DOCIRENA

Main information

  • Trade name:
  • DOCIRENA Concentrate for Soln for Inf 20 Mg/Ml
  • Dosage:
  • 20 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DOCIRENA Concentrate for Soln for Inf 20 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0566/059/001
  • Authorization date:
  • 26-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Docirena20mg/1mlconcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlofconcentratecontains20mgdocetaxelanhydrous.

Onevialof1mlofconcentratecontains20mgofdocetaxel.

Eachvialof1mlofconcentratecontains0.57mlofethanol96%(0.46g).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Theconcentrateisaclearviscous,colourlesstobrownish-yellowsterilesolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Breastcancer

Docirenaincombinationwithdoxorubicinandcyclophosphamideisindicatedfortheadjuvanttreatmentofpatients

with:

operablenode-positivebreastcancer.

operablenode-negativebreastcancer.

Forpatientswithoperablenode-negativebreastcancer,adjuvanttreatmentshouldberestrictedtopatientseligibleto

receivechemotherapyaccordingtointernationallyestablishedcriteriaforprimarytherapyofearlybreastcancer(see

section5.1).

Docirenaincombinationwithdoxorubicinisindicatedforthetreatmentofpatientswithlocallyadvancedormetastatic

breastcancerwhohavenotpreviouslyreceivedcytotoxictherapyforthiscondition.

Docirenamonotherapyisindicatedforthetreatmentofpatientswithlocallyadvancedormetastaticbreastcancerafter

failureofcytotoxictherapy.Previouschemotherapyshouldhaveincludedananthracyclineoranalkylatingagent.

Docirenaincombinationwithtrastuzumabisindicatedforthetreatmentofpatientswithmetastaticbreastcancerwhose

tumoursoverexpressHER2andwhopreviouslyhavenotreceivedchemotherapyformetastaticdisease.

Docirenaincombinationwithcapecitabineisindicatedforthetreatmentofpatientswithlocallyadvancedormetastatic

breastcancerafterfailureofcytotoxicchemotherapy.Previoustherapyshouldhaveincludedananthracycline.

Non-smallcelllungcancer

Docirenaisindicatedforthetreatmentofpatientswithlocallyadvancedormetastaticnon-smallcelllungcancerafter

failureofpriorchemotherapy.

Docirenaincombinationwithcisplatinisindicatedforthetreatmentofpatientswithunresectable,locallyadvancedor

metastaticnon-smallcelllungcancer,inpatientswhohavenotpreviouslyreceivedchemotherapyforthiscondition.

Prostatecancer

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refractorymetastaticprostatecancer.

Gastricadenocarcinoma

Docirenaincombinationwithcisplatinand5-fluorouracilisindicatedforthetreatmentofpatientswithmetastatic

gastricadenocarcinoma,includingadenocarcinomaofthegastroesophagealjunction,whohavenotreceivedprior

chemotherapyformetastaticdisease.

Headandneckcancer

Docirenaincombinationwithcisplatinand5-fluorouracilisindicatedfortheinductiontreatmentofpatientswith

locallyadvancedsquamouscellcarcinomaoftheheadandneck.

4.2Posologyandmethodofadministration

Theuseofdocetaxelshouldbeconfinedtounitsspecialisedintheadministrationofcytotoxicchemotherapyandit

shouldonlybeadministeredunderthesupervisionofaphysicianqualifiedintheuseofanticancerchemotherapy(see

section6.6).

Recommendeddose

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

suchasdexamethasone16mgperday(e.g.8mgBID)for3daysstarting1daypriortodocetaxeladministration,

unlesscontraindicated,canbeused(seesection4.4).ProphylacticG-CSFmaybeusedtomitigatetheriskof

haematologicaltoxicities.

Forprostatecancer,giventheconcurrentuseofprednisoneorprednisolonetherecommendedpremedicationregimenis

oraldexamethasone8mg,12hours,3hoursand1hourbeforethedocetaxelinfusion(seesection4.4).

Docetaxelisadministeredasaone-hourinfusioneverythreeweeks.

Breastcancer

Intheadjuvanttreatmentofoperablenode-positiveandnode-negativebreastcancer,therecommendeddoseof

docetaxelis75mg/m 2

administered1-hourafterdoxorubicin50mg/m 2

andcyclophosphamide500mg/m 2

every

3weeksfor6cycles(TACregimen)(seealsoDoseadjustmentsduringtreatment).

Forthetreatmentofpatientswithlocallyadvancedormetastaticbreastcancer,therecommendeddoseofdocetaxelis

100mg/m 2

inmonotherapy.Infirst-linetreatment,docetaxel75mg/m 2

isgivenincombinationtherapywith

doxorubicin(50mg/m 2

Incombinationwithtrastuzumabtherecommendeddoseofdocetaxelis100mg/m 2

everythreeweeks,with

trastuzumabadministeredweekly.Inthepivotalstudytheinitialdocetaxelinfusionwasstartedthedayfollowingthe

firstdoseoftrastuzumab.Thesubsequentdocetaxeldoseswereadministeredimmediatelyaftercompletionofthe

trastuzumabinfusion,iftheprecedingdoseoftrastuzumabwaswelltolerated.Fortrastuzumabdoseand

administration,seetrastuzumabsummaryofproductcharacteristics.

Incombinationwithcapecitabine,therecommendeddoseofdocetaxelis75mg/m 2

everythreeweeks,combinedwith

capecitabineat1250mg/m 2

twicedaily(within30minutesafterameal)for2weeksfollowedbya1-weekrestperiod.

Forcapecitabinedosecalculationaccordingtobodysurfacearea,seecapecitabinesummaryofproductcharacteristics.

Non-smallcelllungcancer

Inchemotherapynaïvepatientstreatedfornon-smallcelllungcancer,therecommendeddoseregimenisdocetaxel

75mg/m 2

immediatelyfollowedbycisplatin75mg/m 2

over30-60minutes.Fortreatmentafterfailureofprior

platinum-basedchemotherapy,therecommendeddoseis75mg/m²asasingleagent.

Prostatecancer

Therecommendeddoseofdocetaxelis75mg/m 2

.Prednisoneorprednisolone5mgorallytwicedailyisadministered

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Gastricadenocarcinoma

Therecommendeddoseofdocetaxelis75mg/m 2

asa1-hourinfusion,followedbycisplatin75mg/m 2

,asa1-to3-

hourinfusion(bothonday1only),followedby5-fluorouracil750mg/m 2

perdaygivenasa24-hourcontinuous

infusionfor5days,startingattheendofthecisplatininfusion.Treatmentisrepeatedeverythreeweeks.Patientsmust

receivepremedicationwithantiemeticsandappropriatehydrationforcisplatinadministration.ProphylacticG-CSF

shouldbeusedtomitigatetheriskofhaematologicaltoxicities(seealsoDoseadjustmentsduringtreatment).

Headandneckcancer

Patientsmustreceivepremedicationwithantiemeticsandappropriatehydration(priortoandaftercisplatin

administration).ProphylacticG-CSFmaybeusedtomitigatetheriskofhaematologicaltoxicities.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,lowprobabilityofsurgical

cure,andaimingatorganpreservation)squamouscellcarcinomaoftheheadandneck(SCCHN),therecommended

doseofdocetaxelis75mg/m 2

asa1hourintravenousinfusiononday1,followedbycisplatin100mg/m 2

administeredasa30-minuteto3-hourinfusion,followedby5-fluorouracil1000mg/m 2

/dayasacontinuous

infusionfromday1today4.Thisregimenisadministeredevery3weeksfor3cycles.Followingchemotherapy,

patientsshouldreceivechemoradiotherapy.

Forcisplatinand5-fluorouracildosemodifications,seethecorrespondingsummaryofproductcharacteristics.

Doseadjustmentsduringtreatment

General

Docetaxelshouldbeadministeredwhentheneutrophilcountis ≥1,500cells/mm 3

Inpatientswhoexperiencedeitherfebrileneutropenia,neutrophilcount<500cells/mm 3

formorethanoneweek,

severeorcumulativecutaneousreactionsorsevereperipheralneuropathyduringdocetaxeltherapy,thedoseof

docetaxelshouldbereducedfrom100mg/m 2

to75mg/m 2

and/orfrom75to60mg/m².Ifthepatientcontinuesto

experiencethesereactionsat60mg/m²,thetreatmentshouldbediscontinued.

Adjuvanttherapyforbreastcancer

PrimaryG-CSFprophylaxisshouldbeconsideredinpatientswhoreceivedocetaxel,doxorubicinand

cyclophosphamide(TAC)adjuvanttherapyforbreastcancer.Patientswhoexperiencefebrile

neutropeniaand/orneutropenicinfectionshouldhavetheirdocetaxeldosereducedto60mg/m 2

inallsubsequent

cycles(seesections4.4and4.8).PatientswhoexperienceGrade3or4stomatitisshouldhavetheirdosedecreasedto

60mg/m 2

Incombinationwithcisplatin

Forpatientswhoaredosedinitiallyatdocetaxel75mg/m 2

incombinationwithcisplatinandwhosenadirofplatelet

countduringthepreviouscourseoftherapyis<25,000cells/mm 3

,orinpatientswhoexperiencefebrileneutropenia,or

inpatientswithseriousnon-haematologictoxicities,thedocetaxeldoseinsubsequentcyclesshouldbereducedto

65mg/m 2

.Forcisplatindoseadjustments,seethecorrespondingsummaryofproductcharacteristics.

Incombinationwithcapecitabine

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ForpatientsdevelopingthefirstappearanceofGrade2toxicity,whichpersistsatthetimeofthenext

docetaxel/capecitabinetreatment,delaytreatmentuntilresolvedtoGrade0-1,andresumeat100%oftheoriginal

dose.

ForpatientsdevelopingthesecondappearanceofGrade2toxicity,orthefirstappearanceofGrade3toxicity,at

anytimeduringthetreatmentcycle,delaytreatmentuntilresolvedtoGrade0-1andthenresumetreatmentwith

docetaxel55mg/m².

Foranysubsequentappearancesoftoxicities,oranyGrade4toxicities,discontinuethedocetaxeldose.

Fortrastuzumabdosemodifications,seetrastuzumabsummaryofproductcharacteristics.

Incombinationwithcisplatinand5-fluorouracil

Ifanepisodeoffebrileneutropenia,prolongedneutropeniaorneutropenicinfectionoccursdespiteG-CSFuse,the

docetaxeldoseshouldbereducedfrom75to60mg/m 2

.Ifsubsequentepisodesofcomplicatedneutropeniaoccurthe

docetaxeldoseshouldbereducedfrom60to45mg/m 2

.IncaseofGrade4thrombocytopeniathedocetaxeldose

shouldbereducedfrom75to60mg/m 2

.Patientsshouldnotberetreatedwithsubsequentcyclesofdocetaxeluntil

neutrophilsrecovertoalevel>1,500cells/mm 3

andplateletsrecovertoalevel>100,000cells/mm 3

.Discontinue

treatmentifthesetoxicitiespersist(seesection4.4).

Recommendeddosemodificationsfortoxicitiesinpatientstreatedwithdocetaxelincombinationwithcisplatinand

5-fluorouracil(5-FU):

Forcisplatinand5-fluorouracildoseadjustments,seethecorrespondingsummaryofproductcharacteristics.

InthepivotalSCCHNstudiespatientswhoexperiencedcomplicatedneutropenia(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

5.2).Forthosepatientswithserumbilirubin>ULNand/orALTandAST>3.5timestheULNassociatedwithalkaline

phosphatase>6timestheULN,nodose-reductioncanberecommendedanddocetaxelshouldnotbeusedunless

strictlyindicated.

Incombinationwithcisplatinand5-fluorouracilforthetreatmentofpatientswithgastricadenocarcinoma,thepivotal

clinicalstudyexcludedpatientswithALTand/orAST>1.5×ULNassociatedwithalkalinephosphatase>2.5×ULN,

andbilirubin>1xULN;forthesepatients,nodose-reductionscanberecommendedanddocetaxelshouldnotbeused

unlessstrictlyindicated.Nodataareavailableinpatientswithhepaticimpairmenttreatedbydocetaxelincombination

intheotherindications.

Paediatricpopulation

Toxicity Doseadjustment

Diarrhoeagrade3 Firstepisode:reduce5-FUdoseby20%.

Secondepisode:thenreducedocetaxeldoseby20%.

Diarrhoeagrade4 Firstepisode:reducedocetaxeland5-FUdosesby20%.

Secondepisode:discontinuetreatment.

Stomatitis/mucositis

grade3 Firstepisode:reduce5-FUdoseby20%.

Secondepisode:stop5-FUonly,atallsubsequentcycles.

Thirdepisode:reducedocetaxeldoseby20%.

Stomatitis/mucositis

grade4 Firstepisode:stop5-FUonly,atallsubsequentcycles.

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notyetbeenestablished.

Thereisnorelevantuseofdocetaxelinthepaediatricpopulationintheindicationsbreastcancer,non-smallcelllung

cancer,prostatecancer,gastriccarcinomaandheadandneckcancer,notincludingtypeIIandIIIlessdifferentiated

nasopharyngealcarcinoma.

Elderly

Basedonapopulationpharmacokineticanalysis,therearenospecialinstructionsforuseintheelderly.

Incombinationwithcapecitabine,forpatients60yearsofageormore,astartingdosereductionofcapecitabineto75%

isrecommended(seecapecitabinesummaryofproductcharacteristics).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Patientswithbaselineneutrophilcountof<1,500cells/mm 3

Patientswithsevereliverimpairment(seesections4.2and4.4).

Contraindicationsforothermedicinalproductsalsoapply,whencombinedwithdocetaxel.

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/mm3(seesection4.2).

Inthecaseofsevereneutropenia(<500cells/mm ≥forsevendaysormore)duringacourseofdocetaxeltherapy,a

reductionindoseforsubsequentcoursesoftherapyortheuseofappropriatesymptomaticmeasuresarerecommended

(seesection4.2).

Inpatientstreatedwithdocetaxelincombinationwithcisplatinand5-fluorouracil(TCF),febrileneutropeniaand

neutropenicinfectionoccurredatlowerrateswhenpatientsreceivedprophylacticG-CSF.PatientstreatedwithTCF

shouldreceiveprophylacticG-CSFtomitigatetheriskofcomplicatedneutropenia(febrileneutropenia,prolonged

neutropeniaorneutropenicinfection).PatientsreceivingTCFshouldbecloselymonitored(seesections4.2and4.8).

Inpatientstreatedwithdocetaxelincombinationwithdoxorubicinandcyclophosphamide(TAC),febrile

neutropeniaand/orneutropenicinfectionoccurredatlowerrateswhenpatientsreceivedprimaryG-CSF

prophylaxis.PrimaryG-CSFprophylaxisshouldbeconsideredinpatientswhoreceiveadjuvanttherapywith

TACforbreastcancertomitigatetheriskofcomplicatedneutropenia(febrileneutropenia,prolongedneutropenia

orneutropenicinfection).PatientsreceivingTACshouldbecloselymonitored(seesections4.2and4.8).

Hypersensitivityreactions

Patientsshouldbeobservedcloselyforhypersensitivityreactionsespeciallyduringthefirstandsecondinfusions.

Hypersensitivityreactionsmayoccurwithinafewminutesfollowingtheinitiationoftheinfusionofdocetaxel,thus

facilitiesforthetreatmentofhypotensionandbronchospasmshouldbeavailable.Ifhypersensitivityreactionsoccur,

minorsymptomssuchasflushingorlocalisedcutaneousreactionsdonotrequireinterruptionoftherapy.However,

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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-fluorouracilforthetreatmentofpatientswithgastricadenocarcinoma,thepivotal

clinicalstudyexcludedpatientswithALTand/orAST>1.5xULNassociatedwithalkalinephosphatase>2.5xULN,and

bilirubin>1xULN;forthesepatients,nodose-reductionscanberecommendedanddocetaxelshouldnotbeused

unlessstrictlyindicated.Nodataareavailableinpatientswithhepaticimpairmenttreatedbydocetaxelincombination

intheotherindications.

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

Contraceptivemeasuresmustbetakenbybothmenandwomenduringtreatmentandformenatleast6monthsafter

cessationoftherapy(seesection4.6).

Additionalcautionsforuseinadjuvanttreatmentofbreastcancer

Complicatedneutropenia

Forpatientswhoexperiencecomplicatedneutropenia(prolongedneutropenia,febrileneutropeniaorinfection),G-CSF

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Gastrointestinalreactions

Symptomssuchasearlyabdominalpainandtenderness,fever,diarrhoea,withorwithoutneutropenia,maybeearly

manifestationsofseriousgastrointestinaltoxicityandshouldbeevaluatedandtreatedpromptly.

Congestiveheartfailure

Patientsshouldbemonitoredforsymptomsofcongestiveheartfailureduringtherapyandduringthefollowupperiod.

Leukaemia

Inthedocetaxel,doxorubicinandcyclophosphamide(TAC)treatedpatients,theriskofdelayedmyelodysplasiaor

myeloidleukaemiarequireshaematologicalfollow-up.

Patientswith4+nodes

Thebenefit/riskratioforTACinpatientswith4+nodeswasnotdefinedfullyattheinterimanalysis(seesection5.1).

Elderly

Therearelimiteddataavailableinpatients>70yearsofageondocetaxeluseincombinationwithdoxorubicinand

cyclophosphamide.

Ofthe333patientstreatedwithdocetaxeleverythreeweeksinaprostatecancerstudy,209patientswere65yearsof

ageorgreaterand68patientswereolderthan75years.Inpatientstreatedwithdocetaxeleverythreeweeks,the

incidenceofrelatednailchangesoccurredatarate 10%higherinpatientswhowere65yearsofageorgreater

comparedtoyoungerpatients.Theincidenceofrelatedfever,diarrhoea,anorexia,andperipheraloedemaoccurredat

rates 10%higherinpatientswhowere75yearsofageorgreaterversuslessthan65years.

Amongthe300(221patientsinthephaseIIIpartofthestudyand79patientsinthephaseIIpart)patientstreatedwith

docetaxelincombinationwithcisplatinand5-fluorouracilinthegastriccancerstudy,74were65yearsofageorolder

and4patientswere75yearsofageorolder.Theincidenceofseriousadverseeventswashigherintheelderlypatients

comparedtoyoungerpatients.Theincidenceofthefollowingadverseevents(allgrades):lethargy,stomatitis,

neutropenicinfectionoccurredatrates 10%higherinpatientswhowere65yearsofageoroldercomparedto

youngerpatients.

ElderlypatientstreatedwithTCFshouldbecloselymonitored.

Excipients

Thismedicinalproductcontainsapproximately55vol%ethanol(alcohol),i.e.upto0.459g(0.57ml)ethanol96%

pervial,equivalentto12mlofbeeror5mlwinepervial.

Harmfulforthosesufferingfromalcoholism.

Tobetakenintoaccountinpregnantorbreast-feedingwomen,childrenandhigh-riskgroupssuchaspatientswithliver

disease,orepilepsy.

Theamountofalcoholinthismedicinalproductmayaltertheeffectsofothermedicinalproducts.

Theamountofalcoholinthismedicinalproductmayimpairthepatientsabilitytodriveorusemachines.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Invitrostudieshaveshownthatthemetabolismofdocetaxelmaybemodifiedbytheconcomitantadministrationof

compoundswhichinduce,inhibitoraremetabolisedby(andthusmayinhibittheenzymecompetitively)cytochrome

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

beexercisedwhentreatingpatientswiththesemedicinalproductsasconcomitanttherapysincethereisapotentialfora

significantinteraction.

Docetaxelishighlyproteinbound(>95%).Althoughthepossibleinvivointeractionofdocetaxelwithconcomitantly

administeredmedicinalproducthasnotbeeninvestigatedformally,invitrointeractionswithtightlyprotein-bound

agentssuchaserythromycin,diphenhydramine,propranolol,propafenone,phenytoin,salicylate,sulfamethoxazoleand

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ofdocetaxel.Docetaxeldidnotinfluencethebindingofdigitoxin.

Thepharmacokineticsofdocetaxel,doxorubicinandcyclophosphamidewerenotinfluencedbytheirco-administration.

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,docetaxelmustnotbeusedduringpregnancy

unlessclearlyindicated.

Womenofchildbearingpotential/contraception:

Womenofchildbearingagereceivingdocetaxelshouldbeadvisedtoavoidbecomingpregnant,andtoinformthe

treatingphysicianimmediatelyshouldthisoccur.

Aneffectivemethodofcontraceptionshouldbeusedduringtreatment.

Innonclinicalstudies,docetaxelhasgenotoxiceffectsandmayaltermalefertility(seesection5.3).Therefore,men

beingtreatedwithdocetaxelareadvisednottofatherachildduringandupto6monthsaftertreatmentandtoseek

adviceonconservationofspermpriortotreatment.

Lactation:

Docetaxelisalipophilicsubstancebutitisnotknownwhetheritisexcretedinhumanmilk.Consequently,becauseof

thepotentialforadversereactionsinnursinginfants,breastfeedingmustbediscontinuedforthedurationofdocetaxel

therapy.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

4.8Undesirableeffects

Theadversereactionsconsideredtobepossiblyorprobablyrelatedtotheadministrationofdocetaxelhavebeen

obtainedin:

1312and121patientswhoreceived100mg/m²and75mg/m²ofdocetaxelasasingleagentrespectively.

258patientswhoreceiveddocetaxelincombinationwithdoxorubicin.

406patientswhoreceiveddocetaxelincombinationwithcisplatin.

92patientstreatedwithdocetaxelincombinationwithtrastuzumab.

255patientswhoreceiveddocetaxelincombinationwithcapecitabine.

332patientswhoreceiveddocetaxelincombinationwithprednisoneorprednisolone(clinicallyimportant

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1276patients(744and532inTAX316andGEICAM9805respectively)whoreceiveddocetaxelincombination

withdoxorubicinandcyclophosphamide(clinicallyimportanttreatmentrelatedadverseeventsarepresented).

300gastricadenocarcinomapatients(221patientsinthephaseIIIpartofthestudyand79patientsinthephaseII

part)whoreceiveddocetaxelincombinationwithcisplatinand5-fluorouracil(clinicallyimportanttreatment

relatedadverseeventsarepresented).

174and251headandneckcancerpatientswhoreceiveddocetaxelincombinationwithcisplatinand

5-fluorouracil(clinicallyimportanttreatmentrelatedadverseeventsarepresented).

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

grade4=G4)andtheCOSTARTandtheMedDRAterms.

Frequenciesaredefinedas:

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Themostcommonlyreportedadversereactionsofdocetaxelaloneare:neutropenia(whichwasreversibleandnot

cumulative;themediandaytonadirwas7daysandthemediandurationofsevereneutropenia(<500cells/mm 3

)was

7days),anaemia,alopecia,nausea,vomiting,stomatitis,diarrhoeaandasthenia.Theseverityofadverseeventsof

docetaxelmaybeincreasedwhendocetaxelisgivenincombinationwithotherchemotherapeuticagents.

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

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

docetaxelmonotherapy.

Forcombinationwithcapecitabine,themostfrequenttreatment-relatedundesirableeffects( ≥5%)reportedina

phaseIIIstudyinbreastcancerpatientsfailinganthracyclinetreatmentarepresented(seecapecitabinesummaryof

productcharacteristics).

Thefollowingadversereactionsarefrequentlyobservedwithdocetaxel:

Immunesystemdisorders

Hypersensitivityreactionshavegenerallyoccurredwithinafewminutesfollowingthestartoftheinfusionofdocetaxel

andwereusuallymildtomoderate.Themostfrequentlyreportedsymptomswereflushing,rashwithorwithout

pruritus,chesttightness,backpain,dyspnoeaandfeverorchills.Severereactionswerecharacterisedbyhypotension

and/orbronchospasmorgeneralizedrash/erythema(seesection4.4).

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

verycommon ( ≥1/10)

common ( ≥1/100to<1/10)

uncommon ≥1/1000to<1/100)

rare ( ≥1/10,000to<1/1000)

veryrare (<1/10000)

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4.2and4.4).Severenaildisordersarecharacterisedbyhypo-orhyperpigmentationandsometimespainand

onycholysis.

Generaldisordersandadministrationsiteconditions

Infusionsitereactionsweregenerallymildandconsistedofhyperpigmentation,inflammation,rednessordrynessof

theskin,phlebitisorextravasationandswellingofthevein.

Fluidretentionincludeseventssuchasperipheraloedemaandlessfrequentlypleuraleffusion,pericardialeffusion,

ascitesandweightgain.Theperipheraloedemausuallystartsatthelowerextremitiesandmaybecomegeneralised

withaweightgainof3kgormore.Fluidretentioniscumulativeinincidenceandseverity(seesection4.4).

Docetaxel100mg/m²singleagent

Infectionsandinfestations Infections(G3/4:5.7%;

includingsepsisand

pneumonia,fatalin1.7%) Infectionassociatedwith

G4neutropenia(G3/4:

4.6%)

Bloodandlymphatic

systemdisorders Neutropenia(G4:76.4%);

Anaemia(G3/4:8.9%);

Febrileneutropenia Thrombocytopenia(G4:

0.2%)

Immunesystemdisorders Hypersensitivity(G3/4:

5.3%)

Metabolismandnutrition

disorders Anorexia

Nervoussystemdisorders Peripheralsensory

neuropathy(G3:4.1%);

Peripheralmotor

neuropathy(G3/4:4%);

Dysgeusia(severe:0.07%)

Cardiacdisorders Arrhythmia(G3/4:0.7%) Cardiacfailure

Vasculardisorders Hypotension;

Hypertension;

Haemorrhage

Respiratory,thoracicand

mediastinaldisorders Dyspnoea(severe:2.7%)

Gastrointestinaldisorders 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

connectivetissuedisorders Myalgia(severe:1.4%) Arthralgia

Generaldisordersand

administrationsite

conditions Fluidretention(severe:

6.5%);

Asthenia(severe:11.2%);

Pain Infusionsitereaction;

Non-cardiacchestpain

(severe:0.4%)

Investigations G3/4Bloodbilirubin

increased(<5%);

MedDRAsystemorgan

classes Verycommonadverse

reactions Commonadverse

reactions Uncommonadverse

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Bloodandlymphaticsystemdisorders

Rare:bleedingepisodesassociatedwithgrade3/4thrombocytopenia.

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.

phosphataseincreased

(<4%);

G3/4ASTincreased

(<3%);

G3/4ALTincreased(<2%)

MedDRAsystemorganclasses Verycommonadverse

reactions Commonadversereactions

Infectionsandinfestations Infections(G3/4:5%)

Bloodandthelymphaticsystem

disorders Neutropenia(G4:54.2%);

Anaemia(G3/4:10.8%);

Thrombocytopenia(G4:1.7%) Febrileneutropenia

Immunesystemdisorders Hypersensitivity(nosevere)

Metabolismandnutrition

disorders Anorexia

Nervoussystemdisorders Peripheralsensoryneuropathy

(G3/4:0.8%) Peripheralmotorneuropathy

(G3/4:2.5%)

Cardiacdisorders Arrhythmia(nosevere)

Vasculardisorders Hypotension

Gastrointestinaldisorders Nausea(G3/4:3.3%);

Stomatitis(G3/4:1.7%);

Vomiting(G3/4:0.8%);

Diarrhoea(G3/4:1.7%) Constipation

Skinandsubcutaneoustissue

disorders Alopecia;

Skinreaction(G3/4:0.8%) Naildisorders(severe0.8%)

Musculoskeletalandconnective

tissuedisorders Myalgia

Generaldisordersand

administrationsiteconditions Asthenia(severe12.4%);

Fluidretention(severe0.8%);

Pain

Investigations G3/4Bloodbilirubinincreased

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Docetaxel75mg/m²incombinationwithdoxorubicin:

MedDRAsystemorgan

classes Verycommonadverse

reactions Commonadverse

reactions Uncommonadverse

reactions

Infectionsand

infestations Infection(G3/4:7.8%)

Bloodandthelymphatic

systemdisorders Neutropenia(G4:

91.7%);

Anaemia(G3/4:9.4%);

Febrileneutropenia;

Thrombocytopenia(G4:

0.8%)

Immunesystem

disorders Hypersensitivity(G3/4:

1.2%)

Metabolismand

nutrition

disorders Anorexia

Nervoussystem

disorders Peripheralsensory

neuropathy(G3:0.4%) Peripheralmotor

neuropathy(G3/4:

0.4%)

Cardiacdisorders Cardiacfailure;

Arrhythmia(nosevere)

Vasculardisorders Hypotension

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(no

severe)

Musculoskeletaland

connective

tissuedisorders Myalgia

Generaldisordersand

administrationsite

conditions Asthenia(severe8.1%);

Fluidretention(severe

1.2%);

Pain Infusionsitereaction

Investigations G3/4Bloodbilirubin

increased(<2.5%);

G3/4Bloodalkaline

phosphataseincreased

(<2.5%) G3/4ASTincreased

(1%);G3/4ALT

increased(<1%)

Infectionsandinfestations Infection(G3/4:5.7%)

Bloodandlymphatic

systemdisorders Neutropenia(G4:51.5%);

Anaemia(G3/4:6.9%);

Thrombocytopenia(G4: Febrileneutropenia MedDRAsystemorgan

classes Verycommonadverse

reactions Commonadverse

reactions Uncommonadverse

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0.5%)

Immunesystemdisorders Hypersensitivity(G3/4:

2.5%)

Metabolismandnutrition

disorders Anorexia

Nervoussystemdisorders Peripheralsensory

neuropathy(G3:3.7%);

Peripheralmotor

neuropathy(G3/4:2%)

Cardiacdisorders Arrhythmia(G3/4:0.7%) Cardiacfailure

Vasculardisorders Hypotension(G3/4:0.7%)

Gastrointestinaldisorders Nausea(G3/4:9.6%);

Vomiting(G3/4:7.6%);

Diarrhoea(G3/4:6.4%);

Stomatitis(G3/4:2%) Constipation

Skinandsubcutaneous

tissuedisorders Alopecia;

Naildisorders(severe:

0.7%);

Skinreaction(G3/4:0.2%)

Musculoskeletaland

connectivetissuedisorders Myalgia(severe:0.5%)

Generaldisordersand

administrationsite

conditions Asthenia(severe:9.9%);

Fluidretention(severe:

0.7%);

Fever(G3/4:1.2%) Infusionsitereaction;

Pain

Investigations G3/4Bloodbilirubin

increased(2.1%);

G3/4ALTincreased(1.3%) G3/4ASTincreased

(0.5%);

G3/4Bloodalkaline

phosphataseincreased

(0.3%)

Bloodandlymphaticsystem

disorders Neutropenia(G3/4:32%);

Febrileneutropenia(includes

neutropeniaassociatedwithfeverand

antibioticuse)orneutropenicsepsis

Metabolismandnutritiondisorders Anorexia

Psychiatricdisorders Insomnia

Nervoussystemdisorders Paresthesia;Headache;Dysgeusia;

Hypoaesthesia

Eyedisorders Lacrimationincreased;Conjunctivitis

Cardiacdisorders Cardiacfailure

Vasculardisorders Lymphoedema

Respiratory,thoracicandmediastinal

disorders Epistaxis;Pharyngolaryngealpain;

Nasopharyngitis;Dyspnoea;

Cough;Rhinorrhoea

Gastrointestinaldisorders Nausea;Diarrhoea;Vomiting;

Constipation;Stomatitis;Dyspepsia;

Abdominalpain

Skinandsubcutaneoustissue

disorders Alopecia;Erythema;Rash;Nail

disorders

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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).

Cardiacdisorders

Symptomaticcardiacfailurewasreportedin2.2%ofthepatientswhoreceiveddocetaxelplustrastuzumabcomparedto

0%ofpatientsgivendocetaxelalone.Inthedocetaxelplustrastuzumabarm,64%hadreceivedaprioranthracyclineas

adjuvanttherapycomparedwith55%inthedocetaxelarmalone.

tissuedisorders extremity;Bonepain;Backpain

Generaldisordersandadministration

siteconditions Asthenia;Oedemaperipheral;

Pyrexia;Fatigue;Mucosal

inflammation;Pain;Influenzalike

illness;Chestpain;Chills Lethargy

Investigations Weightincreased

MedDRAsystemorganclasses Verycommonadverse

reactions Commonadversereactions

Infectionsandinfestations Oralcandidiasis(G3/4:<1%)

Bloodandthelymphaticsystem

disorders Neutropenia(G3/4:63%);

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

Metabolismandnutrition

disorders Anorexia(G3/4:1%);

Decreasedappetite Dehydration(G3/4:2%);

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

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

Headache(G3/4:<1%);

Neuropathyperipheral

Eyedisorders Lacrimationincreased

Respiratory,thoracicand

mediastinaldisorders Pharyngolaryngealpain

(G3/4:2%) 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%);Naildiscolouration;

Onycholysis(G3/4:1%)

Musculoskeletalandconnective

tissuedisorders Myalgia(G3/4:2%);

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

Backpain(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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Docetaxel75mg/m²incombinationwithprednisoneorprednisolone

Adjuvanttherapywithdocetaxel75mg/m 2

incombinationwithdoxorubicinandcyclophosphamideinpatients

G3/4Bloodbilirubinincreased

(9%)

Infectionsandinfestations Infection(G3/4:3.3%)

Bloodandlymphaticsystem

disorders Neutropenia(G3/4:32%);

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

Febrileneutropenia

Immunesystemdisorders Hypersensitivity(G3/4:0.6%)

Metabolismandnutritiondisorders Anorexia(G3/4:0.6%)

Nervoussystemdisorders Peripheralsensoryneuropathy(G3/4:

1.2%);

Dysgeusia(G3/4:0%) Peripheralmotorneuropathy(G3/4:

Eyedisorders Lacrimationincreased(G3/4:0.6%)

Cardiacdisorders Cardiacleftventricularfunction

decrease(G3/4:0.3%)

Respiratory,thoracicandmediastinal

disorders 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(nosevere) Exfoliativerash(G3/4:0.3%)

Musculoskeletalandconnectivebone

disorders Arthralgia(G3/4:0.3%);

Myalgia(G3/4:0.3%)

Generaldisordersandadministration

siteconditions Fatigue(G3/4:3.9%);

Fluidretention(severe:0.6%)

Infectionsandinfestations Infection(G3/4:2.4%);

Neutropenicinfection.

(G3/4:2.7%)

Bloodandlymphatic

systemdisorders Anaemia(G3/4:3%);

Neutropenia(G3/4:59.2%);

Thrombocytopenia(G3/4:

1.6%);

Febrileneutropenia

(G3/4:NA)

Immunesystemdisorders Hypersensitivity

(G3/4:0.6%)

Metabolismandnutrition

disorders Anorexia(G3/4:1.5%)

Nervoussystemdisorders Dysgeusia(G3/4:0.6%);

Peripheralsensory Peripheralmotor

neuropathy(G3/4:0%); Syncope(G3/4:0%);

MedDRAsystemorganclasses Verycommonadversereactions Commonadversereactions

MedDRAsystemorgan

classes Verycommonadverse

reactions Commonadverse

reactions Uncommonadverse

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Nervoussystemdisorders

Peripheralsensoryneuropathywasobservedtobeongoingduringfollow-upin12patientsoutofthe83patientswith

peripheralsensoryneuropathyattheendofthechemotherapy.

Cardiacdisorders

CongestiveHeartFailure(CHF)hasbeenreportedin18of1276patientsduringthefollow-upperiod.Inthenode

positivestudy(TAX316)onepatientineachtreatmentarmdiedbecauseofcardiacfailure.

Skinandsubcutaneoustissuedisorders

Alopeciawasobservedtobeongoingduringfollow-upin25patientsoutofthe736patientswithalopeciaattheendof

thechemotherapy.

Reproductivesystemandbreastdisorders

Amenorrhoeawasobservedtobeongoingduringfollow-upin140patientsoutofthe251patientswithamenorrhoeaat

theendofthechemotherapy.

Generaldisordersandadministrationsiteconditions

Peripheraloedemawasobservedtobeongoingduringfollow-uptimein18patientsoutofthe112patientswith

peripheraloedemaattheendofthechemotherapyinstudyTAX316,whereaslymphoedemawasobservedtobe

ongoingin4ofthe5patientswithlymphoedemaattheendofthechemotherapyinthestudyGEICAM9805.

Acuteleukaemia/Myelodysplasticsyndrome.

Atamedianfollow-uptimeof77months,acuteleukaemiaoccurredin1of532(0.2%)patientswhoreceived

neuropathy(G3/4:<0.1%) Somnolence(G3/4:0%)

Eyedisorders Conjunctivitis

(G3/4:<0.1%) Lacrimationincreased

(G3/4:0.1%)

Cardiacdisorders Arrhythmia(G3/4:0.2%);

Vasculardisorders

Hotflush(G3/4:0.5%) Hypotension(G3/4:0%)

Phlebitis(G3/4:0%) ;

Lymphoedema(G3/4:0%)

Respiratory,thoracicand

mediastinaldisorders Cough(G3/4:0%)

Gastrointestinaldisorders Nausea(G3/4:5.0%);

Stomatitis(G3/4:6.0%);

Vomiting(G3/4:4.2%);

Diarrhoea(G3/4:3.4%);

Constipation(G3/4:0.5%) Abdominalpain(G3/4:

0.4%)

Skinandsubcutaneous

tissuedisorders Alopecia(G3/4:<0.1%);

Skindisorder(G3/4:0.6%);

Naildisorders(G3/4:0.4%)

Musculoskeletaland

connectivetissuedisorders Myalgia(G3/4:0.7%);

Arthralgia(G3/4:0.2%)

Reproductivesystemand

breastdisorders Amenorrhoea(G3/4:NA)

Generaldisordersand

administrationsite

conditions Asthenia(G3/4:10.0%);

Pyrexia(G3/4:NA)

Oedemaperipheral(G3/4:

0.2%)

Investigations Weightincreased

(G3/4:0%);

Weightdecreased

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receivedfluorouracil,doxorubicinandcyclophosphamide.Nopatientwasdiagnosedwithmyelodysplastic

syndromeineithertreatmentgroups.

TablebelowshowsthattheincidenceofGrade4neutropenia,febrileneutropeniaandneutropenicinfectionwas

decreasedinpatientswhoreceivedprimaryG-CSFprophylaxisafteritwasmademandatoryintheTACarm—

GEICAMstudy.

NeutropeniccomplicationsinpatientsreceivingTACwithorwithoutprimaryG-CSFprophylaxis

Docetaxel75mg/m²incombinationwithcisplatinand5-fluorouracilforgastricadenocarcinomacancer

Bloodandlymphaticsystemdisorders

Withoutprimary

G-CSFprophylaxis

(n=111)

N(%) Withprimary

G-CSFprophylaxis

(n=421)

N(%)

Neutropenia(Grade4) 104(93.7) 135(32.1)

Febrileneutropenia 28(25.2) 23(5.5)

Neutropenicinfection 14(12.6) 21(5.0)

Neutropenicinfection

(Grade3-4) 2(1.8) 5(1.2)

Infectionsandinfestations Neutropenicinfection;

Infection(G3/4:11.7%)

Bloodandlymphaticsystem

disorders Anaemia(G3/4:20.9%);

Neutropenia(G3/4:83.2%);

Thrombocytopenia(G3/4:8.8%);

Febrileneutropenia

Immunesystemdisorders Hypersensitivity(G3/4:1.7%)

Metabolismandnutritiondisorders Anorexia(G3/4:11.7%)

Nervoussystemdisorders Peripheralsensoryneuropathy(G3/4:

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

Peripheralmotorneuropathy(G3/4:

1.3%)

Eyedisorders Lacrimationincreased(G3/4:0%)

Earandlabyrinthdisorders Hearingimpaired(G3/4:0%)

Cardiacdisorders Arrhythmia(G3/4:1.0%)

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/odynophagia

(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%)

Generaldisordersandadministration

siteconditions Lethargy(G3/4:19.0%);

Fever(G3/4:2.3%);

Fluidretention(severe/life-

(GEICAM9805)

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

andneutropenicinfectionoccurredrespectivelyin12.1%and3.4%ofpatientswhenpatientsreceivedprophylactic

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

Docetaxel75mg/m²incombinationwithcisplatinand5-fluorouracilforheadandneckcancer

Inductionchemotherapyfollowedbyradiotherapy(TAX323)

Infectionsandinfestations Infection(G3/4:6.3%);

Neutropenicinfection

Neoplasmsbenign,

malignantandunspecified

(inclcystsandpolyps) Cancerpain(G3/4:0.6%)

Bloodandlymphatic

systemdisorders Neutropenia(G3/4:76.3%);

Anaemia(G3/4:9.2%);

Thrombocytopenia(G3/4:

5.2%) Febrileneutropenia

Immunesystemdisorders Hypersensitivity(no

severe)

Metabolismandnutrition

disorders Anorexia(G3/4:0.6%)

Nervoussystemdisorders Dysgeusia/Parosmia;

Peripheralsensory

neuropathy(G3/4:0.6%) Dizziness

Eyedisorders Lacrimationincreased;

Conjunctivitis

Earandlabyrinthdisorders Hearingimpaired

Cardiacdisorders Myocardialischemia

(G3/4:1.7%) Arrhythmia(G3/4:0.6%)

Vasculardisorders Venousdisorder(G3/4:

0.6%)

Gastrointestinaldisorders Nausea(G3/4:0.6%);

Stomatitis(G3/4:4.0%);

Diarrhoea(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

connectivetissuedisorders Myalgia(G3/4:0.6%)

Generaldisordersand

administrationsite

conditions Lethargy(G3/4:3.4%);

Pyrexia(G3/4:0.6%);

Fluidretention;

Oedema

MedDRAsystemorgan

classes Verycommonadverse

reactions Commonadverse

reactions Uncommonadverse

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Post-marketingexperience

Neoplasmsbenign,malignantandunspecified(inclcystsandpolyps)

Veryrarecasesofacutemyeloidleukaemiaandmyelodysplasticsyndromehavebeenreportedinassociationwith

docetaxelwhenusedincombinationwithotherchemotherapyagentsand/orradiotherapy.

Bloodandlymphaticsystemdisorders

Bonemarrowsuppressionandotherhaematologicadversereactionshavebeenreported.Disseminatedintravascular

Infectionsandinfestations Infection(G3/4:3.6%) Neutropenicinfection

Neoplasmsbenign,

malignantandunspecified

(inclcystsandpolyps) Cancerpain(G3/4:1.2%)

Bloodandlymphatic

systemdisorders Neutropenia(G3/4:

83.5%);

Anaemia(G3/4:12.4%);

Thrombocytopenia

(G3/4:4.0%);

Febrileneutropenia

Immunesystemdisorders Hypersensitivity

Metabolismandnutrition

disorders Anorexia(G3/4:12.0%)

Nervoussystemdisorders Dysgeusia/Parosmia

(G3/4:0.4%);

Peripheralsensory

neuropathy(G3/4:1.2%) Dizziness(G3/4:2.0%);

Peripheralmotor

neuropathy(G3/4:0.4%)

Eyedisorders Lacrimationincreased Conjunctivitis

Earandlabyrinthdisorders Hearingimpaired

(G3/4:1.2%)

Cardiacdisorders Arrhythmia(G3/4:2.0%) Ischemiamyocardial

Vasculardisorders Venousdisorder

Gastrointestinaldisorders Nausea(G3/4:13.9%);

Stomatitis(G3/4:20.7%);

Vomiting(G3/4:8.4%);

Diarrhoea(G3/4:6.8%);

Esophagitis/dysphagia/

odynophagia(G3/4:

12.0%);

Constipation(G3/4:0.4%) Dyspepsia(G3/4:0.8%);

Gastrointestinalpain

(G3/4:1.2%);

Gastrointestinal

haemorrhage(G3/4:0.4%)

Skinandsubcutaneous

tissuedisorders Alopecia(G3/4:4.0%);

Rashpruritic Dryskin;

Desquamation

Musculoskeletal,

connectivetissuebone

disorders Myalgia(G3/4:0.4%)

Generaldisordersand

administrationsite

conditions Lethargy(G3/4:4.0%);

Pyrexia(G3/4:3.6%);

Fluidretention(G3/4:

1.2%);

Oedema(G3/4:1.2%)

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Immunesystemdisorders

Somecasesofanaphylacticshock,sometimesfatal,havebeenreported.

Nervoussystemdisorders

Rarecasesofconvulsionortransientlossofconsciousnesshavebeenobservedwithdocetaxeladministration.These

reactionssometimesappearduringtheinfusionofthemedicinalproduct.

Eyedisorders

Veryrarecasesoftransientvisualdisturbances(flashes,flashinglights,scotomata)typicallyoccurringduringinfusion

ofthemedicinalproductandinassociationwithhypersensitivityreactionshavebeenreported.Thesewerereversible

upondiscontinuationoftheinfusion.Casesoflacrimationwithorwithoutconjunctivitis,ascasesoflacrimalduct

obstructionresultinginexcessivetearinghavebeenrarelyreported.

Earandlabyrinthdisorders

Rarecasesofototoxicity,hearingimpairedand/orhearinglosshavebeenreported.

Cardiacdisorders

Rarecasesofmyocardialinfarctionhavebeenreported.

Vasculardisorders

Venousthromboemboliceventshaverarelybeenreported.

Respiratory,thoracicandmediastinaldisorders

Acuterespiratorydistresssyndrome,interstitialpneumoniaandpulmonaryfibrosishaverarelybeenreported.Rare

casesofradiationpneumonitishavebeenreportedinpatientsreceivingconcomitantradiotherapy.

Gastrointestinaldisorders

Rareoccurrencesofdehydrationasaconsequenceofgastrointestinalevents,gastrointestinalperforation,colitis

ischaemic,colitisandneutropenicenterocolitishavebeenreported.Rarecasesofileusandintestinalobstructionhave

beenreported.

Hepatobiliarydisorders

Veryrarecasesofhepatitis,sometimesfatalprimarilyinpatientswithpre-existingliverdisorders,havebeenreported.

Skinandsubcutaneoustissuedisorders

Veryrarecasesofcutaneouslupuserythematosusandbullouseruptionssuchaserythemamultiforme,Stevens-Johnson

syndrome,toxicepidermalnecrolysis,havebeenreportedwithdocetaxel.Insomecasesconcomitantfactorsmayhave

contributedtothedevelopmentoftheseeffects.Sclerodermal-likechangesusuallyprecededbyperipheral

lymphoedemahavebeenreportedwithdocetaxel.

Generaldisordersandadministrationsiteconditions

Radiationrecallphenomenahaverarelybeenreported.

Fluidretentionhasnotbeenaccompaniedbyacuteepisodesofoliguriaorhypotension.Dehydrationandpulmonary

oedemahaverarelybeenreported.

4.9Overdose

Therewereafewreportsofoverdose.Thereisnoknownantidotefordocetaxeloverdose.Incaseofoverdose,the

patientshouldbekeptinaspecialisedunitandvitalfunctionscloselymonitored.Incasesofoverdose,exacerbationof

adverseeventsmaybeexpected.Theprimaryanticipatedcomplicationsofoverdosewouldconsistofbonemarrow

suppression,peripheralneurotoxicityandmucositis.PatientsshouldreceivetherapeuticG-CSFassoonaspossible

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Taxanes,ATCCode:L01CD02

Preclinicaldata

Docetaxelisanantineoplasticagentwhichactsbypromotingtheassemblyoftubulinintostablemicrotubulesand

inhibitstheirdisassemblywhichleadstoamarkeddecreaseoffreetubulin.Thebindingofdocetaxeltomicrotubules

doesnotalterthenumberofprotofilaments.

Docetaxelhasbeenshowninvitrotodisruptthemicrotubularnetworkincellswhichisessentialforvitalmitoticand

interphasecellularfunctions.

Docetaxelwasfoundtobecytotoxicinvitroagainstvariousmurineandhumantumourcelllinesandagainstfreshly

excisedhumantumourcellsinclonogenicassays.Docetaxelachieveshighintracellularconcentrationswithalongcell

residencetime.Inaddition,docetaxelwasfoundtobeactiveonsomebutnotallcelllinesoverexpressingthe

p-glycoproteinwhichisencodedbythemultidrugresistancegene.Invivo,docetaxelisscheduleindependentandhasa

broadspectrumofexperimentalantitumouractivityagainstadvancedmurineandhumangraftedtumours.

Clinicaldata

Breastcancer

Docetaxelincombinationwithdoxorubicinandcyclophosphamide:adjuvanttherapy

Patientswithoperablenode-positivebreastcancer(TAX316)

Datafromamulticenteropenlabelrandomizedstudysupporttheuseofdocetaxelfortheadjuvanttreatmentofpatients

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).PatientsontheTACarmreceivedantibioticprophylaxiswithciprofloxacin500mgorallytwicedailyfor

10daysstartingonday5ofeachcycle,orequivalent.Inbotharms,afterthelastcycleofchemotherapy,patientswith

positiveestrogenand/orprogesteronereceptorsreceivedtamoxifen20mgdailyforupto5years.Adjuvantradiation

therapywasprescribedaccordingtoguidelinesinplaceatparticipatinginstitutionsandwasgivento69%ofpatients

whoreceivedTACand72%ofpatientswhoreceivedFAC.

Aninterimanalysiswasperformedwithamedianfollowupof55months.Significantlylongerdisease-freesurvivalfor

theTACarmcomparedtotheFACarmwasdemonstrated.Incidenceofrelapsesat5yearswasreducedinpatients

receivingTACcomparedtothosewhoreceivedFAC(25%versus32%,respectively)i.e.anabsoluteriskreductionby

7%(p=0.001).Overallsurvivalat5yearswasalsosignificantlyincreasedwithTACcomparedtoFAC(87%versus

81%,respectively)i.e.anabsolutereductionoftheriskofdeathby6%(p=0.008).TAC-treatedpatientsubsets

accordingtoprospectivelydefinedmajorprognosticfactorswereanalyzed:

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

Patientsubset Number

of

patients Hazard

ratio* 95%CI p= Hazard

ratio* 95%CI p=

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*ahazardratiooflessthan1indicatesthatTACisassociatedwithalongerdisease-freesurvivalandoverallsurvival

comparedtoFAC

ThebeneficialeffectofTACwasnotproveninpatientswith4andmorepositivenodes(37%ofthepopulation)atthe

interimanalysisstage.Theeffectappearstobelesspronouncedthaninpatientswith1-3positivenodes.The

benefit/riskratiowasnotdefinedfullyinpatientswith4andmorepositivenodesatthisanalysisstage.

Patientswithoperablenode-negativebreastcancereligibletoreceivechemotherapy(GEICAM9805)

Datafromamulticenteropenlabelreandomizedtrialsupporttheuseofdocestaxelfortheadjuvanttreatmentof

patientswithoperablenode-negativebreastcancereligibletoreceivechemotherapy.

1060patientswererandomizedtoreceiveeitherDocirena75mg/m 2

administered1-hourafterdoxorubicin50mg/m 2

andcyclophosphamide500mg/m 2

(539patientsinTACarm),ordoxorubicin50mg/m 2

followedbyfluorouracil500

mg/m 2

andcyclosphosphamide500mg/m 2

(521patientsinFACarm),asadjuvanttreatmentofoperablenode-

negativebreastcancerpatientswithhighriskofrelapseaccordingto1998St.Gallencriteria(tumoursize>2cmand/or

negativeERandPRand/orhighhistological/nucleargrade(grade2to3)and/orage<35years).).Bothregimenswere

administeredonceevery3weeksfor6cycles.Docirenawasadministeredasa1-hourinfusion,allotherdrugswere

givenintraveinously onday1everythreeweeks.PrimaryprophylacticG-CSFwasmademandatoryinTACarmafter

230patientswererandomized.TheincidenceofGrade4neutropenia,febrileneutropeniaandneutropenicinfection

wasdecreasedinpatientswhoreceivedprimaryG-CSFprophylaxis(seesection4.8).Inbotharms,afterthelastcycle

ofchemotherapy,patientswithER+and/orPgR+tumoursreceivedtamoxifen20mgonceadayforupto5years.

Adjuvantradiationtherapywasadministeredaccordingtoguidelinesinplaceatparticipatinginstitutionsandwasgiven

to57.3%ofpatientswhoreceivedTACand51.2%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(hazardratio=0.76,95%

CI(0.46-1.26,p=0.29).However,thedistributionofOSwasnotsignificantlydifferentbetweenthe2groups.

TAC-treatedpatientsubsetsaccordingtoprospectivelydefinedmajorprognosticfactorswereanalyzed(see

tablebelow):

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 Numberof

patientsin

TACgroup DiseaseFreeSurvival

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

0.52-1.01

Hormonal

receptorstatus

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

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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

ER/PR-negativeorGrade3ortumoursize>5cm

TheestimatedhazardratiowasusingCoxproportionalhazardmodelwithtreatmentgroupasthefactor.

Docetaxelassingleagent

TworandomisedphaseIIIcomparativestudies,involvingatotalof326alkylatingor392anthracyclinefailure

metastaticbreastcancerpatients,havebeenperformedwithdocetaxelattherecommendeddoseandregimenof

100mg/m²every3weeks.

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

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

27weeksvs.doxorubicin23weeks,p=0.54),docetaxelincreasedresponserate(52%vs.37%,p=0.01)and

shortenedtimetoresponse(12weeksvs.23weeks,p=0.007).Threedocetaxelpatients(2%)discontinuedthe

treatmentduetofluidretention,whereas15doxorubicinpatients(9%)discontinuedduetocardiactoxicity(threecases

offatalcongestiveheartfailure).

Inanthracycline-failurepatients,docetaxelwascomparedtothecombinationofmitomycinCandvinblastine

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

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

9months,p=0.01).

DuringthesetwophaseIIIstudies,thesafetyprofileofdocetaxelwasconsistentwiththesafetyprofileobservedin

phaseIIstudies(seesection4.8).

Histologicalgrade

Grade1(includes

gradenotassessed)

Grade2

Grade3 64

0.79

0.77

0.59 0.24-2.6

0.46-1.3

0.39-0.9

Menopausalstatus

Pre-Menopausal

Post-Menopausal 285

0.64

0.72 0.40-1

0.47-

1.12

Subgroups TAC

(n=539) FAC

(n=521) Hazard

ratio

(TAC/FAC)

(95%CI) p-value

Meetingrelative

indicationfor

chemotherapy a

18/214 26/227 0.796(0.434-1.459) 0.4593

(8.4%) (11.5%)

48/325 69/294 0.606(0.42-0.877) 0.0072

(14.8%) (23.5%)

PR=progesteronereceptor

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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

(60mg/m²)incombinationwithcyclophosphamide(600mg/m²)(ACarm).Bothregimenswereadministeredonday1

every3weeks.

Timetoprogression(TTP)wassignificantlylongerintheATarmversusACarm,p=0.0138.ThemedianTTP

was37.3weeks(95%CI:33.4-42.1)inATarmand31.9weeks(95%CI:27.4-36.0)inACarm.

Overallresponserate(ORR)wassignificantlyhigherintheATarmversusACarm,p=0.009.TheORRwas

59.3%(95%CI:52.8-65.9)inATarmversus46.5%(95%CI:39.8-53.2)inACarm.

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

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

versus0%)thanACarm.Ontheotherhand,ACarmshowedahigherincidenceofsevereanaemia(15.8%versus

8.5%)thanATarm,and,inaddition,ahigherincidenceofseverecardiactoxicity:congestiveheartfailure(3.8%

versus2.8%),absoluteLVEFdecrease³20%(13.1%versus6.1%),absoluteLVEFdecrease³30%(6.2%versus

1.1%).Toxicdeathsoccurredin1patientintheATarm(congestiveheartfailure)andin4patientsintheACarm

(1duetosepticshockand3duetocongestiveheartfailure).

Inbotharms,qualityoflifemeasuredbytheEORTCquestionnairewascomparableandstableduringtreatmentand

follow-up.

Docetaxelincombinationwithtrastuzumab

Docetaxelincombinationwithtrastuzumabwasstudiedforthetreatmentofpatientswithmetastaticbreastcancer

whosetumoursoverexpressHER2,andwhopreviouslyhadnotreceivedchemotherapyformetastaticdisease.One

hundredeightysixpatientswererandomizedtoreceivedocetaxel(100mg/m 2

)withorwithouttrastuzumab;60%of

patientsreceivedprioranthracycline-basedadjuvantchemotherapy.Docetaxelplustrastuzumabwasefficaciousin

patientswhetherornottheyhadreceivedprioradjuvantanthracyclines.ThemaintestmethodusedtodetermineHER2

positivityinthispivotalstudywasimmunohistochemistry(IHC).Aminorityofpatientsweretestedusingfluorescence

in-situhybridization(FISH).Inthisstudy,87%ofpatientshaddiseasethatwasIHC3+,and95%ofpatientsentered

haddiseasethatwasIHC3+and/orFISHpositive.Efficacyresultsaresummarizedinthefollowingtable:

TTP=timetoprogression;“ne”indicatesthatitcouldnotbeestimatedoritwasnotyetreached.

Fullanalysisset(intent-to-treat)

Estimatedmediansurvival

Docetaxelincombinationwithcapecitabine

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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withcapecitabinefortreatmentofpatientswithlocallyadvancedormetastaticbreastcancerafterfailureofcytotoxic

chemotherapy,includingananthracycline.Inthisstudy,255patientswererandomisedtotreatmentwithdocetaxel

(75mg/m 2

asa1hourintravenousinfusionevery3weeks)andcapecitabine(1250mg/m 2

twicedailyfor2weeks

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

asa

1hourintravenousinfusionevery3weeks).Survivalwassuperiorinthedocetaxel+capecitabinecombinationarm

(p=0.0126).Mediansurvivalwas442days(docetaxel+capecitabine)vs.352days(docetaxelalone).Theoverall

objectiveresponseratesintheall-randomisedpopulation(investigatorassessment)were41.6%(docetaxel+

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

capecitabinecombinationarm(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-related

medicinalproducts(p=0.06)andradiotherapy(p<0.01)inpatientstreatedwithdocetaxelat75mg/m²comparedto

thosewithBSC.

Theoverallresponseratewas6.8%intheevaluablepatients,andthemediandurationofresponsewas26.1weeks.

Docetaxelincombinationwithplatinumagentsinchemotherapy-naïvepatients

InaphaseIIIstudy,1218patientswithunresectablestageIIIBorIVNSCLC,withKPSof70%orgreater,andwho

didnotreceivepreviouschemotherapyforthiscondition,wererandomisedtoeitherdocetaxel(T)75mg/m 2

asa

1hourinfusionimmediatelyfollowedbycisplatin(Cis)75mg/m 2

over30-60minutesevery3weeks(TCis),docetaxel

75mg/m 2

asa1hourinfusionincombinationwithcarboplatin(AUC6mg/ml.min)over30-60minutesevery3weeks,

orvinorelbine(V)25mg/m 2

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

administeredonday1ofcyclesrepeatedevery4weeks(VCis).

Survivaldata,mediantimetoprogressionandresponseratesfortwoarmsofthestudyareillustratedinthefollowing

table:

*:Correctedformultiplecomparisonsandadjustedforstratificationfactors(stageofdiseaseandregionof

treatment),basedonevaluablepatientpopulation.

Secondaryend-pointsincludedchangeofpain,globalratingofqualityoflifebyEuroQoL-5D,LungCancerSymptom

Scale,andchangesinKarnosfkyperformancestatus.Resultsontheseend-pointsweresupportiveoftheprimaryend-

TCis

n=408 VCis

n=404 Statisticalanalysis

Overallsurvival

(Primaryend-point):

Mediansurvival(months) 11.3 10.1 Hazardratio:1.122

[97.2%CI:0.937;1.342]*

1-yearSurvival(%) 46 41 Treatmentdifference:5.4%

[95%CI:-1.1;12.0]

2-yearSurvival(%) 21 14 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

refractorymetastaticprostatecancerwereevaluatedinarandomizedmulticenterphaseIIIstudy.Atotalof

1006patientswithKPS 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,randomizedstudywasconductedtoevaluatethesafetyandefficacyofdocetaxelforthe

Endpoint Docetaxel

every3weeks Docetaxel

everyweek Mitoxantrone

every3weeks

Numberofpatients

Mediansurvival(months)

95%CI

Hazardratio

95%CI

p-value †

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

Tumourresponserate(%)

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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junction,whohadnotreceivedpriorchemotherapyformetastaticdisease.Atotalof445patientswithKPS>70were

treatedwitheitherdocetaxel(T)(75mg/m 2

onday1)incombinationwithcisplatin(C)(75mg/m 2

onday1)and5-

fluorouracil(F)(750mg/m 2

perdayfor5days)orcisplatin(100mg/m 2

onday1)and5-fluorouracil(1000mg/m 2

dayfor5days).Thelengthofatreatmentcyclewas3weeksfortheTCFarmand4weeksfortheCFarm.Themedian

numberofcyclesadministeredperpatientwas6(witharangeof1-16)fortheTCFarmcomparedto4(witharangeof

1-12)fortheCFarm.Timetoprogression(TTP)wastheprimaryendpoint.Theriskreductionofprogressionwas

32.1%andwasassociatedwithasignificantlylongerTTP(p=0.0004)infavoroftheTCFarm.Overallsurvivalwas

alsosignificantlylonger(p=0.0201)infavoroftheTCFarmwithariskreductionofmortalityof22.7%.Efficacy

resultsaresummarizedinthefollowingtable:

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,randomizedstudy(TAX323).Inthisstudy,

358patientswithinoperablelocallyadvancedSCCHN,andWHOperfomancestatus0or1,wererandomizedtooneof

twotreatmentarms.Patientsonthedocetaxelarmreceiveddocetaxel(T)75mg/m 2

followedbycisplatin(P)75mg/m 2

followedby5-fluorouracil(F)750mg/m 2

perdayasacontinuousinfusionfor5days.Thisregimenwasadministered

everythreeweeksfor4cyclesincaseatleastaminorresponse( ≥25%reductioninbidimensionallymeasuredtumour

size)wasobservedafter2cycles.Attheendofchemotherapy,withaminimalintervalof4weeksandamaximal

intervalof7weeks,patientswhosediseasedidnotprogressreceivedradiotherapy(RT)accordingtoinstitutional

guidelinesfor7weeks(TPF/RT).Patientsonthecomparatorarmreceivedcisplatin(P)100mg/m 2

followedby

5-fluorouracil(F)1000mg/m 2

Endpoint TCF

n=221 CF

n=224

MedianTTP(months) 5.6 3.7

(95%CI) (4.86-5.91) (3.45-4.47)

Hazardratio 1.473

(95%CI) (1.189-1.825)

*p-value 0.0004

Mediansurvival(months) 9.2 8.6

(95%CI) (8.38-10.58) (7.16-9.46)

2-yearestimate(%) 18.4 8.8

Hazardratio 1.293

(95%CI) (1.041-1.606)

*p-value 0.0201

Overallresponserate(CR+PR)(%) 36.7 25.4

p-value 0.0106

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caseatleastaminorresponse( ≥25%reductioninbidimensionallymeasuredtumoursize)wasobservedafter2cycles.

Attheendofchemotherapy,withaminimalintervalof4weeksandamaximalintervalof7weeks,patientswhose

diseasedidnotprogressreceivedradiotherapy(RT)accordingtoinstitutionalguidelinesfor7weeks(PF/RT).

Locoregionaltherapywithradiationwasdeliveredeitherwithaconventionalfraction(1.8Gy-2.0Gyonceaday,

5daysperweekforatotaldoseof66to70Gy),oraccelerated/hyperfractionatedregimensofradiationtherapy(twice

aday,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:

EfficacyofdocetaxelintheinductiontreatmentofpatientswithinoperablelocallyadvancedSCCHN(Intent-to-

TreatAnalysis)

Ahazardratiooflessthan1favorsdocetaxel+cisplatin+5-FU

*Coxmodel(adjustmentforPrimarytumoursite,TandNclinicalstagesandPSWHO)

**Logranktest

***Chi-squaretest

Qualityoflifeparameters

PatientstreatedwithTPFexperiencedsignificantlylessdeteriorationoftheirGlobalhealthscorecomparedtothose

treatedwithPF(p=0.01,usingtheEORTCQLQ-C30scale).

Clinicalbenefitparameters

Theperformancestatusscale,forheadandneck(PSS-HN)subscalesdesignedtomeasureunderstandabilityofspeech,

Endpoint Docetaxel+

Cis+5-FU

n=177 Cis+5-FU

n=181

Medianprogressionfreesurvival(months)

(95%CI) 11.4

(10.1-14.0) 8.3

(7.4-9.1)

Adjustedhazardratio

(95%CI)

*p-value 0.70

(0.55-0.89)

0.0042

Mediansurvival(months)

(95%CI) 18.6

(15.7-24.0) 14.5

(11.6-18.7)

Hazardratio

(95%CI)

**p-value 0.72

(0.56-0.93)

0.0128

Bestoverallresponsetochemotherapy(%)

(95%CI) 67.8

(60.4-74.6) 53.6

(46.0-61.0)

***p-value 0.006

Bestoverallresponsetostudytreatment

[chemotherapy+/-radiotherapy](%)

(95%CI) 72.3

(65.1-78.8) 58.6

(51.0-65.8)

***p-value 0.006

Mediandurationofresponsetochemotherapy ±

radiotherapy(months)

(95%CI) n=128

15.7

(13.4-24.6) n=106

11.7

(10.2-17.4)

Hazardratio

(95%CI)

**p-value 0.72

(0.52-0.99)

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MediantimetofirstdeteriorationofWHOperformancestatuswassignificantlylongerintheTPFarmcomparedtoPF.

Painintensityscoreimprovedduringtreatmentinbothgroupsindicatingadequatepainmanagement.

Inductionchemotherapyfollowedbychemoradiotherapy(TAX324)

Thesafetyandefficacyofdocetaxelintheinductiontreatmentofpatientswithlocallyadvancedsquamouscell

carcinomaoftheheadandneck(SCCHN)wasevaluatedinarandomized,multicenteropen-label,phaseIIIstudy

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

randomizedtooneoftwoarms.Thestudypopulationcomprisedpatientswithtechnicallyunresectabledisease,patients

withlowprobabilityofsurgicalcureandpatientsaimingatorganpreservation.Theefficacyandsafetyevaluation

solelyaddressedsurvivalendpointsandthesuccessoforganpreservationwasnotformallyaddressed.Patientsonthe

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

administeredasa30-minutetothree-hourintravenousinfusion,followedbythecontinuousintravenousinfusionof

5-fluorouracil(F)1000mg/m²/dayfromday1today4.Thecycleswererepeatedevery3weeksfor3cycles.All

patientswhodidnothaveprogressivediseaseweretoreceivechemoradiotherapy(CRT)asperprotocol(TPF/CRT).

Patientsonthecomparatorarmreceivedcisplatin(P)100mg/m²asa30-minutetothree-hourintravenousinfusionon

day1followedbythecontinuousintravenousinfusionof5-fluorouracil(F)1000mg/m²/dayfromday1today5.The

cycleswererepeatedevery3weeksfor3cycles.Allpatientswhodidnothaveprogressivediseaseweretoreceive

CRTasperprotocol(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)withanoverallmedianfollowuptimeof41.9months.Thesecondaryendpoint,PFS,demonstrateda

29%riskreductionofprogressionordeathanda22monthimprovementinmedianPFS(35.5monthsforTPFand13.1

forPF).ThiswasalsostatisticallysignificantwithanHRof0.71;95%CI0.56-0.90;log-ranktestp=0.004.Efficacy

resultsarepresentedinthetablebelow:

EfficacyofdocetaxelintheinductiontreatmentofpatientswithlocallyadvancedSCCHN(Intent-to-Treat

Analysis)

Endpoint Docetaxel+Cis+5-FU

n=255 Cis+5-FU

n=246

Medianoverallsurvival(months)

(95%CI) 70.6

(49.0-NA) 30.1

(20.9-51.5)

Hazardratio:

(95%CI)

*p-value 0.70

(0.54-0.90)

0.0058

MedianPFS(months)

(95%CI) 35.5

(19.3-NA) 13.1

(10.6-20.2)

Hazardratio:

(95%CI)

**p-value 0.71

(0.56-0.90)

0.004

Bestoverallresponse(CR+PR)to

chemotherapy(%)

(95%CI) 71.8

(65.8-77.2) 64.2

(57.9-70.2)

***p-value 0.070

Bestoverallresponse(CR+PR)to

studytreatment[chemotherapy+/-

chemoradiotherapy](%)

(95%CI) 76.5

(70.8-81.5) 71.5

(65.5-77.1)

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Ahazardratiooflessthan1favorsdocetaxel+cisplatin+fluorouracil

*un-adjustedlog-ranktest

**un-adjustedlog-ranktest,notadjustedformultiplecomparisons

***Chisquaretest,notadjustedformultiplecomparisons

NA-notapplicable

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithdocetaxelinall

subsetsofthepaediatricpopulationinbreastcancer,non-smallcelllungcancer,prostatedcancer,gastriccarcinoma

andheadandneckcancer,notincludingtypeIIandIIIlessdifferentiatednasopharyngealcarcinoma(seesection

4.2forinformationonpaediatricuse).

5.2Pharmacokineticproperties

Thepharmacokineticsofdocetaxelhavebeenevaluatedincancerpatientsafteradministrationof

20-115mg/m 2

inphaseIstudies.Thekineticprofileofdocetaxelisdoseindependentandconsistentwithathree-

compartmentpharmacokineticmodelwithhalflivesforthea,bandgphasesof4min,36minand11.1h,respectively.

Thelatephaseisdue,inpart,toarelativelysloweffluxofdocetaxelfromtheperipheralcompartment.Followingthe

administrationofa100mg/m 2

dosegivenasaone-hourinfusionameanpeakplasmalevelof3.7µg/mlwasobtained

withacorrespondingAUCof4.6h.µg/ml.Meanvaluesfortotalbodyclearanceandsteady-statevolumeofdistribution

were21l/h/m 2

and113l,respectively.Interindividualvariationintotalbodyclearancewasapproximately50%.

Docetaxelismorethan95%boundtoplasmaproteins.

Astudyof 14

C-docetaxelhasbeenconductedinthreecancerpatients.Docetaxelwaseliminatedinboththeurineand

faecesfollowingcytochromeP450-mediatedoxidativemetabolismofthetert-butylestergroup,withinsevendays,the

urinaryandfaecalexcretionaccountedforabout6%and75%oftheadministeredradioactivity,respectively.About

80%oftheradioactivityrecoveredinfaecesisexcretedduringthefirst48hoursasonemajorinactivemetaboliteand

3minorinactivemetabolitesandverylowamountsofunchangedmedicinalproduct.

Apopulationpharmacokineticanalysishasbeenperformedwithdocetaxelin577patients.Pharmacokineticparameters

estimatedbythemodelwereveryclosetothoseestimatedfromphaseIstudies.Thepharmacokineticsofdocetaxel

werenotalteredbytheageorsexofthepatient.Inasmallnumberofpatients(n=23)withclinicalchemistrydata

suggestiveofmildtomoderateliverfunctionimpairment(ALT,AST ≥1.5timestheULNassociatedwithalkaline

phosphatase ≥2.5timestheULN),totalclearancewasloweredby27%onaverage(seesection4.2).Docetaxel

clearancewasnotmodifiedinpatientswithmildtomoderatefluidretentionandtherearenodataavailableinpatients

withseverefluidretention.

Whenusedincombination,docetaxeldoesnotinfluencetheclearanceofdoxorubicinandtheplasmalevelsof

doxorubicinol(adoxorubicinmetabolite).Thepharmacokineticsofdocetaxel,doxorubicinandcyclophosphamide

werenotinfluencedbytheirco-administration.

PhaseIstudyevaluatingtheeffectofcapecitabineonthepharmacokineticsofdocetaxelandviceversashowedno

effectbycapecitabineonthepharmacokineticsofdocetaxel(CmaxandAUC)andnoeffectbydocetaxelonthe

pharmacokineticsofarelevantcapecitabinemetabolite5’-DFUR.

Clearanceofdocetaxelincombinationtherapywithcisplatinwassimilartothatobservedfollowingmonotherapy.The

pharmacokineticprofileofcisplatinadministeredshortlyafterdocetaxelinfusionissimilartothatobservedwith

cisplatinalone.

Thecombinedadministrationofdocetaxel,cisplatinand5-fluorouracilin12patientswithsolidtumourshadno

influenceonthepharmacokineticsofeachindividualmedicinalproduct.

Theeffectofprednisoneonthepharmacokineticsofdocetaxeladministeredwithstandarddexamethasone

premedicationhasbeenstudiedin42patients.Noeffectofprednisoneonthepharmacokineticsofdocetaxelwas

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5.3Preclinicalsafetydata

Thecarcinogenicpotentialofdocetaxelhasnotbeenstudied.

DocetaxelhasbeenshowntobemutagenicintheinvitromicronucleusandchromosomeaberrationtestinCHO-K1

cellsandintheinvivomicronucleustestinthemouse.However,itdidnotinducemutagenicityintheAmestestorthe

CHO/HGPRTgenemutationassay.Theseresultsareconsistentwiththepharmacologicalactivityofdocetaxel.

Undesirableeffectsonthetestisobservedinrodenttoxicitystudiessuggestthatdocetaxelmayimpairmalefertility.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Polysorbate80

Ethanol96%

Citricacidmonohydrate

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Vial

24months

Afteropeningofthevial

Eachvialisforsingleuseandshouldbeusedimmediatelyafteropening.Ifnotusedimmediately,in-usestoragetimes

andconditionsaretheresponsibilityoftheuser.

Onceaddedtotheinfusionbag

Frommicrobiologicalpointofview,reconstitution/dilutionmusttakeplaceincontrolledandasepticconditionsandthe

medicinalproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimesandconditionsarethe

responsibilityoftheuser.

Onceaddedasrecommendedintotheinfusionbag(PP)orinfusionbottle(PE),thedocetaxelinfusionsolution,if

storedbelow25°C,isstablefor8hoursininfusionbottleorfor6hoursininfusionbag.Itshouldbeusedwithin6-8

hours(includingtheonehourinfusionIVadministration).

Inaddition,physicalandchemicalin-usestabilityoftheinfusionsolutionpreparedasrecommendedhasbeen

demonstratedinnon-PVCbagsupto48hourswhenstoredbetween2to8°C.

Docetaxelinfusionsolutionissupersaturated,thereforemaycrystallizeovertime.Ifcrystalsappear,thesolutionmust

nolongerbeusedandshallbediscarded.

6.4Specialprecautionsforstorage

Storeinarefrigerator(2°C–8°C).Storeintheoriginalpackageinordertoprotectfromlight.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

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consistingofanaluminiumshellandagreenplasticflip-offbutton.TherubberstopperiscoatedwithaTeflon®barrier

film.

Eachboxcontainsonevialwith1mlfillvolume

6.6Specialprecautionsfordisposalandotherhandling

Docirenaisanantineoplasticagentand,aswithotherpotentiallytoxiccompounds,cautionshouldbeexercisedwhen

handlingitandpreparingDocirenasolutions.Theuseofglovesisrecommended.

IfDocirenaconcentrateorinfusionsolutionshouldcomeintocontactwithskin,washimmediatelyandthoroughlywith

soapandwater.IfDocirenaconcentrateorinfusionsolutionshouldcomeintocontactwithmucousmembranes,wash

immediatelyandthoroughlywithwater.

Preparationfortheintravenousadministration

Preparationoftheinfusionsolution

DONOTuseotherdocetaxelmedicinalproductsconsistingofmorethanonevial(concentrateandsolvent)with

thismedicinalproduct(Docirena20mg/1mlconcentrateforsolutionforinfusion,whichcontainsonly1vial).

Docirena20mg/1mlconcentrateforsolutionforinfusionrequiresNOpriordilutionwithasolventandisready

toaddtotheinfusionsolution.

Eachvialisofsingleuseandshouldbeusedimmediately.

AllowtherequirednumberofboxesofDocirenaconcentrateforsolutionforinfusiontostandbelow25°Cfor

5minutesbeforeuse.

MorethanonevialofDocirenaconcentrateforsolutionforinfusionmaybenecessarytoobtaintherequireddosefor

thepatient.AsepticallywithdrawtherequiredamountofDocirenaconcentrateforsolutionforinfusionusinga

calibratedsyringe.

InDocirena20mg/1mlvialtheconcentrationofdocetaxelis20mg/ml.

TherequiredvolumeofDocirenaconcentrateforsolutionforinfusionmustbeinjectedintoa250mlinfusionbagor

bottlecontainingeitherglucosesolution50mg/ml(5%)orsodiumchloride9mg/ml(0.9%)solutionforinfusion.

Ifadosegreaterthan190mgofdocetaxelisrequired,usealargervolumeoftheinfusionvehiclesothataconcentration

of0.74mg/mldocetaxelisnotexceeded.

Mixtheinfusionbagorbottlemanuallyusingarockingmotion.

Theinfusionbagsolutionshouldbeusedwithin8hoursbelow25°Cincludingtheonehourinfusiontothepatient.

Aswithallparenteralproducts,Docirenainfusionsolutionshouldbevisuallyinspectedpriortouse,solutions

containingaprecipitateshouldbediscarded.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

FreseniusKabiLimited

CestrianCourt,EastgateWay

ManorPark,Runcorn

CheshireWA71NT

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8MARKETINGAUTHORISATIONNUMBER

PA566/59/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26thAugust2011

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