithgastric

adenocarcinoma,thepivotalclinicaltrialexcludedpatientswithALTand/orAST>1.5×ULNassociatedwithalkaline

phosphatase>2.5×ULN,andbilirubin>1xULN;forthesepatients,nodose-reductionscanberecommendedand

docetaxelshouldnotbeusedunlessstrictlyindicated.Nodataareavailableinpatientswithhepaticimpairmenttreated

bydocetaxelincombinationintheotherindications.

Thismedicinalproductcontains27vol%ethanol(alcohol).Thishastobetakenintoaccountinhigh-riskgroupssuch

aspatientswithliverdisease.

Patientswithrenalimpairment

Therearenodataavailableinpatientswithseverelyimpairedrenalfunctiontreatedwithdocetaxel.

Childrenandadolescents

DocetaxelEbeweisnotrecommendedforuseinchildrenduetoinsufficientdataonsafetyandefficacy.

Elderly

Basedonapopulationpharmacokineticanalysis,therearenospecialinstructionsforuseintheelderly.Incombination

withcapecitabine,forpatients60yearsofageormore,astartingdosereductionofcapecitabineto75%is

recommended(seecapecitabinesummaryofproductcharacteristics).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

DocetaxelEbewemustnotbeusedinpatientswithbaselineneutrophilcountof<1,500cells/mm 3

DocetaxelEbewemustnotbeusedinpregnantorbreast-feedingwomen(seesection4.6).

DocetaxelEbewemustnotbeusedinpatientswithsevereliverimpairmentsincethereisnodataavailable(see

sections4.2and4.4).

Contraindicationsforothermedicinalproductsalsoapply,whencombinedwithDocetaxelEbewe.

4.4Specialwarningsandprecautionsforuse

Forbreastandnon-smallcelllungcancers,premedicationconsistingofanoralcorticosteroid,suchasdexamethasone

16mgperday(e.g.8mgBID)for3daysstarting1daypriortodocetaxeladministration,unlesscontraindicated,can

reducetheincidenceandseverityoffluidretentionaswellastheseverityofhypersensitivityreactions.Forprostate

cancer,thepremedicationisoraldexamethasone8mg,12hours,3hoursand1hourbeforethedocetaxelinfusion(see

section4.2).

Haematology

Neutropeniaisthemostfrequentadversereactionofdocetaxel.Neutrophilnadirsoccurredatamedianof7daysbut

thisintervalmaybeshorterinheavilypre-treatedpatients.Frequentmonitoringofcompletebloodcountsshouldbe

conductedonallpatientsreceivingdocetaxel.Patientsshouldberetreatedwithdocetaxelwhenneutrophilsrecovertoa

level 1,500cells/mm 3

(seesection4.2).

Inthecaseofsevereneutropenia(<500cells/mm 3

forsevendaysormore)duringacourseofdocetaxeltherapy,a

reductionindoseforsubsequentcoursesoftherapyortheuseofappropriatesymptomaticmeasuresarerecommended

(seesection4.2).

Inpatientstreatedwithdocetaxelincombinationwithcisplatinand5-fluorouracil(TCF),febrileneutropeniaand

neutropenicinfectionoccurredatlowerrateswhenpatientsreceivedprophylacticG-CSF.PatientstreatedwithTCF

shouldreceiveprophylacticG-CSFtomitigatetheriskofcomplicatedneutropenia(febrileneutropenia,prolonged

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Hypersensitivityreactions

Patientsshouldbeobservedcloselyforhypersensitivityreactionsespeciallyduringthefirstandsecondinfusions.

Hypersensitivityreactionsmayoccurwithinafewminutesfollowingtheinitiationoftheinfusionofdocetaxel,thus

facilitiesforthetreatmentofhypotensionandbronchospasmshouldbeavailable.Ifhypersensitivityreactionsoccur,

minorsymptomssuchasflushingorlocalisedcutaneousreactionsdonotrequireinterruptionoftherapy.However,

severereactions,suchasseverehypotension,bronchospasmorgeneralisedrash/erythemarequireimmediate

discontinuationofdocetaxelandappropriatetherapy.Patientswhohavedevelopedseverehypersensitivityreactions

shouldnotbere-challengedwithdocetaxel.

Cutaneousreactions

Localisedskinerythemaoftheextremities(palmsofthehandsandsolesofthefeet)withoedemafollowedby

desquamationhasbeenobserved.Severesymptomssuchaseruptionsfollowedbydesquamationwhichleadto

interruptionordiscontinuationofdocetaxeltreatmentwerereported(seesection4.2).

Fluidretention

Patientswithseverefluidretentionsuchaspleuraleffusion,pericardialeffusionandascitesshouldbemonitored

closely.

Patientswithliverimpairment

Inpatientstreatedwithdocetaxelat100mg/m 2

assingleagentwhohaveserumtransaminaselevels(ALTand/orAST)

greaterthan1.5timestheULNconcurrentwithserumalkalinephosphataselevelsgreaterthan2.5timestheULN,

thereisahigherriskofdevelopingsevereadversereactionssuchastoxicdeathsincludingsepsisandgastrointestinal

haemorrhagewhichcanbefatal,febrileneutropenia,infections,thrombocytopenia,stomatitisandasthenia.Therefore,

therecommendeddoseofdocetaxelinthosepatientswithelevatedliverfunctiontest(LFTs)is75mg/m 2

andLFTs

shouldbemeasuredatbaselineandbeforeeachcycle(seesection4.2).

Forpatientswithserumbilirubinlevels>ULNand/orALTandAST>3.5timestheULNconcurrentwithserum

alkalinephosphataselevels>6timestheULN,nodose-reductioncanberecommendedanddocetaxelshouldnotbe

usedunlessstrictlyindicated.Incombinationwithcisplatinand5-fluorouracilforthetreatmentofpatientswithgastric

adenocarcinoma,thepivotalclinicaltrialexcludedpatientswithALTand/orAST>1.5×ULNassociatedwithalkaline

phosphatase>2.5×ULN,andbilirubin>1xULN;forthesepatients,nodose-reductionscanberecommendedand

docetaxelshouldnotbeusedunlessstrictlyindicated.Nodataareavailableinpatientswithhepaticimpairmenttreated

bydocetaxelincombinationintheotherindications.

Patientswithrenalimpairment

Therearenodataavailableinpatientswithseverelyimpairedrenalfunctiontreatedwithdocetaxel.

Nervoussystem

Thedevelopmentofsevereperipheralneurotoxicityrequiresareductionofdose(seesection4.2).

Cardiactoxicity

Heartfailurehasbeenobservedinpatientsreceivingdocetaxelincombinationwithtrastuzumab,particularlyfollowing

anthracycline(doxorubicinorepirubicin)-containingchemotherapy.Thismaybemoderatetosevereandhasbeen

associatedwithdeath(seesection4.8).

Whenpatientsarecandidatesfortreatmentwithdocetaxelincombinationwithtrastuzumab,theyshouldundergo

baselinecardiacassessment.Cardiacfunctionshouldbefurthermonitoredduringtreatment(e.g.everythreemonths)to

helpidentifypatientswhomaydevelopcardiacdysfunction.Formoredetailsseesummaryofproductcharacteristicsof

trastuzumab.

Others

Contraceptivemeasuresmustbetakenbybothmenandwomenduringandforatleastthreemonthsaftercessationof

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Additionalcautionsforuseinadjuvanttreatmentofbreastcancer

Complicatedneutropenia

Forpatientswhoexperiencecomplicatedneutropenia(prolongedneutropenia,febrileneutropeniaorinfection),G-CSF

anddosereductionshouldbeconsidered(seesection4.2).

Gastrointestinalreactions

Symptomssuchasearlyabdominalpainandtenderness,fever,diarrhea,withorwithoutneutropenia,maybeearly

manifestationsofseriousgastrointestinaltoxicityandshouldbeevaluatedandtreatedpromptly.

Congestiveheartfailure

Patientsshouldbemonitoredforsymptomsofcongestiveheartfailureduringtherapyandduringthefollowupperiod.

Leukemia

Inthedocetaxel,doxorubicinandcyclophosphamide(TAC)treatedpatients,theriskofdelayedmyelodysplasiaor

myeloidleukemiarequireshaematologicalfollow-up.

Patientswith4+nodes

Thebenefit/riskratioforTACinpatientswith4+nodeswasnotdefinedfullyattheinterimanalysis(seesection5.1).

Elderly

Therearenodataavailableinpatients>70yearsofageondocetaxeluseincombinationwithdoxorubicinand

cyclophosphamide.

Ofthe333patientstreatedwithdocetaxeleverythreeweeksinaprostatecancerstudy,209patientswere65yearsof

ageorgreaterand68patientswereolderthan75years.Inpatientstreatedwithdocetaxeleverythreeweeks,the

incidenceofrelatednailchangesoccurredatarate 10%higherinpatientswhowere65yearsofageorgreater

comparedtoyoungerpatients.Theincidenceofrelatedfever,diarrhea,anorexia,andperipheraledemaoccurredat

rates 10%higherinpatientswhowere75yearsofageorgreaterversuslessthan65years.

Amongthe300(221patientsinthephaseIIIpartofthestudyand79patientsinthephaseIIpart)patientstreatedwith

docetaxelincombinationwithcisplatinand5-fluorouracilinthegastriccancerstudy,74were65yearsofageorolder

and4patientswere75yearsofageorolder.Theincidenceofseriousadverseeventswashigherintheelderlypatients

comparedtoyoungerpatients.Theincidenceofthefollowingadverseevents(allgrades):lethargy,stomatitis,

neutropenicinfectionoccurredatrates 10%higherinpatientswhowere65yearsofageoroldercomparedto

youngerpatients.ElderlypatientstreatedwithTCFshouldbecloselymonitored.

Specialwarning

Thismedicinalproductcontains27vol%ethanol(alcohol),i.e.160mg(averagedose)contains4100mgalcohol,

equivalenttolessthan100mlbeer.

Harmfulforthosesufferingfromalcoholism.Tobetakenintoaccountinpregnantorbreast-feedingwomen,children

andhigh-riskgroupssuchaspatientswithliverdiseaseorotherdiseasesaffectingthecentralnervoussystem(e.g.

epilepsy).

Theamountofalcoholinthismedicinalproductmayaltertheeffectsofothermedicines.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Invitrostudieshaveshownthatthemetabolismofdocetaxelmaybemodifiedbytheconcomitantadministrationof

compoundswhichinduce,inhibitoraremetabolisedby(andthusmayinhibittheenzymecompetitively)cytochrome

P450-3Asuchasciclosporine,terfenadine,ketoconazole,erythromycinandtroleandomycin.Asaresult,cautionshould

beexercisedwhentreatingpatientswiththesemedicinalproductsasconcomitanttherapysincethereisapotentialfora

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Docetaxelishighlyproteinbound(>95%).Althoughthepossibleinvivointeractionofdocetaxelwithconcomitantly

administeredmedicationhasnotbeeninvestigatedformally,invitrointeractionswithtightlyprotein-boundagentssuch

aserythromycin,diphenhydramine,propranolol,propafenone,phenytoin,salicylate,sulfamethoxazoleandsodium

valproatedidnotaffectproteinbindingofdocetaxel.Inaddition,dexamethasonedidnotaffectproteinbindingof

docetaxel.Docetaxeldidnotinfluencethebindingofdigitoxin.

Thepharmacokineticsofdocetaxel,doxorubicinandcyclophosphamidewerenotinfluencedbytheircoadministration.

Limiteddatafromasingleuncontrolledstudyweresuggestiveofaninteractionbetweendocetaxelandcarboplatin.

Whencombinedtodocetaxel,theclearanceofcarboplatinwasabout50%higherthanvaluespreviouslyreportedfor

carboplatinmonotherapy.

Docetaxelpharmacokineticsinthepresenceofprednisonewasstudiedinpatientswithmetastaticprostatecancer.

DocetaxelismetabolisedbyCYP3A4andprednisoneisknowntoinduceCYP3A4.Nostatisticallysignificanteffectof

prednisoneonthepharmacokineticsofdocetaxelwasobserved.

DocetaxelshouldbeadministeredwithcautioninpatientsconcomitantlyreceivingpotentCYP3A4inhibitors(e.g.

proteaseinhibitorslikeritonavir,azoleantifungalslikeketoconazoleoritraconazole).Adruginteractionstudy

performedinpatientsreceivingketoconazoleanddocetaxelshowedthattheclearanceofdocetaxelwasreducedbyhalf

byketoconazole,probablybecausethemetabolismofdocetaxelinvolvesCYP3A4asamajor(single)metabolic

pathway.Reducedtoleranceofdocetaxelmayoccur,evenatlowerdoses.

4.6Fertility,pregnancyandlactation

Thereisnoinformationontheuseofdocetaxelinpregnantwomen.Docetaxelhasbeenshowntobebothembryotoxic

andfoetotoxicinrabbitsandrats,andtoreducefertilityinrats.Aswithothercytotoxicmedicinalproducts,docetaxel

maycausefoetalharmwhenadministeredtopregnantwomen.Therefore,docetaxelmustnotbeusedduring

pregnancy.Womenofchildbearingagereceivingdocetaxelshouldbeadvisedtoavoidbecomingpregnant,andto

informthetreatingphysicianimmediatelyshouldthisoccur.

Docetaxelisalipophilicsubstancebutitisnotknownwhetheritisexcretedinhumanmilk.

Consequently,becauseofthepotentialforadversereactionsinnursinginfants,breastfeedingmustbediscontinuedfor

thedurationofdocetaxeltherapy.

4.7Effectsonabilitytodriveandusemachines

Thismedicinalproductcontains27vol%ethanol(alcohol),i.e.160mg(averagedose)contains4100mgalcohol,

equivalenttolessthan100mlbeer.

Theamountofalcoholinthismedicinalproductmayimpairtheabilitytodriveorusemachines.

4.8Undesirableeffects

Theadversereactionsconsideredtobepossiblyorprobablyrelatedtotheadministrationofdocetaxelhavebeen

obtainedin:

1312and121patientswhoreceived100mg/m²and75mg/m²ofdocetaxelasasingleagentrespectively.

258patientswhoreceiveddocetaxelincombinationwithdoxorubicin.

406patientswhoreceiveddocetaxelincombinationwithcisplatin.

92patientstreatedwithdocetaxelincombinationwithtrastuzumab.

255patientswhoreceiveddocetaxelincombinationwithcapecitabine.

332patientswhoreceiveddocetaxelincombinationwithprednisoneorprednisolone(clinicallyimportant

treatmentrelatedadverseeventsarepresented).

744patientswhoreceiveddocetaxelincombinationwithdoxorubicinandcyclophosphamide(clinically

importanttreatmentrelatedadverseeventsarepresented).

300gastricadenocarcinomapatients(221patientsinthephaseIIIpartofthestudyand

79patientsinthephaseIIpart)whoreceiveddocetaxelincombinationwithcisplatinand5-fluorouracil

(clinicallyimportanttreatmentrelatedadverseeventsarepresented).

174and251headandneckcancerpatientswhoreceiveddocetaxelincombinationwithcisplatinand5-

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ThesereactionsweredescribedusingtheNCICommonToxicityCriteria(grade3=G3;grade3-4=G3/4;grade4=

G4)andtheCOSTARTterms.Frequenciesaredefinedas: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).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Themostcommonlyreportedadversereactionsofdocetaxelaloneare:neutropenia(whichwasreversibleandnot

cumulative;themediandaytonadirwas7daysandthemediandurationofsevereneutropenia(<500cells/mm 3

)was7

days),anemia,alopecia,nausea,vomiting,stomatitis,diarrheaandasthenia.Theseverityofadverseeventsofdocetaxel

maybeincreasedwhendocetaxelisgivenincombinationwithotherchemotherapeuticagents.

Forcombinationwithtrastuzumab,adverseevents(allgrades)reportedin 10%aredisplayed.Therewasanincreased

incidenceofSAEs(40%vs.31%)andGrade4AEs(34%vs.23%)inthetrastuzumabcombinationarmcomparedto

docetaxelmonotherapy.

Forcombinationwithcapecitabine,themostfrequenttreatment-relatedundesirableeffects(5%)reportedinaphase

IIItrialinbreastcancerpatientsfailinganthracyclinetreatmentarepresented(seecapecitabinesummaryofproduct

characteristics).

Thefollowingadversereactionsarefrequentlyobservedwithdocetaxel:

Nervoussystemdisorders

Thedevelopmentofsevereperipheralneurotoxicityrequiresareductionofdose(seesections4.2and4.4).Mildto

moderateneuro-sensorysignsarecharacterisedbyparesthesia,dysesthesiaorpainincludingburning.Neuro-motor

eventsaremainlycharacterisedbyweakness.

Skinandsubcutaneoustissuedisorders

Reversiblecutaneousreactionshavebeenobservedandweregenerallyconsideredasmildtomoderate.Reactionswere

characterisedbyarashincludinglocalisederuptionsmainlyonthefeetandhands(includingseverehandandfoot

syndrome),butalsoonthearms,faceorthorax,andfrequentlyassociatedwithpruritus.Eruptionsgenerallyoccurred

withinoneweekafterthedocetaxelinfusion.Lessfrequently,severesymptomssuchaseruptionsfollowedby

desquamationwhichrarelyleadtointerruptionordiscontinuationofdocetaxeltreatmentwerereported(seesections

4.2and4.4).Severenaildisordersarecharacterisedbyhypo-orhyperpigmentationandsometimespainand

onycholysis.

Generaldisordersandadministrationsiteconditions

Infusionsitereactionsweregenerallymildandconsistedofhyperpigmentation,inflammation,rednessordrynessof

theskin,phlebitisorextravasationandswellingofthevein.Fluidretentionincludeseventssuchasperipheraloedema

andlessfrequentlypleuraleffusion,pericardialeffusion,ascitesandweightgain.Theperipheraloedemausuallystarts

atthelowerextremitiesandmaybecomegeneralisedwithaweightgainof3kgormore.Fluidretentioniscumulative

inincidenceandseverity(seesection4.4).

Immunesystemdisorders

Hypersensitivityreactionshavegenerallyoccurredwithinafewminutesfollowingthestartoftheinfusionofdocetaxel

andwereusuallymildtomoderate.Themostfrequentlyreportedsymptomswereflushing,rashwithorwithout

pruritus,chesttightness,backpain,dyspnoeaandfeverorchills.Severereactionswerecharacterisedbyhypotension

and/orbronchospasmorgeneralizedrash/erythema(seesection4.4).

DOCETAXEL100mg/m²singleagent

MedDRASystem

Organclasses Verycommonadverse

reactions

10%ofpatients Commonadverse

reactions

1to<10%of

patients Uncommonadverse

reactions

0.1to<1%of

patients

Investigations G3/4Bloodbilirubin

increased(<5%);

G3/4Bloodalkaline

phosphataseincreased(<

4%);

G3/4ASTincreased

(<3%);

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Bloodandlymphaticsystemdisorders

(<2%)

Cardiacdisorders Arrhythmia(G3/4:

0.7%) Cardiacfailure

Bloodandlymphatic

systemdisorders Neutropenia(G4:

76.4%);

Anaemia(G3/4:8.9%);

Febrileneutropenia Thrombocytopenia(G4:

0.2%)

Nervoussystem

disorders Peripheralsensory

neuropathy(G3:4.1%);

Peripheralmotor

neuropathy(G3/4:4%);

Dysgeusia(severe:

0.07%)

Respiratory,thoracicand

mediastinal

disorders Dyspnoea(severe:2.7%)

Gastrointestinal

disorders Stomatitis(G3/4:

5.3%);

Diarrhoea(G3/4:4%);

Nausea(G3/4:4%);

Vomiting(G3/4:3%) Constipation(severe:

0.2%);

Abdominalpain(severe:

1%);

Gastrointestinal

haemorrhage(severe:

0.3%) Oesophagitis(severe:

0.4%)

Skinandsubcutaneous

tissuedisorders Alopecia;

Skinreaction(G3/4:

5.9%);

Naildisorders(severe:

2.6%)

Musculoskeletaland

connectivetissue

disorders Myalgia(severe:1.4%) Arthralgia

Metabolismandnutrition

disorders Anorexia

Infectionsand

infestations Infections(G3/4:5.7%;

includingsepsisand

pneumonia,fatalin

1.7%) Infectionassociated

withG4neutropenia

(G3/4:4.6%)

Vasculardisorders; Hypotension

Hypertension;

Haemorrhage

Generaldisordersand

administrationsite

conditions Fluidretention(severe:

6.5%);

Asthenia(severe:

11.2%);

Pain Infusionsitereaction;

Non-cardiacchestpain

(severe:0.4%)

Immunesystem

disorders Hypersensitivity

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Nervoussystemdisorders

Reversibilitydataareavailableamong35.3%ofpatientswhodevelopedneurotoxicityfollowingdocetaxeltreatmentat

100mg/m²assingleagent.Theeventswerespontaneouslyreversiblewithin3months.

Skinandsubcutaneoustissuedisorders

Veryrare:onecaseofalopecianon-reversibleattheendofthestudy.73%ofthecutaneousreactionswerereversible

within21days.

Generaldisordersandadministrationsiteconditions

Themediancumulativedosetotreatmentdiscontinuationwasmorethan1,000mg/m 2

andthemediantimetofluid

retentionreversibilitywas16.4weeks(range0to42weeks).Theonsetofmoderateandsevereretentionisdelayed

(mediancumulativedose:818.9mg/m 2

)inpatientswithpremedicationcomparedwithpatientswithoutpremedication

(mediancumulativedose:489.7mg/m 2

);however,ithasbeenreportedinsomepatientsduringtheearlycoursesof

therapy.

DOCETAXEL75mg/m²singleagent

MedDRASystemOrganclasses Verycommonadverse

reactions 10%ofpatients Commonadversereactions 1

to<10%ofpatients

Investigations G3/4Bloodbilirubinincreased(<

Cardiacdisorders Arrhythmia(nosevere)

Bloodandlymphaticsystem

disorders Neutropenia(G4:54.2%);

Anaemia(G3/4:10.8%);

Thrombocytopenia(G4:1.7%) Febrileneutropenia

Nervoussystemdisorders Peripheralsensoryneuropathy

(G3/4:0.8%) Peripheralmotorneuropathy

(G3/4:2.5%)

Gastrointestinaldisorders Nausea(G3/4:3.3%);

Stomatitis(G3/4:1.7%);

Vomiting(G3/4:0.8%);

Diarrhea(G3/4:1.7%) Constipation

Skinandsubcutaneoustissue

disorders Alopecia;

Skinreaction(G3/4:0.8%) Naildisorders(severe:0.8%)

Musculoskeletalandconnective

tissuedisorders Myalgia

Metabolismandnutrition

disorders Anorexia

Infectionsandinfestations Infections(G3/4:5%)

Vasculardisorders Hypotension

Generaldisordersand

administrationsiteconditions Asthenia(severe:12.4%);

Fluidretention(severe:0.8%);

Pain

Immunesystemdisorders Hypersensitivity(nosevere)

MedDRASystem

Organclasses Verycommonadverse

reactions 10%of

patients Commonadverse

reactions 1to<10%

ofpatients Uncommonadverse

reactions 0.1to<1%

ofpatients

Investigations G3/4Bloodbilirubin

increased(<2.5%);

G3/4Bloodalkaline

phosphataseincreased(<

2.5%) G3/4ASTincreased(<

1%);

G3/4ALTincreased(<

Cardiacdisorders Cardiacfailure;

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Bloodandlymphatic

systemdisorders Neutropenia(G4:

91.7%);

Anaemia(G3/4:9.4%);

Febrileneutropenia;

Thrombocytopenia(G4:

0.8%)

Nervoussystem

disorders Peripheralsensory

neuropathy(G3:0.4%) Peripheralmotor

neuropathy(G3/4:0.4%)

Gastrointestinal

disorders Nausea(G3/4:5%);

Stomatitis(G3/4:7.8%);

Diarrhoea(G3/4:6.2%);

Vomiting(G3/4:5%);

Constipation

Skinandsubcutaneous

tissuedisorders Alopecia;

Naildisorders(severe:

0.4%);

Skinreaction(nosevere)

Musculoskeletaland

connectivetissue

disorders Myalgia

Metabolismandnutrition

disorders Anorexia

Infectionsand

infestations Infection(G3/4:7.8%)

Vasculardisorders Hypotension

Generaldisordersand

administrationsite

conditions Asthenia(severe:

8.1%);

Fluidretention(severe:

1.2%);

Pain Infusionsitereaction

Infusionsitereaction

Immunesystem

disorders Hypersensitivity(G3/4:

1.2%)

MedDRASystem

Organclasses Verycommonadverse

reactions 10%of

patients Commonadverse

reactions 1to<10%

ofpatients Uncommonadverse

reactions 0.1to<1%

ofpatients

Investigations G3/4Bloodbilirubin

increased(2.1%);

G3/4ALTincreased

(1.3%) G3/4ASTincreased

(0.5%);

G3/4Bloodalkaline

phosphataseincreased

(0.3%)

Cardiacdisorders Arrhythmia(G3/4:

0.7%) Cardiacfailure

Bloodandlymphatic

systemdisorders Neutropenia(G4:

51.5%);

Anaemia(G3/4:6.9%);

Thrombocytopenia(G4:

0.5%) Febrileneutropenia

Nervoussystem

disorders Peripheralsensory

neuropathy(G3:3.7%);

Peripheralmotor

neuropathy(G3/4:2%)

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disorders Vomiting(G3/4:7.6%);

Diarrhoea(G3/4:6.4%);

Stomatitis(G3/4:2%)

Skinandsubcutaneous

tissuedisorders Alopecia;

Naildisorders(severe:

0.7%);

Skinreaction(G3/4:

0.2%)

Musculoskeletaland

connectivetissue

disorders Myalgia(severe:0.5%)

Metabolismandnutrition

disorders Anorexia

Infectionsand

infestations Infection(G3/4:5.7%)

Vasculardisorders Hypotension(G3/4:

0.7%)

Generaldisordersand

administrationsite

conditions Asthenia(severe:9.9%);

Fluidretention(severe:

0.7%);

Fever(G3/4:1.2%) Infusionsitereaction;

Pain

Immunesystem

disorders Hypersensitivity(G3/4:

2.5%)

MedDRASystemOrganclasses Verycommonadverse

reactions 10%ofpatients Commonadversereactions 1

to<10%ofpatients

Investigations Weightincreased

Cardiacdisorders Cardiacfailure

Bloodandlymphaticsystem

disorders Neutropenia(G3/4:32%);

Febrileneutropenia(includes

neutropeniaassociatedwithfever

andantibioticuse)orneutropenic

sepsis

Nervoussystemdisorders Paresthesia;Headache;

Dysgeusia;Hypoaesthesia

Eyedisorders Lacrimationincreased;

Conjunctivitis

Respiratory,thoracicand

mediastinaldisorders Epistaxis;Pharyngolaryngeal

pain;Nasopharyngitis;

Dyspnoea;Cough;Rhinorrhoea

Gastrointestinaldisorders Nausea;Diarrhoea;Vomiting

Constipation;Stomatitis;

Dyspepsia;Abdominalpain

Skinandsubcutaneoustissue

disorders Alopecia;Erythema;Rash;Nail

disorders

Musculoskeletalandconnective

tissuedisorders Myalgia;Arthralgia;Painin

extremity;Bonepain;Backpain

Metabolismandnutrition

disorders Anorexia

Vasculardisorders Lymphoedema

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Cardiacdisorders

Symptomaticcardiacfailurewasreportedin2.2%ofthepatientswhoreceiveddocetaxelplustrastuzumabcomparedto

0%ofpatientsgivendocetaxelalone.Inthedocetaxelplustrastuzumabarm,64%hadreceivedaprioranthracyclineas

adjuvanttherapycomparedwith55%inthedocetaxelarmalone.

Bloodandlymphaticsystemdisorders

Verycommon:Haematologicaltoxicitywasincreasedinpatientsreceivingtrastuzumabanddocetaxel,comparedwith

docetaxelalone(32%grade3/4neutropeniaversus22%,usingNCI-CTCcriteria).Notethatthisislikelytobean

underestimatesincedocetaxelaloneatadoseof100mg/m 2

isknowntoresultinneutropeniain97%ofpatients,76%

grade4,basedonnadirbloodcounts.Theincidenceoffebrileneutropenia/neutropenicsepsiswasalsoincreasedin

patientstreatedwithHerceptinplusdocetaxel(23%versus17%forpatientstreatedwithdocetaxelalone).

DOCETAXEL75mg/m²incombinationwithcapecitabine

administrationsiteconditions Pyrexia;Fatigue;Mucosal

inflammation;Pain;Influenza

likeillness;Chestpain;Chills

Psychiatricdisorders Insomnia

MedDRASystemOrganclasses Verycommonadverse

reactions 10%ofpatients Commonadversereactions 1

to<10%ofpatients

Investigations Weightdecreased;G3/4Blood

bilirubinincreased(9%)

Bloodandlymphaticsystem

disorders Neutropenia(G3/4:63%);

Anaemia(G3/4:10%) Thrombocytopenia(G3/4:3%)

Nervoussystemdisorders Dysgeusia(G3/4:<1%);

Paraesthesia(G3/4:<1%) Dizziness;Headache(G3/4:<

1%);Neuropathyperipheral

Eyedisorders Lacrimationincreased

Respiratory,thoracicand

mediastinaldisorders Pharyngolaryngealpain(G3/4:

Dyspnoea(G3/4:1%);

Cough(G3/4:<1%);

Epistaxis(G3/4:<1%)

Gastrointestinaldisorders Stomatitis(G3/4:18%);

Diarrhoea(G3/4:14%);

Nausea(G3/4:6%);

Vomiting(G3/4:4%);

Constipation(G3/4:1%);

Abdominalpain(G3/4:2%);

Dyspepsia Abdominalpainupper;

Drymouth

Skinandsubcutaneoustissue

disorders Hand-footsyndrome(G3/4:

24%);

Alopecia(G3/4:6%);

Naildisorders(G3/4:2%) Dermatitis;Rasherythematous

(G3/4:<1%);Nail

discolouration;Onycholysis

(G3/4:1%)

Musculoskeletalandconnective

tissuedisorders Myalgia(G3/4:2%);

Arthralgia(G3/4:1%) Paininextremity(G3/4:<1%);

Backpain(G3/4:1%)

Metabolismandnutrition

disorders Anorexia(G3/4:1%);Decreased

appetite Dehydration(G3/4:2%)

Infectionsandinfestations Oralcandidiasis(G3/4:<1%)

Generaldisordersand

administrationsiteconditions Asthenia(G3/4:3%);

Pyrexia(G3/4:1%);

Fatigue/weakness(G3/4:5%);

Oedemaperipheral(G3/4:1%) Lethargy;

Pain

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reactions 10%ofpatients to<10%ofpatients

Cardiacdisorders Cardiacleftventricularfunction

decrease(G3/4:0.3%)

Bloodandlymphaticsystem

disorders Neutropenia(G3/4:32%);

Anaemia(G3/4:4.9%) Thrombocytopenia(G3/4:0.6%);

Febrileneutropenia

Nervoussystemdisorders Peripheralsensoryneuropathy

(G3/4:1.2%);

Dysgeusia(G3/4:0%) Peripheralmotorneuropathy

(G3/4:0%)

Eyedisorders Lacrimationincreased(G3/4:

0.6%)

Respiratory,thoracicand

mediastinaldisorders Epistaxis(G3/4:0%);

Dyspnoea(G3/4:0.6%);

Cough(G3/4:0%)

Gastrointestinaldisorders Nausea(G3/4:2.4%);

Diarrhoea(G3/4:1.2%);

Stomatitis/Pharyngitis(G3/4:

0.9%);

Vomiting(G3/4:1.2%)

Skinandsubcutaneoustissue

disorders Alopecia;Naildisorders(no

severe) Exfoliativerash(G3/4:0.3%)

Musculoskeletalandconnective

bonedisorders Arthralgia(G3/4:0.3%);

Myalgia(G3/4:0.3%)

Metabolismandnutrition

disorders Anorexia(G3/4:0.6%)

Infectionsandinfestations Infection(G3/4:3.3%)

Generaldisordersand

administrationsiteconditions Fatigue(G3/4:3.9%);

Fluidretention(severe:0.6%)

Immunesystemdisorders Hypersensitivity(G3/4:0.6%)

MedDRASystem

Organclasses Verycommonadverse

reactions 10%of

patients Commonadverse

reactions 1to<10%

ofpatients Uncommonadverse

reactions 0.1to<1%

ofpatients

Investigations Weightincreasedor

decreased(G3/4:0.3%)

Cardiacdisorders Arrhythmia(G3/4:

0.1%);Congestiveheart

failure

Bloodandlymphatic

systemdisorders Anaemia(G3/4:4.3%);

Neutropenia(G3/4:

65.5%);

Thrombocytopenia

(G3/4:2.0%);Febrile

neutropenia

Nervoussystem

disorders Dysgeusia(G3/4:0.7%);

Peripheralsensory

neuropathy(G3/4:0%) Peripheralmotor

neuropathy(G3/4:0%);

Neurocortical(G3/4:

0.3%);Neurocerebellar

(G3/4:0.1%) Syncope(G3/4:0%)

Eyedisorders Lacrimationdisorder

(G3/4:0.1%);

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Cardiacdisorders

CongestiveHeartFailure(CHF)(2.3%at70monthsmedianfollow-up)hasalsobeenreported.Onepatientineach

treatmentarmdiedduetocardiacfailure.

Nervoussystemdisorders

Peripheralsensoryneuropathywasobservedtobeongoingatthemedianfollow-uptimeof55monthsin9patientsout

ofthe73patientswithperipheralsensoryneuropathyattheendofthechemotherapy.

Skinandsubcutaneoustissuedisorders

Alopeciawasobservedtobeongoingatthemedianfollow-uptimeof55monthsin22patientsoutofthe687patients

withalopeciaattheendofthechemotherapy.

Generaldisordersandadministrationsiteconditions

Oedemaperipheralwasobservedtobeongoingatthemedianfollow-uptimeof55monthsin18patientsoutofthe112

patientswithoedemaperipheralattheendofthechemotherapy.

Reproductivesystemandbreastdisorders

Amenorrhoeawasobservedtobeongoingatthemedianfollow-uptimeof55monthsin133patientsoutofthe233

0.3%)

Respiratory,thoracicand

mediastinaldisorders Cough(G3/4:0%)

Gastrointestinal

disorders Nausea(G3/4:5.1%);

Stomatitis(G3/4:7.1%);

Vomiting(G3/4:4.3%);

Diarrhoea(G3/4:3.2%);

Constipation(G3/4:

0.4%) Abdominalpain(G3/4:

0.5%) Colitis/enteritis/large

intestineperforation

Skinandsubcutaneous

tissuedisorders Alopecia;Skintoxicity

(G3/4:0.7%);Nail

disorders(G3/4:0.4%)

Musculoskeletaland

connectivetissue

disorders Myalgia(G3/4:0.8%);

Arthralgia(G3/4:0.4%)

Metabolismandnutrition

disorders Anorexia(G3/4:2.2%)

Infectionsand

infestations Infection(G3/4:3.2%);

Neutropenicinfection.

Therewerenoseptic

deaths.

Vasculardisorders Vasodilatation(G3/4:

0.9%) Hypotension(G3/4:0%) Phlebitis(G3/4:0%);

Lymphoedema(G3/4:

Generaldisordersand

administrationsite

conditions Asthenia(G3/4:11%);

Fever(G3/4:1.2%);

Oedemaperipheral

(G3/4:0.4%)

Immunesystem

disorders Hypersensitivity(G3/4:

1.1%)

Reproductivesystemand

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DOCETAXEL75mg/m²incombinationwithcisplatinand5-fluorouracilforgastricadenocarcinomacancer

Bloodandlymphaticsystemdisorders

Febrileneutropeniaandneutropenicinfectionoccurredin17.2%and13.5%ofpatientsrespectively,regardlessofG-

CSFuse.G-CSFwasusedforsecondaryprophylaxisin19.3%ofpatients(10.7%ofthecycles).Febrileneutropenia

andneutropenicinfectionoccurredrespectivelyin12.1%and3.4%ofpatientswhenpatientsreceivedprophylacticG-

CSF,in15.6%and12.9%ofpatientswithoutprophylacticG-CSF(seesection4.2).

DOCETAXEL75mg/m²incombinationwithcisplatinand5-fluorouracilforHeadandNeckcancer

MedDRASystemOrganclasses Verycommonadverse

reactions 10%ofpatients Commonadversereactions 1

to<10%ofpatients

Cardiacdisorders Arrhythmia(G3/4:1.0%)

Bloodandlymphaticsystem

disorders Anaemia(G3/4:20.9%);

Neutropenia(G3/4:83.2%);

Thrombocytopenia(G3/4:

8.8%);Febrileneutropenia

Nervoussystemdisorders Peripheralsensoryneuropathy

(G3/4:8.7%) Dizziness(G3/4:2.3%);

Peripheralmotorneuropathy

(G3/4:1.3%)

Eyedisorders Lacrimationincreased(G3/4:

Earandlabyrinthdisorders Hearingimpaired(G3/4:0%)

Gastrointestinaldisorders Diarrhoea(G3/4:19.7%);

Nausea(G3/4:16%);

Stomatitis(G3/4:23.7%);

Vomiting(G3/4:14.3%) Constipation(G3/4:1.0%);

Gastrointestinalpain(G3/4:

1.0%);

Oesophagitis/dysphagia/odynop

hagia(G3/4:0.7%)

Skinandsubcutaneoustissue

disorders Alopecia(G3/4:4.0%) Rashpruritus(G3/4:0.7%);

Naildisorders(G3/4:0.7%);

Skinexfoliation(G3/4:0%)

Metabolismandnutrition

disorders Anorexia(G3/4:11.7%)

Infectionsandinfestations Neutropenicinfection;

Infection(G3/4:11.7%)

Generaldisordersand

administrationsiteconditions Lethargy(G3/4:19.0%);Fever

(G3/4:2.3%);Fluidretention

(severe/lifethreatening:1%)

Immunesystemdisorders Hypersensitivity(G3/4:1.7%)

MedDRASystem

Organclasses Verycommon

adversereactions

10%ofpatients Commonadverse

reactions 1to<10%

ofpatients Uncommonadverse

reactions 0.1to<

1%ofpatients

Investigations Weightincreased

Cardiacdisorders Myocardialischemia

(G3/4:1.7%) Arrhythmia(G3/4:

0.6%)

Bloodandlymphatic

systemdisorders Neutropenia(G3/4:

76.3%);Anemia

(G3/4:9.2%);

Thrombocytopenia

(G3/4:5.2%) Febrileneutropenia

Nervoussystem

disorders Dysgeusia/Parosmia;

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neuropathy(G3/4:

0.6%)

Eyedisorders Lacrimationincreased;

Conjunctivitis

Earandlabyrinth

disorders Hearingimpaired

Gastrointestinal

disorders Nausea(G3/4:0.6%);

Stomatitis(G3/4:

4.0%);Diarrhea

(G3/4:2.9%);

Vomiting(G3/4:

0.6%) Constipation;

Esophagitis/dysphagia/

odynophagia(G3/4:

0.6%);Abdominalpain;

Dyspepsia;

Gastrointestinal

haemorrhage(G3/4:

0.6%)

Skinandsubcutaneous

tissuedisorders Alopecia(G3/4:

10.9%) Rashpruritic;Dryskin;

Skinexfoliative(G3/4:

0.6%)

Musculoskeletaland

connectivetissue

disorders Myalgia(G3/4:0.6%)

Metabolismand

nutritiondisorders Anorexia(G3/4:

0.6%)

Infectionsand

infestations Infection(G3/4:

6.3%);Neutropenic

infection

Neoplasmsbenign,

malignantand

unspecified(inclcysts

andpolyps) Cancerpain(G3/4:

0.6%)

Vasculardisorders Venousdisorder(G3/4:

0.6%)

Generaldisordersand

administrationsite

conditions Lethargy(G3/4:

3.4%);Pyrexia(G3/4:

0.6%);Fluid

retention;Oedema

Immunesystem

disorders Hypersensitivity(no

severe)

MedDRASystem

Organclasses Verycommonadverse

reactions 10%of

patients Commonadverse

reactions 1to<10%

ofpatients Uncommonadverse

reactions 0.1to<

1%ofpatients

Investigations Weightdecreased Weightincreased

Cardiacdisorders Arrhythmia(G3/4:

2.0%) Myocardialischaemia

Bloodandlymphatic

systemdisorders Neutropenia(G3/4:

83.5%);

Anemia(G3/4:12.4%);

Thrombocytopenia

(G3/4:4.0%);

Febrileneutropenia

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disorders (G3/4:0.4%);

Peripheralsensory

neuropathy(G3/4:

1.2%) 2.0%);

Peripheralmotor

neuropathy(G3/4:

0.4%)

Eyedisorders Lacrimationincreased Conjunctivitis

Earandlabyrinth

disorders Hearingimpaired

(G3/4:1.2%)

Gastrointestinal

disorders Nausea(G3/4:13.9%);

Stomatitis(G3/4:

20.7%);

Vomiting(G3/4:

8.4%);

Diarrhea(G3/4:6.8%);

Esophagitis/dysphagia/

odynophagia(G3/4:

12.0%);

Constipation(G3/4:

Dyspepsia(G3/4:

0.8%);

Gastrointestinalpain

(G3/4:1.2%);

Gastrointestinal

haemorrhage(G3/4:

0.4%)

Skinand

subcutaneous

tissuedisorders Alopecia(G3/4:4.0%);

Rashpruritic Dryskin;

Desquamation

Musculoskeletal,

connectivetissue

bone

disorders Myalgia(G3/4:0.4%)

Metabolismand

nutritiondisorders Anorexia(G3/4:

12.0%)

Infectionsand

infestations Infection(G3/4:3.6%) Neutropenicinfection

Neoplasmsbenign,

malignantand

unspecified(incl

cysts

andpolyps) Cancerpain(G3/4:

1.2%)

Vasculardisorders Venousdisorder

Generaldisordersand

administrationsite

conditions Lethargy(G3/4:4.0%);

Pyrexia(G3/4:3.6%);

Fluidretention(G3/4:

1.2);

Oedema(G3/4:1.2%)

Immunesystem

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Post-marketingexperience

Cardiacdisorders

Rarecasesofmyocardialinfarctionhavebeenreported.

Bloodandlymphaticsystemdisorders

Bonemarrowsuppressionandotherhematologicadversereactionshavebeenreported.Disseminatedintravascular

coagulation(DIC),ofteninassociationwithsepsisormultiorganfailure,hasbeenreported.

Nervoussystemdisorders

Rarecasesofconvulsionortransientlossofconsciousnesshavebeenobservedwithdocetaxeladministration.These

reactionssometimesappearduringtheinfusionofthemedicinalproduct.

Eyedisorders

Veryrarecasesoftransientvisualdisturbances(flashes,flashinglights,scotomata)typicallyoccurringduringinfusion

ofthemedicinalproductandinassociationwithhypersensitivityreactionshavebeenreported.Thesewerereversible

upondiscontinuationoftheinfusion.Casesoflacrimationwithorwithoutconjunctivitis,ascasesoflacrimalduct

obstructionresultinginexcessivetearinghavebeenrarelyreported.

Earandlabyrinthdisorders

Rarecasesofototoxicity,hearingimpairedand/orhearinglosshavebeenreported.

Respiratory,thoracicandmediastinaldisorders

Acuterespiratorydistresssyndrome,interstitialpneumoniaandpulmonaryfibrosishaverarelybeenreported.Rare

casesofradiationpneumonitishavebeenreportedinpatientsreceivingconcomitantradiotherapy.

Gastrointestinaldisorders

Rareoccurrencesofdehydrationasaconsequenceofgastrointestinalevents,gastrointestinalperforation,colitis

ischaemic,colitisandneutropenicenterocolitishavebeenreported.Rarecasesofileusandintestinalobstructionhave

beenreported.

Skinandsubcutaneoustissuedisorders

Veryrarecasesofcutaneouslupuserythematosusandbullouseruptionssuchaserythemamultiforme,Stevens-Johnson

syndrome,toxicepidermalnecrolysis,havebeenreportedwithdocetaxel.Insomecasesconcomitantfactorsmayhave

contributedtothedevelopmentoftheseeffects.Sclerodermal-likechangesusuallyprecededbyperipherallymphedema

havebeenreportedwithdocetaxel.

Neoplasmsbenign,malignantandunspecified(inclcystsandpolyps)

Veryrarecasesofacutemyeloidleukaemiaandmyelodysplasticsyndromehavebeenreportedinassociationwith

docetaxelwhenusedincombinationwithotherchemotherapyagentsand/orradiotherapy.

Vasculardisorders

Venousthromboemboliceventshaverarelybeenreported.

Generaldisordersandadministrationsiteconditions

Radiationrecallphenomenahaverarelybeenreported.Fluidretentionhasnotbeenaccompaniedbyacuteepisodesof

oliguriaorhypotension.Dehydrationandpulmonaryoedemahaverarelybeenreported.

Immunesystemdisorders

Somecasesofanaphylacticshock,sometimesfatal,havebeenreported.

Hepatobiliarydisorders

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4.9Overdose

Therewereafewreportsofoverdose.Thereisnoknownantidotefordocetaxeloverdose.Incaseofoverdose,the

patientshouldbekeptinaspecialisedunitandvitalfunctionscloselymonitored.Incasesofoverdose,exacerbationof

adverseeventsmaybeexpected.Theprimaryanticipatedcomplicationsofoverdosewouldconsistofbonemarrow

suppression,peripheralneurotoxicityandmucositis.PatientsshouldreceivetherapeuticG-CSFassoonaspossible

afterdiscoveryofoverdose.Otherappropriatesymptomaticmeasuresshouldbetaken,asneeded.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Taxanes,ATCCode:L01CD02

Preclinicaldata

Docetaxelisanantineoplasticagentwhichactsbypromotingtheassemblyoftubulinintostablemicrotubulesand

inhibitstheirdisassemblywhichleadstoamarkeddecreaseoffreetubulin.Thebindingofdocetaxeltomicrotubules

doesnotalterthenumberofprotofilaments.

Docetaxelhasbeenshowninvitrotodisruptthemicrotubularnetworkincellswhichisessentialforvitalmitoticand

interphasecellularfunctions.

Docetaxelwasfoundtobecytotoxicinvitroagainstvariousmurineandhumantumourcelllinesandagainstfreshly

excisedhumantumourcellsinclonogenicassays.Docetaxelachieveshighintracellularconcentrationswithalongcell

residencetime.Inaddition,docetaxelwasfoundtobeactiveonsomebutnotallcelllinesoverexpressingthep-

glycoproteinwhichisencodedbythemultidrugresistancegene.Invivo,docetaxelisscheduleindependentandhasa

broadspectrumofexperimentalantitumouractivityagainstadvancedmurineandhumangraftedtumours.

Clinicaldata

Breastcancer

DOCETAXELincombinationwithdoxorubicinandcyclophosphamide:adjuvanttherapy

Patientswithoperablenode-positivebreastcancer

Datafromamulticenteropenlabelrandomizedtrialsupporttheuseofdocetaxelfortheadjuvanttreatmentofpatients

withoperablenode-positivebreastcancerandKPS 80%,between18and70yearsofage.Afterstratification

accordingtothenumberofpositivelymphnodes(1-3,4+),1491patientswererandomizedtoreceiveeitherdocetaxel

75mg/m 2

administered1-hourafterdoxorubicin50mg/m 2

andcyclophosphamide500mg/m 2

(TACarm),or

doxorubicin50mg/m 2

followedbyfluorouracil500mg/m 2

andcyclosphosphamide500mg/m 2

(FACarm).Both

regimenswereadministeredonceevery3weeksfor6cycles.Docetaxelwasadministeredasa1-hourinfusion,all

othermedicinalproductsweregivenasintravenousbolusondayone.G-CSFwasadministeredassecondary

prophylaxistopatientswhoexperiencedcomplicatedneutropenia(febrileneutropenia,prolongedneutropenia,or

infection).PatientsontheTACarmreceivedantibioticprophylaxiswithciprofloxacin500mgorallytwicedailyfor10

daysstartingonday5ofeachcycle,orequivalent.Inbotharms,afterthelastcycleofchemotherapy,patientswith

positiveestrogenand/orprogesteronereceptorsreceivedtamoxifen20mgdailyforupto5years.Adjuvantradiation

therapywasprescribedaccordingtoguidelinesinplaceatparticipatinginstitutionsandwasgivento69%ofpatients

whoreceivedTACand72%ofpatientswhoreceivedFAC.Aninterimanalysiswasperformedwithamedianfollow

upof55months.Significantlylongerdisease-freesurvivalfortheTACarmcomparedtotheFACarmwas

demonstrated.Incidenceofrelapsesat5yearswasreducedinpatientsreceivingTACcomparedtothosewhoreceived

FAC(25%versus32%,respectively)i.e.anabsoluteriskreductionby7%(p=0.001).Overallsurvivalat5yearswas

alsosignificantlyincreasedwithTACcomparedtoFAC(87%versus81%,respectively)i.e.anabsolutereductionof

theriskofdeathby6%(p=0.008).TAC-treatedpatientsubsetsaccordingtoprospectivelydefinedmajorprognostic

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*ahazardratiooflessthan1indicatesthatTACisassociatedwithalongerdisease-freesurvivalandoverallsurvival

comparedtoFAC

ThebeneficialeffectofTACwasnotproveninpatientswith4andmorepositivenodes(37%ofthepopulation)atthe

interimanalysisstage.Theeffectappearstobelesspronouncedthaninpatientswith1-3positivenodes.The

benefit/riskratiowasnotdefinedfullyinpatientswith4andmorepositivenodesatthisanalysisstage.

Patientswithoperablenode-negativebreastcancereligibletoreceivechemotherapy

Datafromamulticenteropenlabelrandomizedtrialsupporttheuseofdocetaxelfortheadjuvanttreatmentofpatients

withoperablenode-negativebreastcancereligibletoreceivechemotherapy.1060patientswererandomizedtoreceive

eitherdocetaxel75mg/m2administered1-hourafterdoxorubicin50mg/m2andcyclophosphamide500mg/m2(539

patientsinTACarm),ordoxorubicin50mg/m2followedbyfluorouracil500mg/m2andcyclosphosphamide500

mg/m2(521patientsinFACarm),asadjuvanttreatmentofoperablenode-negativebreastcancerpatientswithhigh

riskofrelapseaccordingto1998St.Gallencriteria(tumoursize>2cmand/ornegativeERandPRand/orhigh

histological/nucleargrade(grade2to3)and/orage<35years).).Bothregimenswereadministeredonceevery3weeks

for6cycles.docetaxelwasadministeredasa1-hourinfusion,allotherdrugsweregivenintraveinouslyonday1every

threeweeks.PrimaryprophylacticG-CSFwasmademandatoryinTACarmafter230patientswererandomized.The

incidenceofGrade4neutropenia,febrileneutropeniaandneutropenicinfectionwasdecreasedinpatientswhoreceived

primaryG-CSFprophylaxis(seesection4.8).Inbotharms,afterthelastcycleofchemotherapy,patientswithER+

and/orPgR+tumoursreceivedtamoxifen20mgonceadayforupto5years.Adjuvantradiationtherapywas

administeredaccordingtoguidelinesinplaceatparticipatinginstitutionsandwasgivento57.3%ofpatientswho

receivedTACand51.2%ofpatientswhoreceivedFAC.

Mediandurationoffollow-upwas77months.Significantlylongerdisease-freesurvivalfortheTACarmcomparedto

theFACarmwasdemonstrated.TAC-treatedpatientshada32%reductionintheriskofrelapsecomparedtothose

treatedwithFAC(hazardratio=0.68,95%CI(0.49-0.93),p=0.01).Overallsurvival(OS)wasalsolongerintheTAC

armwithTAC-treatedpatientshavinga24%reductionintheriskofdeathcomparedtoFAC(hazard

ratio=0.76,95%CI(0.46-1.26,p=0.29).However,thedistributionofOSwasnotsignificantlydifferentbetweenthe

2groups.

TAC-treatedpatientsubsetsaccordingtoprospectivelydefinedmajorprognosticfactorswereanalyzed(seetable

below):

SubsetAnalyses-AdjuvantTherapyinPatientswithNode-negativeBreastCancerStudy

DiseaseFreeSurvival OverallSurvival

Patient

subset Number

of

patients Hazard

ratio* 95%CI p= Hazard

ratio* 95%CI p=

Noof

positive

nodes

Overall 745 0.72 0.59-0.88 0.001 0.70 0.53-0.91 0.008

0.61 0.46-0.82 0.0009 0.45 0.29-0.70 0.0002

0.83 0.63-1.08 0.17 0.94 0.66-1.33 0.72

Patientsubset Numberofpatientsin

TACgroup DieaseFreeSurvival

Hazardratio* 95%CI

Overall 539 0.68 0.49-0.93

Agecategory1

<50years

50years 260

0.67

0.67 0.43-1.05

0.43-1.05

Agecategory2

<35years

35years 42

0.31

0.73 0.11-0.89

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*ahazardratio(TAC/FAC)oflessthan1indicatesthatTACisassociatedwithalongerdiseasefreesurvival

comparedtoFAC.

Exploratorysubgroupanalysesfordisease-freesurvivalforpatientswhomeetthe2009St.Gallenchemotherapy

criteria–(ITTpopulation)wereperformedandpresentedherebelow

TAC=docetaxel,doxorubicinandcyclophosphamide

FAC=5-fluorouracil,doxorubicinandcyclophospamide

CI=confidenceinterval;ER=estrogenreceptor

PR=progesteronereceptor

ER/PR-negativeorGrade3ortumorsize>5cm

TheestimatedhazardratiowasusingCoxproportionalhazardmodelwithtreatmentgroupasthefactor.

DOCETAXELassingleagent

TworandomisedphaseIIIcomparativestudies,involvingatotalof326alkylatingor392anthracyclinefailure

metastaticbreastcancerpatients,havebeenperformedwithdocetaxelattherecommendeddoseandregimenof100

mg/m²every3weeks.

Inalkylating-failurepatients,docetaxelwascomparedtodoxorubicin(75mg/m²every3weeks).Withoutaffecting

overallsurvivaltime(docetaxel15monthsvs.doxorubicin14months,p=0.38)ortimetoprogression(docetaxel27

weeksvs.doxorubicin23weeks,p=0.54),docetaxelincreasedresponserate(52%vs.37%,p=0.01)andshortened

timetoresponse(12weeksvs.23weeks,p=0.007).Threedocetaxelpatients(2%)discontinuedthetreatmentdueto

fluidretention,whereas15doxorubicinpatients(9%)discontinuedduetocardiactoxicity(threecasesoffatal

congestiveheartfailure).

Inanthracycline-failurepatients,docetaxelwascomparedtothecombinationofmitomycinCandvinblastine(12

mg/m²every6weeksand6mg/m²every3weeks).Docetaxelincreasedresponserate(33%vs.12%,p<0.0001),

prolongedtimetoprogression(19weeksvs.11weeks,p=0.0004)andprolongedoverallsurvival(11monthsvs.9

months,p=0.01).

DuringthesetwophaseIIIstudies,thesafetyprofileofdocetaxelwasconsistentwiththesafetyprofileobservedin

Hormonalreceptor

status

Negative

Positive 195

0.62 0.45-1.1

0.4-0.97

Tumoursize

2cm

>2cm 285

0.69

0.68 0.43-1.1

0.45-1.04

Histologicalgrade

Grade1(includesgrade

notassessed)

Grade2

Grade3 64

0.79

0.77

0.59 0.24-2.6

0.46-1.3

0.39-0.9

MenopausalstatusPre-

Menopausal

Post-Menopausal 285

0.64

0.72 0.40-1

0.47-1.12

Subgroups TAC

(n=539) TAC

(n=521) Hazardratio

(TAC/FAC)

(95%CI) p-value

Meetingrelative

indicationfor

chemotherapy a

18/214

(8.4%) 26/227

(11.5%) 0.796(0.434-1.459) 0.4593

48/325

(14.8%) 69/294

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Anopen-label,multicenter,randomizedphaseIIIstudywasconductedtocomparedocetaxelmonotherapyand

paclitaxelinthetreatmentofadvancedbreastcancerinpatientswhoseprevioustherapyshouldhaveincludedan

anthracycline.Atotalof449patientswererandomizedtoreceiveeitherdocetaxelmonotherapy100mg/m²asa1hour

infusionorpaclitaxel175mg/m²asa3hourinfusion.Bothregimenswereadministeredevery3weeks.

Withoutaffectingtheprimaryendpoint,overallresponserate(32%vs25%,p=0.10),docetaxelprolongedmedian

timetoprogression(24.6weeksvs15.6weeks;p<0.01)andmediansurvival(15.3monthsvs12.7months;p=0.03).

Moregrade3/4adverseeventswereobservedfordocetaxelmonotherapy(55.4%)comparedtopaclitaxel(23.0%).

DOCETAXELincombinationwithdoxorubicin

OnelargerandomizedphaseIIIstudy,involving429previouslyuntreatedpatientswithmetastaticdisease,hasbeen

performedwithdoxorubicin(50mg/m²)incombinationwithdocetaxel(75mg/m²)(ATarm)versusdoxorubicin(60

mg/m²)incombinationwithcyclophosphamide(600mg/m²)(ACarm).Bothregimenswereadministeredonday1

every3weeks.

Timetoprogression(TTP)wassignificantlylongerintheATarmversusACarm,p=0.0138.ThemedianTTPwas

37.3weeks(95%CI:33.4-42.1)inATarmand31.9weeks(95%CI:27.4-36.0)inACarm.

Overallresponserate(ORR)wassignificantlyhigherintheATarmversusACarm,p=0.009.TheORRwas59.3%

(95%CI:52.8-65.9)inATarmversus46.5%(95%CI:39.8-53.2)inACarm.

Inthistrial,ATarmshowedahigherincidenceofsevereneutropenia(90%versus68.6%),febrileneutropenia(33.3%

versus10%),infection(8%versus2.4%),diarrhea(7.5%versus1.4%),asthenia(8.5%versus2.4%),andpain(2.8%

versus0%)thanACarm.Ontheotherhand,ACarmshowedahigherincidenceofsevereanemia(15.8%versus8.5%)

thanATarm,and,inaddition,ahigherincidenceofseverecardiactoxicity:congestiveheartfailure(3.8%versus

2.8%),absoluteLVEFdecrease 20%(13.1%versus6.1%),absoluteLVEFdecrease 30%(6.2%versus1.1%).

Toxicdeathsoccurredin1patientintheATarm(congestiveheartfailure)andin4patientsintheACarm(1dueto

septicshockand3duetocongestiveheartfailure).

Inbotharms,qualityoflifemeasuredbytheEORTCquestionnairewascomparableandstableduringtreatmentand

follow-up.

DOCETAXELincombinationwithtrastuzumab

Docetaxelincombinationwithtrastuzumabwasstudiedforthetreatmentofpatientswithmetastaticbreastcancer

whosetumorsoverexpressHER2,andwhopreviouslyhadnotreceivedchemotherapyformetastaticdisease.

Onehundredeightysixpatientswererandomizedtoreceivedocetaxel(100mg/m 2

)withorwithouttrastuzumab;60%

ofpatientsreceivedprioranthracycline-basedadjuvantchemotherapy.Docetaxelplustrastuzumabwasefficaciousin

patientswhetherornottheyhadreceivedprioradjuvantanthracyclines.ThemaintestmethodusedtodetermineHER2

positivityinthispivotaltrialwasimmunohistochemistry(IHC).Aminorityofpatientsweretestedusingfluorescence

in-situhybridization(FISH).Inthistrial,87%ofpatientshaddiseasethatwasIHC3+,and95%ofpatientsenteredhad

diseasethatwasIHC3+and/orFISHpositive.Efficacyresultsaresummarizedinthefollowingtable:

TTP=timetoprogression;“ne”indicatesthatitcouldnotbeestimatedoritwasnotyetreached.

Fullanalysisset(intent-to-treat)

Parameter

Docetaxelplustrastuzumab 1

n=92 Docetaxel 1

n=94

Responserate

(95%CI) 61%

(50-71) 34%

(25-45)

MedianDurationofresponse

(months)

(95%CI) 11.4

(9.2-15.0) 5.1

(4.4-6.2)

MedianTTP(months)

(95%CI) 10.6

(7.6-12.9) 5.7

(5.0-6.5)

MedianSurvival(months)

(95%CI) 30.5 2

(26.8-ne) 22.1 2

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DOCETAXELincombinationwithcapecitabine

Datafromonemulticenter,randomised,controlledphaseIIIclinicaltrialsupporttheuseofdocetaxelincombination

withcapecitabinefortreatmentofpatientswithlocallyadvancedormetastaticbreastcancerafterfailureofcytotoxic

chemotherapy,includingananthracycline.Inthistrial,255patientswererandomisedtotreatmentwithdocetaxel(75

mg/m 2

asa1hourintravenousinfusionevery3weeks)andcapecitabine(1250mg/m 2

twicedailyfor2weeks

followedby1-weekrestperiod).256patientswererandomisedtotreatmentwithdocetaxelalone(100mg/m 2

asa1

hourintravenousinfusionevery3weeks).Survivalwassuperiorinthedocetaxel+capecitabinecombinationarm(p=

0.0126).Mediansurvivalwas442days(docetaxel+capecitabine)vs.352days(docetaxelalone).Theoverallobjective

responseratesintheall-randomisedpopulation(investigatorassessment)were41.6%(docetaxel+capecitabine)vs.

29.7%(docetaxelalone);p=0.0058.Timetoprogressivediseasewassuperiorinthedocetaxel+capecitabine

combinationarm(p<0.0001).Themediantimetoprogressionwas186days(docetaxel+capecitabine)vs.128days

(docetaxelalone).

Non-smallcelllungcancer

Patientspreviouslytreatedwithchemotherapywithorwithoutradiotherapy

InaphaseIIIstudy,inpreviouslytreatedpatients,timetoprogression(12.3weeksversus7weeks)andoverallsurvival

weresignificantlylongerfordocetaxelat75mg/m²comparedtoBestSupportiveCare.The1-yearsurvivalratewas

alsosignificantlylongerindocetaxel(40%)versusBSC(16%).Therewaslessuseofmorphinicanalgesic(p<0.01),

non-morphinicanalgesics(p<0.01),otherdisease-relatedmedications(p=0.06)andradiotherapy(p<0.01)in

patientstreatedwithdocetaxelat75mg/m²comparedtothosewithBSC.

Theoverallresponseratewas6.8%intheevaluablepatients,andthemediandurationofresponsewas26.1weeks.

DOCETAXELincombinationwithplatinumagentsinchemotherapy-naïvepatients

InaphaseIIItrial,1218patientswithunresectablestageIIIBorIVNSCLC,withKPSof70%orgreater,andwhodid

notreceivepreviouschemotherapyforthiscondition,wererandomisedtoeitherdocetaxel(T)75mg/m 2

asa1hour

infusionimmediatelyfollowedbycisplatin(Cis)75mg/m 2

over30-60minutesevery3weeks,docetaxel75mg/m 2

asa

1hourinfusionincombinationwithcarboplatin(AUC6mg/ml.min)over30-60minutesevery3weeks,orvinorelbine

(V)25mg/m 2

administeredover6-10minutesondays1,8,15,22followedbycisplatin100mg/m 2

administeredon

day1ofcyclesrepeatedevery4weeks.

Survivaldata,mediantimetoprogressionandresponseratesfortwoarmsofthestudyareillustratedinthefollowing

table:

*:Correctedformultiplecomparisonsandadjustedforstratificationfactors(stageofdiseaseandregionoftreatment),

basedonevaluablepatientpopulation.

Secondaryend-pointsincludedchangeofpain,globalratingofqualityoflifebyEuroQoL-5D,LungCancerSymptom

Scale,andchangesinKarnosfkyperformancestatus.Resultsontheseend-pointsweresupportiveoftheprimaryend-

TCis

n=408 VCis

n=404 StatisticalAnalysis

OverallSurvival

(Primaryend-point):

MedianSurvival(months)

1-yearSurvival(%)

2-yearSurvival(%) 11.3

10.1

HazardRatio:1.122

[97.2%CI:0.937;1.342]*

Treatmentdifference:5.4%

[95%CI:-1.1;12.0]

Treatmentdifference:6.2%

[95%CI:0.2;12.3]

MedianTimetoProgression

(weeks): 22.0 23.0 HazardRatio:1.032

[95%CI:0.876;1.216]

OverallResponseRate(%): 31.6 24.5 Treatmentdifference:7.1%

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Fordocetaxel/carboplatincombination,neitherequivalentnornon-inferiorefficacycouldbeprovencomparedtothe

referencetreatmentcombinationVCis.

Prostatecancer

Thesafetyandefficacyofdocetaxelincombinationwithprednisoneorprednisoloneinpatientswithhormone

refractorymetastaticprostatecancerwereevaluatedinarandomizedmulticenterphaseIIItrial.Atotalof1006patients

withKPS 60wererandomizedtothefollowingtreatmentgroups:

Docetaxel75mg/m 2

every3weeksfor10cycles.

Docetaxel30mg/m 2

administeredweeklyforthefirst5weeksina6weekcyclefor5cycles.

Mitoxantrone12mg/m 2

every3weeksfor10cycles.

All3regimenswereadministeredincombinationwithprednisoneorprednisolone5mgtwicedaily,continuously.

Patientswhoreceiveddocetaxeleverythreeweeksdemonstratedsignificantlylongeroverallsurvivalcomparedto

thosetreatedwithmitoxantrone.Theincreaseinsurvivalseeninthedocetaxelweeklyarmwasnotstatistically

significantcomparedtothemitoxantronecontrolarm.Efficacyendpointsforthedocetaxelarmsversusthecontrolarm

aresummarizedinthefollowingtable:

Stratifiedlogranktest

Thresholdforstatisticalsignificance=0.0175

PSA:Prostate-SpecificAntigen

Giventhefactthatdocetaxeleveryweekpresentedaslightlybettersafetyprofilethandocetaxelevery3weeks,itis

possiblethatcertainpatientsmaybenefitfromdocetaxeleveryweek.

NostatisticaldifferenceswereobservedbetweentreatmentgroupsforGlobalQualityofLife.

Gastricadenocarcinoma

Amulticenter,open-label,randomizedtrial,wasconductedtoevaluatethesafetyandefficacyofdocetaxelforthe

treatmentofpatientswithmetastaticgastricadenocarcinoma,includingadenocarcinomaofthegastroesophageal

Endpoint Docetaxelevery

3weeks Docetaxelevery

week Mitoxantrone

every3weeks

Numberofpatients

Mediansurvival(months)

95%CI

Hazardratio

95%CI

p-value †* 335

18.9

(17.0-21.2)

0.761

(0.619-0.936)

0.0094 334

17.4

(15.7-19.0)

0.912

(0.747-1.113)

0.3624 337

16.5

(14.4-18.6)

Numberofpatients

PSA**responserate(%)

95%CI

p-value * 291

45.4

(39.5-51.3)

0.0005 282

47.9

(41.9-53.9)

<0.0001 300

31.7

(26.4-37.3)

Numberofpatients

Painresponserate(%)

95%CI

p-value * 153

34.6

(27.1-42.7)

0.0107 154

31.2

(24.0-39.1)

0.0798 157

21.7

(15.5-28.9)

Numberofpatients

Tumorresponserate(%)

95%CI

p-value * 141

12.1

(7.2-18.6)

0.1112 134

(4.2-14.2)

0.5853 137

(3.0-12.1)

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Atotalof445patientswithKPS>70weretreatedwitheitherdocetaxel(T)(75mg/m 2

onday1)incombinationwith

cisplatin(C)(75mg/m 2

onday1)and5-fluorouracil(F)(750mg/m 2

perdayfor5days)orcisplatin(100mg/m 2

day1)and5-fluorouracil(1000mg/m 2

perdayfor5days).Thelengthofatreatmentcyclewas3weeksfortheTCF

armand4weeksfortheCFarm.Themediannumberofcyclesadministeredperpatientwas6(witharangeof1-16)

fortheTCFarmcomparedto4(witharangeof1-12)fortheCFarm.Timetoprogression(TTP)wastheprimary

endpoint.Theriskreductionofprogressionwas32.1%andwasassociatedwithasignificantlylongerTTP(p=0.0004)

infavoroftheTCFarm.Overallsurvivalwasalsosignificantlylonger(p=0.0201)infavoroftheTCFarmwitharisk

reductionofmortalityof22.7%.Efficacyresultsaresummarizedinthefollowingtable:

Efficacyofdocetaxelinthetreatmentofpatientswithgastricadenocarcinoma

*Unstratifiedlogranktest

Subgroupanalysesacrossage,genderandraceconsistentlyfavoredtheTCFarmcomparedtotheCFarm.

Asurvivalupdateanalysisconductedwithamedianfollow-uptimeof41.6monthsnolongershowedastatistically

significantdifferencealthoughalwaysinfavouroftheTCFregimenandshowedthatthebenefitofTCFoverCFis

clearlyobservedbetween18and30monthsoffollowup.

Overall,qualityoflife(QoL)andclinicalbenefitresultsconsistentlyindicatedimprovementinfavoroftheTCFarm.

PatientstreatedwithTCFhadalongertimeto5%definitivedeteriorationofglobalhealthstatusontheQLQ-C30

questionnaire(p=0.0121)andalongertimetodefinitiveworseningofKarnofskyperformancestatus(p=0.0088)

comparedtopatientstreatedwithCF.

Headandneckcancer

Inductionchemotherapyfollowedbyradiotherapy(TAX323)

Thesafetyandefficacyofdocetaxelintheinductiontreatmentofpatientswithsquamouscellcarcinomaofthehead

andneck(SCCHN)wasevaluatedinaphaseIII,multicenter,open-label,randomizedtrial(TAX323).Inthisstudy,358

patientswithinoperablelocallyadvancedSCCHN,andWHOperfomancestatus0or1,wererandomizedtooneoftwo

treatmentarms.Patientsonthedocetaxelarmreceiveddocetaxel(T)75mg/m 2

followedbycisplatin(P)75mg/m 2

followedby5-fluorouracil(F)750mg/m 2

perdayasacontinuousinfusionfor5days.Thisregimenwasadministered

everythreeweeksfor4cyclesincaseatleastaminorresponse(25%reductioninbidimensionallymeasuredtumour

size)wasobservedafter2cycles.

Attheendofchemotherapy,withaminimalintervalof4weeksandamaximalintervalof7weeks,patientswhose

diseasedidnotprogressreceivedradiotherapy(RT)accordingtoinstitutionalguidelinesfor7weeks(TPF/RT).

Patientsonthecomparatorarmreceivedcisplatin(P)100mg/m 2

followedby5-fluorouracil(F)1000mg/m 2

perday

for5days.Thisregimenwasadministeredeverythreeweeksfor4cyclesincaseatleastaminorresponse(25%

Endpoint TCF

n=221 CF

n=224

MedianTTP(months)

(95%CI)

Hazardratio

(95%CI)

*p-value 5.6

(4.86-5.91) 3.7

(3.45-4.47)

1.473

(1.189-1.825)

0.0004

Mediansurvival(months)

(95%CI)

2-yearestimate(%)

Hazardratio

(95%CI)

*p-value 9.2

(8.38-10.58)

18.4 8.6

(7.16-9.46)

1.293

(1.041-1.606)

0.0201

OverallResponseRate(CR+PR)(%)

p-value 36.7 25.4

0.0106

ProgressiveDiseaseasBestOverall

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Attheendofchemotherapy,withaminimalintervalof4weeksandamaximalintervalof7weeks,patientswhose

diseasedidnotprogressreceivedradiotherapy(RT)accordingtoinstitutionalguidelinesfor7weeks(PF/RT).

Locoregionaltherapywithradiationwasdeliveredeitherwithaconventionalfraction(1.8Gy-2.0Gyonceaday,5

daysperweekforatotaldoseof66to70Gy),oraccelerated/hyperfractionatedregimensofradiationtherapy(twicea

day,withaminimuminterfractionintervalof6hours,5daysperweek).Atotalof70Gywasrecommendedfor

acceleratedregimensand74Gyforhyperfractionatedschemes.Surgicalresectionwasallowedfollowing

chemotherapy,beforeorafterradiotherapy.PatientsontheTPFarmreceivedantibioticprophylaxiswithciprofloxacin

500mgorallytwicedailyfor10daysstartingonday5ofeachcycle,orequivalent.Theprimaryendpointinthisstudy,

progression-freesurvival(PFS),wassignificantlylongerintheTPFarmcomparedtothePFarm,p=0.0042(median

PFS:11.4vs.8.3monthsrespectively)withanoverallmedianfollowuptimeof33.7months.Medianoverallsurvival

wasalsosignificantlylongerinfavoroftheTPFarmcomparedtothePFarm(medianOS:18.6vs.14.5months

respectively)witha28%riskreductionofmortality,p=0.0128.Efficacyresultsarepresentedinthetablebelow:

Efficacyofdocetaxelintheinductiontreatmentofpatients

withinoperablelocallyadvancedSCCHN(Intent-to-TreatAnalysis)

AHazardratiooflessthan1favorsdocetaxel+cisplatin+5-FU

*Coxmodel(adjustmentforPrimarytumorsite,TandNclinicalstagesandPSWHO)

**Logranktest

***Chi-squaretest

Qualityoflifeparameters

PatientstreatedwithTPFexperiencedsignificantlylessdeteriorationoftheirGlobalhealthscorecomparedtothose

treatedwithPF(p=0.01,usingtheEORTCQLQ-C30scale).

Clinicalbenefitparameters

Theperformancestatusscale,forheadandneck(PSS-HN)subscalesdesignedtomeasureunderstandabilityofspeech,

abilitytoeatinpublic,andnormalcyofdiet,wassignificantlyinfavorofTPFascomparedtoPF.

Endpoint Docetaxel+

Cis+5-FU

n=177 Cis+5-FU

n=181

Medianprogressionfreesurvival(months)

(95%CI)

AdjustedHazardratio

(95%CI)

*p-value 11.4

(10.1-14.0) 8.3

(7.4-9.1)

0.70

(0.55-0.89)

0.0042

Mediansurvival(months)

(95%CI)

Hazardratio

(95%CI)

**p-value 18.6

(15.7-24.0) 14.5

(11.6-18.7)

0.72

(0.56-0.93)

0.0128

Bestoverallresponsetochemotherapy(%)

(95%CI)

***p-value 67.8

(60.4-74.6) 53.6

(46.0-61.0)

0.006

Bestoverallresponsetostudytreatment

[chemotherapy+/-radiotherapy](%)

(95%CI)

***p-value 72.3

(65.1-78.8) 58.6

(51.0-65.8)

0.006

Mediandurationofresponsetochemotherapy+

radiotherapy(months)

(95%CI)

Hazardratio

(95%CI)

**p-value n=128

15.7

(13.4-24.6) n=106

11.7

(10.2-17.4)

0.72

(0.52-0.99)

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Painintensityscoreimprovedduringtreatmentinbothgroupsindicatingadequatepainmanagement.

Inductionchemotherapyfollowedbychemoradiotherapy(TAX324)

Thesafetyandefficacyofdocetaxelintheinductiontreatmentofpatientswithlocallyadvancedsquamouscell

carcinomaoftheheadandneck(SCCHN)wasevaluatedinarandomized,multicenteropen-label,phaseIII,trial

(TAX324).Inthisstudy,501patients,withlocallyadvancedSCCHN,andaWHOperformancestatusof0or1,were

randomizedtooneoftwoarms.Thestudypopulationcomprisedpatientswithtechnicallyunresectabledisease,patients

withlowprobabilityofsurgicalcureandpatientsaimingatorganpreservation.Theefficacyandsafetyevaluation

solelyaddressedsurvivalendpointsandthesuccessoforganpreservationwasnotformallyaddressed.Patientsonthe

docetaxelarmreceiveddocetaxel(T)75mg/m²byintravenousinfusiononday1followedbycisplatin(P)100mg/m²

administeredasa30-minutetothree-hourintravenousinfusion,followedbythecontinuousintravenousinfusionof5-

fluorouracil(F)1000mg/m²/dayfromday1today4.Thecycleswererepeatedevery3weeksfor3cycles.Allpatients

whodidnothaveprogressivediseaseweretoreceivechemoradiotherapy(CRT)asperprotocol(TPF/CRT).Patients

onthecomparatorarmreceivedcisplatin(P)100mg/m²asa30-minutetothree-hourintravenousinfusiononday1

followedbythecontinuousintravenousinfusionof5-fluorouracil(F)1000mg/m²/dayfromday1today5.Thecycles

wererepeatedevery3weeksfor3cycles.AllpatientswhodidnothaveprogressivediseaseweretoreceiveCRTasper

protocol(PF/CRT).

Patientsinbothtreatmentarmsweretoreceive7weeksofCRTfollowinginductionchemotherapywithaminimum

intervalof3weeksandnolaterthan8weeksafterstartofthelastcycle(day22today56oflastcycle).During

radiotherapy,carboplatin(AUC1.5)wasgivenweeklyasaone-hourintravenousinfusionforamaximumof7doses.

Radiationwasdeliveredwithmegavoltageequipmentusingoncedailyfractionation(2Gyperday,5daysperweekfor

7weeks,foratotaldoseof70-72Gy).Surgeryontheprimarysiteofdiseaseand/orneckcouldbeconsideredat

anytimefollowingcompletionofCRT.Allpatientsonthedocetaxel-containingarmofthestudyreceivedprophylactic

antibiotics.

Theprimaryefficacyendpointinthisstudy,overallsurvival(OS)wassignificantlylonger(log-ranktest,p=0.0058)

withthedocetaxel-containingregimencomparedtoPF(medianOS:70.6versus30.1monthsrespectively),witha30%

riskreductioninmortalitycomparedtoPF(hazardratio(HR)=0.70,95%confidenceinterval(CI)=0.54-0.90)with

anoverallmedianfollowuptimeof41.9months.Thesecondaryendpoint,PFS,demonstrateda29%riskreductionof

progressionordeathanda22monthimprovementinmedianPFS(35.5monthsforTPFand13.1forPF).Thiswasalso

statisticallysignificantwithanHRof0.71;95%CI0.56-0.90;log-ranktestp=0.004.Efficacyresultsarepresentedin

thetablebelow:

Efficacyofdocetaxelintheinductiontreatmentofpatients

withlocallyadvancedSCCHN(Intent-to-TreatAnalysis)

Endpoint Docetaxel+Cis+5-FU

n=255 Cis+5-FU

n=246

Medianoverallsurvival(months)

(95%CI)

Hazardratio:

(95%CI)

*p-value 70.6

(49.0-NA) 30.1

(20.9-51.5)

0.70

(0.54-0.90)

0.0058

MedianPFS(months)

(95%CI)

Hazardratio:

(95%CI)

**p-value 35.5

(19.3-NA) 13.1

(10.6-20.2)

0.71

(0.56-0.90)

0.004

Bestoverallresponse(CR+PR)to

chemotherapy(%)

(95%CI)

***p-value 71.8

(65.8-77.2) 64.2

(57.9-70.2)

0.070

Bestoverallresponse(CR+PR)to

studytreatment[chemotherapy+/-

chemoradiotherapy](%) 76.5

(70.8-81.5) 71.5

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AHazardratiooflessthan1favorsdocetaxel+cisplatin+fluorouracil

*un-adjustedlog-ranktest

**un-adjustedlog-ranktest,notadjustedformultiplecomparisons

***Chisquaretest,notadjustedformultiplecomparisons

NA-notapplicable

5.2Pharmacokineticproperties

Thepharmacokineticsofdocetaxelhavebeenevaluatedincancerpatientsafteradministrationof20-115mg/m 2

phaseIstudies.

Apopulationpharmacokineticanalysishasbeenperformedwithdocetaxelin577patients.Pharmacokineticparameters

estimatedbythemodelwereveryclosetothoseestimatedfromphaseIstudies.Thepharmacokineticsofdocetaxel

werenotalteredbytheageorsexofthepatient.

Absorption

Followingtheadministrationofa100mg/m 2

dosegivenasaone-hourinfusionameanpeakplasmalevelof3.7µg/ml

wasobtainedwithacorrespondingAUCof4.6h.µg/ml.

Distribution

Thekineticprofileofdocetaxelisdoseindependentandconsistentwithathree-compartmentpharmacokineticmodel

withhalflivesforthe, and phasesof4min,36minand11.1h,respectively.Thelatephaseisdue,inpart,toa

relativelysloweffluxofdocetaxelfromtheperipheralcompartment.

Docetaxelismorethan96%boundtoplasmaproteins.

Elimination

Meanvaluesfortotalbodyclearanceandsteady-statevolumeofdistributionwere21l/h/m 2

and113l,respectively.

Interindividualvariationintotalbodyclearancewasapproximately50%

Astudyof 14

C-docetaxelhasbeenconductedinthreecancerpatients.Docetaxelwaseliminatedinboththeurineand

faecesfollowingcytochromeP450-mediatedoxidativemetabolismofthetert-butylestergroup,withinsevendays,the

urinaryandfaecalexcretionaccountedforabout6%and75%oftheadministeredradioactivity,respectively.About

80%oftheradioactivityrecoveredinfaecesisexcretedduringthefirst48hoursasonemajorinactivemetaboliteand3

minorinactivemetabolitesandverylowamountsofunchangedmedicinalproduct.

Inasmallnumberofpatients(n=23)withclinicalchemistrydatasuggestiveofmildtomoderateliver1.5timesthe

ULNassociatedwithalkalinefunctionimpairment(ALT,AST phosphatase2.5timestheULN),totalclearancewas

loweredby27%onaverage(seesection4.2).Docetaxelclearancewasnotmodifiedinpatientswithmildtomoderate

fluidretentionandtherearenodataavailableinpatientswithseverefluidretention.

Pharmacokineticinteractionswithothersubstances

Whenusedincombination,docetaxeldoesnotinfluencetheclearanceofdoxorubicinandtheplasmalevelsof

doxorubicinol(adoxorubicinmetabolite).Thepharmacokineticsofdocetaxel,doxorubicinandcyclophosphamide

werenotinfluencedbytheircoadministration.

PhaseIstudyevaluatingtheeffectofcapecitabineonthepharmacokineticsofdocetaxelandviceversashowedno

effectbycapecitabineonthepharmacokineticsofdocetaxel(CmaxandAUC)andnoeffectbydocetaxelonthe

pharmacokineticsofarelevantcapecitabinemetabolite5’-DFUR.

Clearanceofdocetaxelincombinationtherapywithcisplatinwassimilartothatobservedfollowingmonotherapy.The

pharmacokineticprofileofcisplatinadministeredshortlyafterdocetaxelinfusionissimilartothatobservedwith

cisplatinalone.

Thecombinedadministrationofdocetaxel,cisplatinand5-fluorouracilin12patientswithsolidtumorshadno

influenceonthepharmacokineticsofeachindividualmedicinalproduct.

Theeffectofprednisoneonthepharmacokineticsofdocetaxeladministeredwithstandarddexamethasone

premedicationhasbeenstudiedin42patients.Noeffectofprednisoneonthepharmacokineticsofdocetaxelwas

(95%CI)

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5.3Preclinicalsafetydata

Thecarcinogenicpotentialofdocetaxelhasnotbeenstudied.

DocetaxelhasbeenshowntobemutagenicintheinvitromicronucleusandchromosomeaberrationtestinCHO-K1

cellsandintheinvivomicronucleustestinthemouse.However,itdidnotinducemutagenicityintheAmestestorthe

CHO/HGPRTgenemutationassay.Theseresultsareconsistentwiththepharmacologicalactivityofdocetaxel.

Undesirableeffectsonthetestisobservedinrodenttoxicitystudiessuggestthatdocetaxelmayimpairmalefertility.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

CitricAcidAnhydrous

Macrogol300

Polysorbate80

Ethanol(see4.4)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptforthosementionedinsection6.6.

6.3Shelflife

Aspackagedforsale:

Unopened:24months

Afterfirstopening:28daysat2 o

C-8 o

Candatroomtemperaturewithandwithoutlightprotection.

Shelflifeafterdilution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor4hoursat2to8°Cwithlightprotectionandbelow

25°CwithoutlightprotectioninGlucose5%orSodiumChloride0.9%(0.30mg/mland0.74mg/ml).

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuser.

6.4Specialprecautionsforstorage

Aspackagedforsale:

Donotstoreabove25°C.

Donotrefrigerateorfreeze.

Keepthevialintheoutercartoninordertoprotectfromlight.

Forstorageconditionofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

CleartypeIglassvialwithrubberstopperandaluminiumcrimpcap,withorwithoutaprotectiveplasticoverwrap

(Onko-Safe).

Packsizes:

20mg/2ml,80mg/8ml,160mg/16ml:1vial,5vials,10vials

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6.6Specialprecautionsfordisposalandotherhandling

Inspectionpriortouse

Aswithallparenteraldrugproducts,DocetaxelEbeweconcentrateforsolutionforinfusionshouldbeinspected

visuallyforparticulatematteranddiscolouration,priortouse,wheneversolutionandcontainerpermit,solutions

containingaprecipitateshouldbediscarded.

Preparationoftheinfusionsolution

Mustbedilutedbeforeuse.

Infusionsolutionshavetobepreparedwitheither0.9%sodiumchlorideorwith5%glucoseandadministeredasan

intravenousinfusion.

Theinfusionsolutionmaybepreparedatmost4hoursbeforeuse.

Therequiredvolumecanbedirectlywithdrawnfromthevial.

Morethanonevialmaybenecessarytoobtaintherequireddoseforthepatient.Basedontherequireddoseforthe

patientexpressedinmg,asepticallywithdrawthecorrespondingvolumecontaining10mg/mldocetaxelfromthe

appropriatenumberofvialsusinggraduatedsyringesfittedwithaneedle.Forexample,adoseof140mgdocetaxel

wouldrequire14mldocetaxelconcentrateforsolutionforinfusion.

Injecttherequiredvolumeintoa250mlinfusionbagorbottlecontainingeither5%glucosesolutionor0.9%sodium

chloridesolution.

Ifadosegreaterthan200mgofdocetaxelisrequired,usealargervolumeoftheinfusionvehiclesothataconcentration

of0.74mg/mldocetaxelisnotexceeded.

Mixtheinfusionbagorbottlemanuallyusingarockingmotion.

TheDocetaxelinfusionsolutionshouldbeusedwithin4hoursandshouldbeasepticallyadministeredasa1-hour

infusionunderroomtemperature(below25°C)andnormallightingcondition.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.

ContactoftheDocetaxelEbeweconcentratewithplasticizedPVCequipmentordevicesusedtopreparesolutionsfor

infusionisnotrecommended.InordertominimizepatientexposuretotheplasticizerDEHP(di-2-ethylhexyl

phthalate),whichmaybeleachedfromPVCinfusionbagsorsets,thefinalDocetaxelEbewedilutionforinfusion

shouldbestoredinbottles(glass,polypropylene)orplasticbags(polypropylene,polyolefin)andadministeredthrough

polyethylene-linedadministrationsets.

pHandosmolalityofreconstitutedsolution

0.3mg/mLinGlucose5%:pH 3.6;517mOsm/kg

0.74mg/mLinNaCl0.9%:pH 3.3–3.6;849mOsm/kg

GuidelinesfortheSafeHandlingofAntineoplasticAgents:

Cytotoxicpreparationsshouldnotbehandledbypregnantstaff.Trainedpersonnelshoulddilutethedrug.Thisshould

beperformedinadesignatedarea.Theworksurfaceshouldbecoveredwithdisposableplastic-backedabsorbentpaper.

Adequateprotectivegloves,masks,andclothingshouldbeworn.Precautionsshouldbetakentoavoidthedrug

accidentallycomingintocontactwithskinormucousmembranes;theaffectedareashouldbecleanedthoroughlywith

soapandwater.Ifaccidentalcontaminationoccurswiththeeyes,theyshouldbewashedwithwaterthoroughlyand

immediately.

UseLuer-lockfittingsonallsyringesandsets.Largeboreneedlesarerecommendedtominimisepressureandthe

possibleformationofaerosols.Thelattermayalsobereducedbytheuseofaventingneedle.

Anyunusedcontentsshouldbediscarded.Adequatecareandprecautionshouldbetakeninthedisposalofitemsused

todiluteDocetaxelEbewe.Anyunusedproductorcontaminatedmaterialsshouldbeplacedinahigh-riskwastebag.

Sharpobjects(needles,syringes,vials,etc)shouldbeplacedinasuitablerigidcontainer.Personnelconcernedwiththe

collectionanddisposalofthiswasteshouldbeawareofthehazardinvolved.Anyunusedproductorwastematerial

shouldbedisposedofinaccordancewithstandardproceduresapplicabletocytotoxicagents.Anyexcessdrugsolution

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Themedicalproductisforsingleuseonly.

Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproducts.

Administration

DocetaxelEbeweisforintravenoususeonly.

7MARKETINGAUTHORISATIONHOLDER

EbewePharmaGes.m.b.HNfg.KG

Mondseestrasse11

A-4866Unterach

Austria

8MARKETINGAUTHORISATIONNUMBER

PA789/17/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16thJuly2010

10DATEOFREVISIONOFTHETEXT

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