TAXOTERE

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Active ingredient:
DOCETAXEL AS TRIHYDRATE 20 MG / 1 ML
Available from:
SANOFI - AVENTIS ISRAEL LTD
ATC code:
L01CD02
Pharmaceutical form:
CONCENTRATE FOR SOLUTION FOR INFUSION
Administration route:
I.V
Manufactured by:
SANOFI - AVENTIS DEUTSCHLAND GMBH, GERMANY
Therapeutic group:
DOCETAXEL
Therapeutic indications:
Breast cancer: Taxotere (docetaxel) in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node- positive breast cancer. Taxotere (docetaxel) in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition. Taxotere(docetaxel) monotherapy is indicated for the treatment of patients with metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent. Taxotere (docetaxel) in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2 and who previously have not received chemotherapy for metastatic disease. Taxotere (docetaxel) in combination with capecitabine is indicated for the treatment of patients with metastatic breast cancer after failure of cytotoxic chemotherapy.
Authorization number:
144443309201
Authorization date:
2012-11-01

PRESCRIBING INFORMATION

TAXOTERE®

1. NAME OF THE MEDICINAL PRODUCT

TAXOTERE20 mg/1 ml concentrate for solution for infusion

TAXOTERE80 mg/4 ml concentrate for solution for infusion

WARNING

TAXOTERE(DOCETAXEL)CONCENTRATEFORSOLUTIONFORINFUSIONSHOULDBEADMINISTEREDUNDER

THESUPERVISIONOFAPHYSICIANEXPERIENCEDINTHEUSEOFANTINEOPLASTICAGENTS.APPROPRIATE

MANAGEMENTOFCOMPLICATIONSISPOSSIBLEONLYWHENADEQUATEDIAGNOSTICANDTREATMENTFACILITIES

ARE READILY AVAILABLE.

TAXOTERETHERAPYSHOULDNOTBEGIVENTOPATIENTSWITHNEUTROPHILCOUNTSOFLESSTHAN

1,500CELLS/MM 3 .INORDERTOMONITORTHEOCCURRENCEOFNEUTROPENIA,WHICHMAYBESEVEREAND

RESULTININFECTION,ITISRECOMMENDEDTHATFREQUENTBLOODCELLCOUNTSBEPERFORMEDONALL

PATIENTS RECEIVING TAXOTERE.

SEVEREHYPERSENSITIVITYREACTIONSRESULTINGINIMMEDIATEDISCONTINUATIONSOCCURREDIN0.4%

(5OF1260)OFPATIENTS.TAXOTEREMUSTNOTBEGIVENTOPATIENTSWHOHAVEAHISTORYOFSEVERE

HYPERSENSITIVITY REACTIONS TO TAXOTERE OR TO OTHER DRUGS FORMULATED WITH POLYSORBATE 80.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml ofconcentrate contains 20 mg docetaxel (as trihydrate).

TAXOTERE 20 mg/1 ml

One vial of1 ml ofconcentrate contains 20 mg ofdocetaxel.

Excipient with known effect:

Each vial ofconcentrate contains 0.5 ml ofethanol anhydrous (395 mg).

For the full list ofexcipients, see section 6.1.

TAXOTERE 80 mg/4 ml

One vial of4 ml ofconcentrate contains 80 mg ofdocetaxel.

Excipient with known effect:

Each vial ofconcentrate contains 2 ml ofethanol anhydrous (1.58 g).

For the full list ofexcipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

The concentrate is a pale yellow to brownish‑yellow solution.

4. CLINICAL PARTICULARS

4.1.1Therapeutic indications

Breast cancer

TAXOTERE(docetaxel)incombinationwithdoxorubicinandcyclophosphamideisindicatedfortheadjuvant

treatment ofpatients with operable node‑positive breast cancer.

TAXOTERE(docetaxel)incombinationwithdoxorubicinisindicatedforthetreatmentofpatientswithlocally

advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition.

TAXOTERE(docetaxel)monotherapyisindicatedforthetreatmentofpatientswithmetastaticbreastcancerafter

failureofcytotoxictherapy.Previouschemotherapyshouldhaveincludedananthracyclineoranalkylating

agent.

TAXOTERE(docetaxel)incombinationwithtrastuzumabisindicatedforthetreatmentofpatientswithmetastatic

breastcancerwhosetumorsoverexpressHER2andwhopreviouslyhavenotreceivedchemotherapyformetastatic

disease.

TAXOTERE(docetaxel)incombinationwithcapecitabineisindicatedforthetreatmentofpatientswithmetastatic

breast cancer after failure ofcytotoxic chemotherapy. Previous therapy should have included an anthracycline.

DoxorubicinandcyclophosphamidefollowedbyTAXOTEREincombinationwithtrastuzumab(AC‑TH)isindicated

fortheadjuvanttreatmentofpatientswithHER2over‑expressing,node‑positiveorhighrisknode‑negative,

breast cancer.

TAXOTEREincombinationwithtrastuzumabandcarboplatin(TCH)isindicatedfortheadjuvanttreatmentof

patients with HER2 over‑expressing, node‑positive or high risk node‑negative, breast cancer.

Non-small cell lung cancer

TAXOTERE (docetaxel) is indicated for the treatment ofpatients with advanced non‑small cell lung carcinoma.

Ovarian cancer

TAXOTERE(docetaxel)isindicatedfortreatmentofmetastaticcarcinomaoftheovaryafterfailureoffirstlineor

subsequent chemotherapy.

Prostate cancer

TAXOTERE(docetaxel)incombinationwithprednisoneorprednisoloneisindicatedforthetreatmentofpatients

with hormone refractory metastatic prostate cancer.

Esophageal cancer

TAXOTERE (docetaxel) is indicated for the treatment ofesophageal cancer.

Gastric cancer

TAXOTERE (docetaxel) is indicated for the treatment ofadvanced gastric cancer.

Head and neck (SCCHN)

TAXOTERE as monotherapy is indicated for the treatment of patients with recurrent and/or metastatic squamous

cell carcinoma ofthe head and neck after failure ofa previous chemotherapy regimen.

TAXOTERE in combination with cisplatin and 5‑fluorouracil is indicated for the induction treatment of patients

with locally advanced squamous cell carcinoma ofthe head and neck.

4.1.2Additional Therapeutic Activity

Ovarian cancer:

TAXOTERE(docetaxel)incombinationwithcarboplatinisusedfortreatmentofpatientswithadvancedcarcinoma

ofthe ovary who have not previously received cytotoxic therapy for this condition.

Recommended doses are carboplatin AUC 5 plus TAXOTERE (docetaxel) 75 mg/m 2 .

4.2Posology and method ofadministration

Theuseofdocetaxelshouldbeconfinedtounitsspecialisedintheadministrationofcytotoxicchemotherapy

anditshouldonlybeadministeredunderthesupervisionofaphysicianqualifiedintheuseofanticancer

chemotherapy (see section 6.6).

Recommended dose

Forbreast,non‑smallcelllung,ovarian,esophageal,gastric,andheadandneckcancers,premedicationconsisting

ofanoralcorticosteroid,suchasdexamethasone16mgperday(e.g.,8mgBID)for3daysstarting1daypriorto

docetaxel administration, unless contraindicated, can be used (see section 4.4).

Prophylactic G‑CSF may be used to mitigate the risk ofhaematological toxicities.

Forprostatecancer,giventheconcurrentuseofprednisoneorprednisolonetherecommendedpremedication

regimenisoraldexamethasone8mg,12hours,3hoursand1hourbeforethedocetaxelinfusion(seesection

4.4).

Docetaxel is administered as a one‑hour infusion every three weeks.

Breast cancer

Intheadjuvanttreatmentofoperablenode‑positivebreastcancer,therecommendeddoseofdocetaxelis

75mg/m 2 administered1‑hourafterdoxorubicin50mg/m 2 andcyclophosphamide500mg/m 2 every3weeksfor

6 cycles (TAC regimen) (see also Dosage adjustments during treatment).

Forthetreatmentofpatientswithlocallyadvancedormetastaticbreastcancer,therecommendeddoseof

docetaxelis100mg/m 2 inmonotherapy.Infirst‑linetreatment,docetaxel75mg/m 2 isgivenincombination

therapy with doxorubicin (50 mg/m 2 ).

Incombinationwithtrastuzumabtherecommendeddoseofdocetaxelis100mg/m 2 everythreeweeks,with

trastuzumabadministeredweekly.Inthepivotalstudytheinitialdocetaxelinfusionwasstartedthedayfollowing

thefirstdoseoftrastuzumab.Thesubsequentdocetaxeldoseswereadministeredimmediatelyaftercompletion

ofthetrastuzumabinfusion,iftheprecedingdoseoftrastuzumabwaswelltolerated.Fortrastuzumabdosage

and administration, see summary ofproduct characteristics.

Incombinationwithcapecitabine,therecommendeddoseofdocetaxelis75mg/m 2 everythreeweeks,combined

withcapecitabineat1250mg/m 2 twicedaily(within30minutesafterameal)for2weeksfollowedby1‑week

restperiod.Forcapecitabinedosecalculationaccordingtobodysurfacearea,seecapecitabinesummaryof

product characteristics.

IntheadjuvanttreatmentofpatientswithoperablebreastcancerwhosetumoursoverexpressHER2the

recommended TAXOTERE dose is as follows:

‑AC‑TH:

AC(cycles1‑4):doxorubicin(A)60mg/m 2 followedbycyclophosphamide(C)600mg/m 2 administeredevery

three weeks for 4 cycles.

TH(cycles5‑8):docetaxel(T)100mg/m 2 administeredeverythreeweeksfor4cycles,andtrastuzumab(H)

administered weekly according the following schedule:

-Cycle 5 (starting three weeks after the last cycle ofAC):

Day 1: trastuzumab 4 mg/kg (loading dose)

Day 2: docetaxel 100 mg/m 2

Days 8 and 15: trastuzumab 2 mg/kg

-Cycles 6 - 8:

Day 1: docetaxel 100 mg/m 2 and trastuzumab 2 mg/kg

Days 8 and 15: trastuzumab 2 mg/kg

Three weeks after day 1 ofcycle 8: trastuzumab 6 mg/kg is given every three weeks.

Trastuzumab is administered for a total duration of1 year.

‑TCH:

TCH(cycles1‑6):docetaxel(T)75mg/m 2 andcarboplatin(C)atAUCof6mg/mL/minadministeredeverythree

weeks and trastuzumab (H) administered weekly according the following schedule:

- Cycle 1:

Day 1: trastuzumab 4 mg/kg (loading dose)

Day 2: docetaxel 75 mg/m 2 and carboplatin at AUC of6 mg/mL/min

Days 8 and 15: trastuzumab 2 mg/kg

- Cycles 2 - 6:

Day 1: docetaxel 75 mg/m 2 followed by carboplatin at AUC of6 mg/mL/min and trastuzumab 2 mg/kg

Days 8 and 15: trastuzumab 2 mg/kg

Three weeks after day 1 ofcycle 6: trastuzumab 6 mg/kg is given every three weeks.

Non-small cell lung cancer

Inchemotherapynaïvepatientstreatedfornon‑smallcelllungcancer,therecommendeddoseregimenisdocetaxel

75mg/m 2 immediatelyfollowedbycisplatin75mg/m 2 over30‑60minutes.Fortreatmentafterfailureofprior

platinum‑based chemotherapy, the recommended dose is 75 mg/m² as a single agent.

Prostate cancer

Therecommendeddoseofdocetaxelis75mg/m 2 .Prednisoneorprednisolone5mgorallytwicedailyis

administered continuously (see section 5.1).

Gastric adenocarcinoma

Therecommendeddoseofdocetaxelis75mg/m 2 asa1hourinfusion,followedbycisplatin75mg/m 2 ,asa

1to3hourinfusion(bothonday1only),followedby5‑fluorouracil750mg/m 2 perdaygivenasa24‑hour

continuousinfusionfor5days,startingattheendofthecisplatininfusion.Treatmentisrepeatedeverythree

weeks.Patientsmustreceivepremedicationwithantiemeticsandappropriatehydrationforcisplatinadministration.

ProphylacticG‑CSFshouldbeusedtomitigatetheriskofhematologicaltoxicities(seealsoDosageadjustments

during treatment).

Esophageal cancer

Theusualadultdosageis70mg/m 2 (bodysurfacearea)asdocetaxel,intraveneouslydripinfusedover1houronce

a day at the intervals of3‑4 weeks. The dosage may be reduced depending on the patients’ symptoms.

Head and neck

TAXOTERE as monotherapy in the treatment of patients with recurrent and/or metastatic squamous cell carcinoma

ofthe head and neck after failure ofa previous chemotherapy regimen.

Inpatientstreatedforrecurrentand/ormetastaticsquamouscellcarcinomaoftheheadandneckafterfailureof

apreviouschemotherapyregimentherecommendeddosageofTAXOTERE(docetaxel)is100mg/m 2 administered

as a one‑hour infusion every three weeks as a single agent.

TAXOTERE plus cisplatin plus 5‑FU as neoadjuvant in patients with locally advanced unresectable squamous

cell carcinoma ofthe head and neck (SCCHN).

Patientsmustreceivepremedicationwithantiemeticsandappropriatehydration(priortoandaftercisplatin

administration).ProphylacticG‑CSFmaybeusedtomitigatetheriskofhematologicaltoxicities.Allpatientson

the docetaxel‑containing arm ofthe TAX 323 and TAX 324 studies, received prophylactic antibiotics.

Induction chemotherapy followed by radiotherapy (TAX 323)

Fortheinductiontreatmentofinoperablelocallyadvancedsquamouscellcarcinomaoftheheadand

neck(SCCHN),therecommendeddoseofdocetaxelis75mg/m 2 asa1hourinfusionfollowedbycisplatin

75mg/m 2 over1hour,ondayone,followedby5‑fluorouracilasacontinuousinfusionat750mg/m 2 per

dayforfivedays.Thisregimenisadministeredevery3weeksfor4cycles.Followingchemotherapy,patients

should receive radiotherapy.

Induction chemotherapy followed by chemoradiotherapy (TAX 324)

Fortheinductiontreatmentofpatientswithlocallyadvanced(technicallyunresectable,lowprobabilityof

surgicalcure,andaimingatorganpreservation)squamouscellcarcinomaoftheheadandneck(SCCHN),

therecommendeddoseofdocetaxelis75mg/m 2 asa1hourintravenousinfusiononday1,followed

bycisplatin100mg/m 2 administeredasa30‑minuteto3hourinfusion,followedby5‑fluorouracil

1000mg/m 2 /dayasacontinuousinfusionfromday1today4.Thisregimenisadministeredevery3weeks

for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.

Forcisplatinand5‑fluorouracildosemodifications,seethecorrespondingsummaryofproduct

characteristics.

Dosage adjustments during treatment:

General

Docetaxel should be administered when the neutrophil count is³1,500 cells/mm 3 .

Inpatientswhoexperiencedeitherfebrileneutropenia,neutrophil<500cells/mm 3 formorethanoneweek,

severeorcumulativecutaneousreactionsorsevereperipheralneuropathyduringdocetaxeltherapy,thedoseof

docetaxelshouldbereducedfrom100mg/m 2 to75mg/m 2 and/orfrom75to60mg/m².Ifthepatientcontinues

to experience these reactions at 60 mg/m², the treatment should be discontinued.

Adjuvant therapy for breast cancer

PrimaryG‑CSFprophylaxisshouldbeconsideredinpatientswhoreceivedocetaxel,doxorubicinand

cyclophosphamide(TAC)adjuvanttherapyforbreastcancer.Patientswhoexperiencefebrileneutropeniaand/or

neutropenicinfectionshouldhavetheirdocetaxeldosereducedto60mg/m²inallsubsequentcycles(seesections

4.4 and 4.8). Patients who experience Grade 3 or 4 stomatitis should have their dose decreased to 60 mg/m².

In combination with cisplatin:

Forpatientswhoaredosedinitiallyatdocetaxel75mg/m 2 incombinationwithcisplatinandwhosenadir

ofplateletcountduringthepreviouscourseoftherapyis<25,000cells/mm 3 ,orinpatientswhoexperience

febrileneutropenia,orinpatientswithseriousnon‑hematologictoxicities,thedocetaxeldoseinsubsequent

cyclesshouldbereducedto65mg/m 2 .Forcisplatindoseadjustments,seecorrespondingsummaryofproduct

characteristics.

In combination with capecitabine:

For capecitabine dose modifications, see capecitabine summary of product characteristics.

For patients developing the first appearance of a Grade 2 toxicity, which persists at the time of the next

docetaxel/capecitabinetreatment,delaytreatmentuntilresolvedtoGrade0‑1,andresumeat100%ofthe

original dose.

For patients developing the second appearance of a Grade 2 toxicity, or the first appearance of Grade 3 toxicity,

atanytimeduringthetreatmentcycle,delaytreatmentuntilresolvedtoGrade0‑1,thenresumetreatment

with docetaxel 55 mg/m².

For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the docetaxel dose.

For trastuzumab dose modifications, see trastuzumab summary ofproduct characteristics.

In combination with cisplatin and 5-fluorouracil:

Ifanepisodeoffebrileneutropenia,prolongedneutropeniaorneutropenicinfectionoccursdespiteG‑CSFuse,

thedocetaxeldoseshouldbereducedfrom75to60mg/m 2 .Ifsubsequentepisodesofcomplicatedneutropenia

occurthedocetaxeldoseshouldbereducedfrom60to45mg/m 2 .IncaseofGrade4thrombocytopeniathe

docetaxeldoseshouldbereducedfrom75to60mg/m 2 .Patientsshouldnotberetreatedwithsubsequent

cyclesofdocetaxeluntilneutrophilsrecovertoalevel>1,500cells/mm 3 andplateletsrecovertoalevel

>100,000 cells/mm 3 . Discontinue treatment ifthese toxicities persist. (See section 4.4).

Recommendeddosemodificationsfortoxicitiesinpatientstreatedwithdocetaxelincombinationwith

cisplatin and 5-fluorouracil (5-FU):

Toxicity Dosage adjustment

Diarrhea grade 3 First episode: reduce 5‑FU dose by 20%.

Second episode: then reduce docetaxel dose by 20%.

Diarrhea grade 4 First episode: reduce docetaxel and 5‑FU doses by 20%.

Second episode: discontinue treatment.

Stomatitis/mucositis grade 3 First episode: reduce 5‑FU dose by 20%.

Second episode: stop 5‑FU only, at all subsequent cycles.

Third episode: reduce docetaxel dose by 20%.

Stomatitis/mucositis grade 4 First episode: stop 5‑FU only, at all subsequent cycles.

Second episode: reduce docetaxel dose by 20%.

For cisplatin and 5‑fluorouracil dose adjustments, see the corresponding summary ofproduct characteristics.

Patients treated with TAXOTERE in AC-TH or TCH

PatientswhoreceivedAC‑THorTCHadjuvanttherapyforoperablebreastcancerwhosetumoursoverexpress

HER2andwhoexperienceanepisodeoffebrileneutropeniaorinfectionshouldreceiveprophylacticG‑CSFinall

subsequentcycles.Forasecondepisodeoffebrileneutropeniaorinfection,patientsshouldcontinueprophylactic

G‑CSF,andTAXOTEREwillbereducedfrom100mg/m 2 to75mg/m 2 (intheAC‑THregimen);TAXOTEREwillbe

reduced from 75 mg/m 2 to 60 mg/m 2 (in the TCH regimen).

However,inclinicalpracticeneutropeniacouldoccurincycle1.Thus,G‑CSFshouldbeusedinconsiderationof

theneutropenicriskofthepatientandcurrentrecommendations.Dependingonthetreatmentregimen,patients

whoexperienceGrade3or4stomatitisshouldhavetheirdosedecreasedfrom100mg/m 2 to75mg/m 2 (inthe

AC‑TH regimen) or from 75 mg/m 2 to 60 mg/m 2 (in the TCH regimen).

InthepivotalSCCHNstudiespatientswhoexperiencedcomplicatedneutropenia(includingprolongedneutropenia,

febrileneutropenia,orinfection),itwasrecommendedtouseG‑CSFtoprovideprophylacticcoverage(e.g.,day

6 ‑ 15) in all subsequent cycles.

Special populations:

Patients with hepatic impairment:

Basedonpharmacokineticdatawithdocetaxelat100mg/m²assingleagent,patientswhohavebothelevations

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

phosphatasegreaterthan2.5timestheULN,therecommendeddoseofdocetaxelis75mg/m 2 (seesections4.4

and5.2).Forthosepatientswithserumbilirubin>ULNand/orALTandAST>3.5timestheULNassociatedwith

alkalinephosphatase>6timestheULN,nodose‑reductioncanberecommendedanddocetaxelshouldnotbe

used unless strictly indicated.

Incombinationwithcisplatinand5‑fluorouracilforthetreatmentofpatientswithgastricadenocarcinoma,the

pivotalclinicalstudyexcludedpatientswithALTand/orAST>1.5×ULNassociatedwithalkalinephosphatase

>2.5×ULN,andbilirubin>1xULN;forthesepatients,nodose‑reductionscanberecommendedanddocetaxel

should not be used unless strictly indicated.

Nodataareavailableinpatientswithhepaticimpairmenttreatedbydocetaxelincombinationintheother

indications.

Pediatric population:

ThesafetyandefficacyofTAXOTEREinnasopharyngealcarcinomainchildrenaged1monthtolessthan18years

have not yet been established.

ThereisnorelevantuseofTAXOTEREinthepaediatricpopulationintheindicationsbreastcancer,non‑small

celllungcancer,prostatecancer,gastriccarcinomaandheadandneckcancer,notincludingtypeIIandIIIless

differentiated nasopharyngeal carcinoma.

Elderly patients:

Based on a population pharmacokinetic analysis, there are no special instructions for use in the elderly.

Incombinationwithcapecitabine,forpatients60yearsofageormore,astartingdosereductionofcapecitabine

to 75% is recommended (see capecitabine summary ofproduct characteristics).

4.3Contraindications

Hypersensitivity to the active substance or to any ofthe excipients listed in section 6.1.

Patients with baseline neutrophil count of<1,500 cells/mm 3 .

Patients with severe liver impairment (see sections 4.4 and 4.2).

Contraindications for other medicinal products also apply, when combined with docetaxel.

4.4Special warnings and special precautions for use

Premedicationconsistingofanoralcorticosteroid,suchasdexamethasone16mgperday(e.g.,8mgBID)for3days

starting1daypriortodocetaxeladministration,unlesscontraindicated,canreducetheincidenceandseverityof

fluidretentionaswellastheseverityofhypersensitivityreactions.Forprostatecancer,thepremedicationisoral

Haematology

Neutropeniaisthemostfrequentadversereactionofdocetaxel.Neutrophilnadirsoccurredatamedianof7

daysbutthisintervalmaybeshorterinheavilypre‑treatedpatients.Frequentmonitoringofcompleteblood

countsshouldbeconductedonallpatientsreceivingdocetaxel.Patientsshouldberetreatedwithdocetaxelwhen

neutrophils recover to a level³1,500 cells/mm 3 (see section 4.2).

Inthecaseofsevereneutropenia(<500cells/mm 3 forsevendaysormore)duringacourseofdocetaxeltherapy,

areductionindoseforsubsequentcoursesoftherapyortheuseofappropriatesymptomaticmeasuresare

recommended (see section 4.2).

Inpatientstreatedwithdocetaxelincombinationwithcisplatinand5‑fluorouracil(TCF),febrileneutropenia

andneutropenicinfectionoccurredatlowerrateswhenpatientsreceivedprophylacticG‑CSF.Patientstreated

withTCFshouldreceiveprophylacticG‑CSFtomitigatetheriskofcomplicatedneutropenia(febrileneutropenia,

prolongedneutropeniaorneutropenicinfection).PatientsreceivingTCFshouldbecloselymonitored(seesections

4.2 and 4.8).

Inpatientstreatedwithdocetaxelincombinationwithdoxorubicinandcyclophosphamide(TAC),febrileneutropenia

and/orneutropenicinfectionoccurredatlowerrateswhenpatientsreceivedprimaryG‑CSFprophylaxis.Primary

G‑CSFprophylaxisshouldbeconsideredinpatientswhoreceiveadjuvanttherapywithTACforbreastcancerto

mitigatetheriskofcomplicatedneutropenia(febrileneutropenia,prolongedneutropeniaorneutropenicinfection).

Patients receiving TAC should be closely monitored (see sections 4.2 and 4.8).

Hypersensitivity reactions

Patientsshouldbeobservedcloselyforhypersensitivityreactionsespeciallyduringthefirstandsecondinfusions.

Hypersensitivityreactionsmayoccurwithinafewminutesfollowingtheinitiationoftheinfusionofdocetaxel,

thusfacilitiesforthetreatmentofhypotensionandbronchospasmshouldbeavailable.Ifhypersensitivity

reactionsoccur,minorsymptomssuchasflushingorlocalisedcutaneousreactionsdonotrequireinterruption

oftherapy.However,severereactions,suchasseverehypotension,bronchospasmorgeneralisedrash/erythema

requireimmediatediscontinuationofdocetaxelandappropriatetherapy.Patientswhohavedevelopedsevere

hypersensitivity reactions should not be re‑challenged with docetaxel.

Cutaneous reactions

Localisedskinerythemaoftheextremities(palmsofthehandsandsolesofthefeet)withoedemafollowedby

desquamationhasbeenobserved.Severesymptomssuchaseruptionsfollowedbydesquamationwhichleadto

interruption or discontinuation ofdocetaxel treatment were reported (see section 4.2).

Fluid retention

Patientswithseverefluidretentionsuchaspleuraleffusion,pericardialeffusionandascitesshouldbemonitored

closely.

Patients with liver impairment

Inpatientstreatedwithdocetaxelat100mg/m 2 assingleagentwhohaveserumtransaminaselevels(ALT

and/orAST)greaterthan1.5timestheULNconcurrentwithserumalkalinephosphataselevelsgreaterthan

2.5timestheULN,thereisahigherriskofdevelopingsevereadversereactionssuchastoxicdeathsincludingsepsis

andgastrointestinalhaemorrhagewhichcanbefatal,febrileneutropenia,infections,thrombocytopenia,stomatitis

andasthenia.Therefore,therecommendeddoseofdocetaxelinthosepatientswithelevatedliverfunctiontest

(LFTs) is 75 mg/m 2 and LFTs should be measured at baseline and before each cycle (see section 4.2).

Forpatientswithserumbilirubinlevels>ULNand/orALTandAST>3.5timestheULNconcurrentwithserum

alkalinephosphataselevels>6timestheULN,nodose‑reductioncanberecommendedanddocetaxelshould

not be used unless strictly indicated.

Incombinationwithcisplatinand5‑fluorouracilforthetreatmentofpatientswithgastricadenocarcinoma,the

pivotalclinicalstudyexcludedpatientswithALTand/orAST>1.5×ULNassociatedwithalkalinephosphatase

>2.5×ULN,andbilirubin>1×ULN;forthesepatients,nodose‑reductionscanberecommendedanddocetaxel

should not be used unless strictly indicated.

Nodataareavailableinpatientswithhepaticimpairmenttreatedbydocetaxelincombinationintheother

indications.

Patients with renal impairment

There are no data available in patients with severely impaired renal function treated with docetaxel.

Nervous system

The development ofsevere peripheral neurotoxicity requires a reduction ofdose (see section 4.2).

Cardiac toxicity

Heartfailurehasbeenobservedinpatientsreceivingdocetaxelincombinationwithtrastuzumab,particularly

followinganthracycline(doxorubicinorepirubicin)‑containingchemotherapy.Thismaybemoderatetosevere

and has been associated with death (see section 4.8).

Whenpatientsarecandidatesfortreatmentwithdocetaxelincombinationwithtrastuzumab,theyshouldundergo

baselinecardiacassessment.Cardiacfunctionshouldbefurthermonitoredduringtreatment(e.g.,everythree

months)tohelpidentifypatientswhomaydevelopcardiacdysfunction.Formoredetailsseesummaryofproduct

characteristics oftrastuzumab.

Others

Contraceptivemeasuresmustbetakenbybothmenandwomenduringtreatmentandformenatleast6months

after cessation oftherapy (see section 4.6).

Additional cautions for use in adjuvant treatment ofbreast cancer

Complicated neutropenia

Forpatientswhoexperiencecomplicatedneutropenia(prolongedneutropenia,febrileneutropeniaorinfection),

G‑CSF and dose reduction should be considered (see section 4.2).

Gastrointestinal reactions

Symptomssuchasearlyabdominalpainandtenderness,fever,diarrhea,withorwithoutneutropenia,maybe

early manifestations ofserious gastrointestinal toxicity and should be evaluated and treated promptly.

Congestive heart failure (CHF)

Patientsshouldbemonitoredforsymptomsofcongestiveheartfailureduringtherapyandduringthefollow‑up

period.InpatientstreatedwiththeTACregimenfornode‑positivebreastcancer,theriskofCHFhasbeenshown

to be higher during the first year after treatment (see sections 4.8 and 5.1).

Leukemia

Inthedocetaxel,doxorubicinandcyclophosphamide(TAC)treatedpatients,theriskofdelayedmyelodysplasia

or myeloid leukemia requires haematological follow‑up.

Patients with 4+ nodes

Asthebenefitobservedinpatientwith4+nodeswasnotstatisticallysignificantondisease‑freesurvival(DFS)and

overallsurvival(OS),thepositivebenefit/riskratioforTACinpatientswith4+nodeswasnotfullydemonstrated

at the final analysis (see section 5.1).

Elderly patients

Therearelimiteddataavailableinpatients>70yearsofageondocetaxeluseincombinationwithdoxorubicin

and cyclophosphamide.

Ofthe333patientstreatedwithdocetaxeleverythreeweeksinaprostatecancerstudy,209patientswere65years

ofageorgreaterand68patientswereolderthan75years.Inpatientstreatedwithdocetaxeleverythreeweeks,the

incidenceofrelatednailchangesoccurredatarate³10%higherinpatientswhowere65yearsofageorgreater

comparedtoyoungerpatients.Theincidenceofrelatedfever,diarrhea,anorexia,andperipheraledemaoccurred

at rates³10% higher in patients who were 75 years ofage or greater versus less than 65 years.

Amongthe300(221patientsinthephaseIIIpartofthestudyand79patientsinthephaseIIpart)patientstreated

withdocetaxelincombinationwithcisplatinand5‑fluorouracilinthegastriccancerstudy,74were65yearsof

ageorolderand4patientswere75yearsofageorolder.Theincidenceofseriousadverseeventswashigherin

theelderlypatientscomparedtoyoungerpatients.Theincidenceofthefollowingadverseevents(allgrades):

lethargy,stomatitis,neutropenicinfectionoccurredatrates³10%higherinpatientswhowere65yearsofageor

older compared to younger patients.

Elderly patients treated with TCF should be closely monitored.

Theproportionofelderlypatientswas5.5%and6.6%intheAC‑THandTCHregimens,respectivelyandistoolimited

to allow for conclusions regarding the adverse events occurring by age (<65 years vs. ≥65 years).

Excipients

TAXOTERE20mg/1mlconcentrateforsolutionforinfusion‑Thismedicinalproductcontains50vol%ethanol

(alcohol), i.e., up to 0.395 g (0.5 ml) per vial, equivalent to 10 ml ofbeer or 4 ml wine per vial.

TAXOTERE80mg/4mlconcentrateforsolutionforinfusion‑Thismedicinalproductcontains50vol%ethanol

(alcohol), i.e., up to 1.58 g (2 ml) per vial, equivalent to 40 ml ofbeer or 17 ml wine per vial.

Harmful for those suffering from alcoholism.

Tobetakenintoaccountinpregnantorbreast‑feedingwomen,childrenandhigh‑riskgroupssuchaspatients

with liver disease, or epilepsy.

The amount ofalcohol in this medicinal product may alter the effects ofother medicinal products.

The amount ofalcohol in this medicinal product may impair the patient’s ability to drive or use machines.

4.5Interaction with other medicinal products and other forms ofinteraction

Invitrostudieshaveshownthatthemetabolismofdocetaxelmaybemodifiedbytheconcomitantadministration

ofcompoundswhichinduce,inhibitoraremetabolisedby(andthusmayinhibittheenzymecompetitively)

cytochromeP450‑3Asuchasciclosporine,terfenadine,ketoconazole,erythromycinandtroleandomycin.Asa

result,cautionshouldbeexercisedwhentreatingpatientswiththesemedicinalproductsasconcomitanttherapy

since there is a potential for a significant interaction.

Docetaxelishighlyproteinbound(>95%).Althoughthepossibleinvivointeractionofdocetaxelwithconcomitantly

administeredmedicinalproducthasnotbeeninvestigatedformally,invitrointeractionswithtightlyprotein‑bound

agentssuchaserythromycin,diphenhydramine,propranolol,propafenone,phenytoin,salicylate,sulfamethoxazole

andsodiumvalproatedidnotaffectproteinbindingofdocetaxel.Inaddition,dexamethasonedidnotaffect

protein binding ofdocetaxel. Docetaxel did not influence the binding ofdigitoxin.

Thepharmacokineticsofdocetaxel,doxorubicinandcyclophosphamidewerenotinfluencedbytheir

co‑administration.Limiteddatafromasingleuncontrolledstudyweresuggestiveofaninteractionbetween

docetaxelandcarboplatin.Whencombinedtodocetaxel,theclearanceofcarboplatinwasabout50%higherthan

values previously reported for carboplatin monotherapy.

Docetaxelpharmacokineticsinthepresenceofprednisonewasstudiedinpatientswithmetastaticprostatecancer.

DocetaxelismetabolisedbyCYP3A4andprednisoneisknowntoinduceCYP3A4.Nostatisticallysignificanteffect

ofprednisone on the pharmacokinetics ofdocetaxel was observed.

Clinicalcasesconsistentwithanincreaseindocetaxeltoxicitywerereportedwhenitwascombinedwithritonavir.

ThemechanismbehindthisinteractionisaCYP3A4inhibition,themainisoenzymeinvolvedindocetaxel

metabolismbyritonavir.Basedonextrapolationfromapharmacokineticstudywithketoconazolein7patients,

considera50%docetaxeldosereductionifpatientsrequireco‑administrationofastrongCYP3A4inhibitorsuch

as azole antifungals, ritonavir and some macrolides (clarithromycin, telithromycin).

4.6Fertility, pregnancy and lactation

Pregnancy

Thereisnoinformationontheuseofdocetaxelinpregnantwomen.Docetaxelhasbeenshowntobeboth

embryotoxicandfoetotoxicinrabbitsandrats,andtoreducefertilityinrats.Aswithothercytotoxicmedicinal

products,docetaxelmaycausefoetalharmwhenadministeredtopregnantwomen.Therefore,docetaxelmust

not be used during pregnancy unless clearly indicated.

Womenofchildbearingagereceivingdocetaxelshouldbeadvisedtoavoidbecomingpregnant,andtoinform

the treating physician immediately should this occur.

Breast-feeding

Docetaxelisalipophilicsubstancebutitisnotknownwhetheritisexcretedinhumanmilk.Consequently,

becauseofthepotentialforadversereactionsinnursinginfants,breast‑feedingmustbediscontinuedforthe

duration ofdocetaxel therapy.

Fertility

An effective method ofcontraception should be used during treatment.

In non‑clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3).

Therefore,menbeingtreatedwithdocetaxelareadvisednottofatherachildduringandupto6monthsafter

treatment and to seek advice on conservation ofsperm prior to treatment.

4.7Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8Undesirable effects

Summary ofthe safety profile for all indications

Theadversereactionsconsideredtobepossiblyorprobablyrelatedtotheadministrationofdocetaxelhave

been obtained in:

1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent respectively.

258 patients who received docetaxel in combination with doxorubicin.

406 patients who received docetaxel in combination with cisplatin.

92 patients treated with docetaxel in combination with trastuzumab.

255 patients who received docetaxel in combination with capecitabine.

332 patients who received docetaxel in combination with prednisone or prednisolone (clinically important

1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received docetaxel in combination with

doxorubicin and cyclophosphamide (clinically important treatment related adverse events are presented).

300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patients in the phase

IIpart)whoreceiveddocetaxelincombinationwithcisplatinand5‑fluorouracil(clinicallyimportanttreatment

related adverse events are presented).

174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin and

5‑fluorouracil (clinically important treatment related adverse events are presented).

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

grade4=G4),theCOSTARTandtheMedDRAterms.Frequenciesaredefinedas:verycommon( ≥1/10);

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

(<1/10,000); not known (cannot be estimated from available data).

Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Themostcommonlyreportedadversereactionsofdocetaxelaloneare:neutropenia(whichwasreversibleandnot

cumulative;themediandaytonadirwas7daysandthemediandurationofsevereneutropenia[<500cells/mm 3 ]

was7days),anaemia,alopecia,nausea,vomiting,stomatits,diarrhoeaandasthenia.Theseverityofadverseevents

ofdocetaxel may be increased when docetaxel is given in combination with other chemotherapeutic agents.

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

increasedincidenceofSAEs(40%vs.31%)andGrade4AEs(34%vs.23%)inthetrastuzumabcombinationarm

compared to docetaxel monotherapy.

Forcombinationwithcapecitabine,themostfrequenttreatment‑relatedundesirableeffects(≥5%)reportedina

phaseIIIstudyinbreastcancerpatientsfailinganthracyclinetreatmentarepresented(seecapecitabinesummary

ofproduct characteristics).

The following adverse reactions are frequently observed with docetaxel:

Immune system disorders

Hypersensitivityreactionshavegenerallyoccurredwithinafewminutesfollowingthestartoftheinfusionof

docetaxelandwereusuallymildtomoderate.Themostfrequentlyreportedsymptomswereflushing,rashwith

orwithoutpruritus,chesttightness,backpain,dyspnoeaandfeverorchills.Severereactionswerecharacterised

by hypotension and/or bronchospasm or generalized rash/erythema (see section 4.4).

Nervous system disorders

Thedevelopmentofsevereperipheralneurotoxicityrequiresareductionofdose(seesections4.2and4.4).

Mildtomoderateneuro‑sensorysignsarecharacterisedbyparesthesia,dysesthesiaorpainincludingburning.

Neuro‑motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversiblecutaneousreactionshavebeenobservedandweregenerallyconsideredasmildtomoderate.Reactions

werecharacterisedbyarashincludinglocalisederuptionsmainlyonthefeetandhands(includingseverehand

andfootsyndrome),butalsoonthearms,faceorthorax,andfrequentlyassociatedwithpruritus.Eruptions

generallyoccurredwithinoneweekafterthedocetaxelinfusion.Lessfrequently,severesymptomssuchas

eruptionsfollowedbydesquamationwhichrarelyleadtointerruptionordiscontinuationofdocetaxeltreatment

werereported(seesections4.2and4.4).Severenaildisordersarecharacterisedbyhypo‑orhyperpigmentation

and sometimes pain and onycholysis.

General disorders and administration site conditions

Infusionsitereactionsweregenerallymildandconsistedofhyper‑pigmentation,inflammation,rednessordryness

ofthe skin, phlebitis or extravasation and swelling ofthe vein.

Fluidretentionincludeseventssuchasperipheraloedemaandlessfrequentlypleuraleffusion,pericardialeffusion,

ascitesandweightgain.Theperipheraloedemausuallystartsatthelowerextremitiesandmaybecomegeneralised

with a weight gain of3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

Tabulated list ofadverse reactions in breast cancer for TAXOTERE 100 mg/m² single agent

MedDRA System

Organ classes Very common adverse

reactions Common adverse

reactions Uncommon adverse

reactions

Investigations G3/4 Blood bilirubin

increased (<5%);

G3/4 Blood alkaline

phosphataseincreased(<4%);

G3/4 AST increased (<3%);

G3/4 ALT increased (<2%)

Cardiac disorders Arrhythmia (G3/4: 0.7%) Cardiac failure

Blood and lymphatic

system disorders Neutropenia (G4: 76.4%);

Anaemia (G3/4: 8.9%);

Febrile neutropenia Thrombocytopenia (G4: 0.2%)

Nervous system

disorders Peripheral sensory

neuropathy (G3: 4.1%);

Peripheral motor neuropathy

(G3/4: 4%);

Dysgeusia (severe: 0.07%)

Respiratory, thoracic

and 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%);

Abdominal pain (severe: 1%);

Gastrointestinal haemorrhage

(severe: 0.3%) Oesophagitis (severe: 0.4%)

Skin and

subcutaneous tissue

disorders Alopecia;

Skin reaction (G3/4: 5.9%);

Nail disorders (severe: 2.6%)

Musculoskeletal and

connective tissue

disorders Myalgia (severe: 1.4%) Arthralgia

Metabolism and

nutrition disorders Anorexia

Infections and

infestations Infections (G3/4: 5.7%;

including sepsis and

pneumonia, fatal in 1.7%) Infection associated with G4

neutropenia (G3/4: 4.6%)

Vascular disorders Hypotension;

Hypertension;

Haemorrhage

General disorders

and administration

site conditions Fluid retention (severe: 6.5%);

Asthenia (severe: 11.2%);

Pain Infusion site reaction;

Non‑cardiac chest pain

(severe: 0.4%)

Immune system

disorders Hypersensitivity (G3/4: 5.3%)

Description ofselected adverse reactions in breast cancer for TAXOTERE 100 mg/m² single agent

Blood and lymphatic system disorders

Rare: bleeding episodes associated with grade 3/4 thrombocytopenia.

Nervous system disorders

Reversibilitydataareavailableamong35.3%ofpatientswhodevelopedneurotoxicityfollowingdocetaxeltreatment

at 100 mg/m² as single agent. The events were spontaneously reversible within 3 months.

Skin and subcutaneous tissue disorders

Veryrare:onecaseofalopecianon‑reversibleattheendofthestudy.73%ofthecutaneousreactionswere

reversible within 21 days.

General disorders and administration site conditions

Themediancumulativedosetotreatmentdiscontinuationwasmorethan1,000mg/m 2 andthemediantimeto

fluidretention reversibility was16.4weeks (range 0to42 weeks).The onsetofmoderateand severe retentionis

delayed(mediancumulativedose:818.9mg/m 2 )inpatientswithpremedicationcomparedwithpatientswithout

premedication(mediancumulativedose:489.7mg/m 2 );however,ithasbeenreportedinsomepatientsduring

the early courses oftherapy.

Tabulated list ofadverse reactions in breast cancer for TAXOTERE 75 mg/m² single agent

MedDRA System Organ classes Very common adverse reactions Common adverse reactions

Investigations G3/4 Blood bilirubin increased (<2%)

Cardiac disorders Arrhythmia (no severe)

Blood and lymphatic system

disorders Neutropenia (G4: 54.2%);

Anaemia (G3/4: 10.8%);

Thrombocytopenia (G4: 1.7%) Febrile neutropenia

Nervous system disorders Peripheral sensory neuropathy

(G3/4: 0.8%) Peripheral motor neuropathy (G3/4:

2.5%)

Gastrointestinal disorders Nausea (G3/4: 3.3%);

Stomatitis (G3/4: 1.7%);

Vomiting (G3/4: 0.8%);

Diarrhea (G3/4: 1.7%) Constipation

Skin and subcutaneous tissue

disorders Alopecia;

Skin reaction (G3/4: 0.8%) Nail disorders (severe: 0.8%)

Musculoskeletal and connective

tissue disorders Myalgia

Metabolism and nutrition disordersAnorexia

Infections and infestations Infections (G3/4: 5%)

Vascular disorders Hypotension

General disorders and

administration site conditions Asthenia (severe: 12.4%);

Fluid retention (severe: 0.8%);

Pain

Immune system disorders Hypersensitivity (no severe)

Tabulated list ofadverse reactions in breast cancer for TAXOTERE 75 mg/m² in combination with doxorubicin

MedDRA System

Organ classes Very common adverse

reactions Common adverse

reactions Uncommon adverse

reactions

Investigations G3/4 Blood bilirubin

increased (<2.5%);

G3/4 Blood alkaline

phosphatase increased

(<2.5%) G3/4 AST increased (<1%);

G3/4 ALT increased (<1%)

Cardiac disorders Cardiac failure;

Arrhythmia (no severe)

Blood and

lymphatic system

disorders Neutropenia (G4: 91.7%);

Anaemia (G3/4: 9.4%);

Febrile neutropenia;

Thrombocytopenia (G4: 0.8%)

Nervous system

disorders Peripheral sensory

neuropathy (G3: 0.4%) Peripheral motor 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

Skin and

subcutaneous tissue

disorders Alopecia;

Nail disorders (severe: 0.4%);

Skin reaction (no severe)

Musculoskeletal and

connective tissue

disorders Myalgia

Metabolism and

nutrition disorders Anorexia

Infections and

infestations Infection (G3/4: 7.8%)

Vascular disorders Hypotension

General disorders

and administration

site conditions Asthenia (severe: 8.1%);

Fluid retention (severe: 1.2%);

MedDRA System

Organ classes Very common adverse

reactions Common adverse

reactions Uncommon adverse

reactions

Immune system

disorders Hypersensitivity (G3/4: 1.2%)

Tabulated list ofadverse reactions in breast cancer for TAXOTERE 75 mg/m² in combination with cisplatin

MedDRA System

Organ classes Very common adverse

reactions Common adverse

reactions Uncommon adverse

reactions

Investigations G3/4 Blood bilirubin

increased (2.1%);

G3/4 ALT increased (1.3%) G3/4 AST increased (0.5%);

G3/4 Blood alkaline

phosphatase increased (0.3%)

Cardiac disorders Arrhythmia (G3/4: 0.7%) Cardiac failure

Blood and

lymphatic system

disorders Neutropenia (G4: 51.5%);

Anaemia (G3/4: 6.9%);

Thrombocytopenia (G4: 0.5%) Febrile neutropenia

Nervous system

disorders Peripheral sensory

neuropathy (G3: 3.7%);

Peripheral motor neuropathy

(G3/4: 2%)

Gastrointestinal

disorders Nausea (G3/4: 9.6%);

Vomiting (G3/4: 7.6%);

Diarrhoea (G3/4: 6.4%);

Stomatitis (G3/4: 2%) Constipation

Skin and

subcutaneous tissue

disorders Alopecia;

Nail disorders (severe: 0.7%);

Skin reaction (G3/4: 0.2%)

Musculoskeletal and

connective tissue

disorders Myalgia (severe: 0.5%)

Metabolism and

nutrition disorders Anorexia

Infections and

infestations Infection (G3/4: 5.7%)

Vascular disorders Hypotension (G3/4: 0.7%)

General disorders

and administration

site conditions Asthenia (severe: 9.9%);

Fluid retention (severe: 0.7%);

Fever (G3/4: 1.2%) Infusion site reaction;

Pain

Immune system

disorders Hypersensitivity (G3/4: 2.5%)

Tabulated list ofadverse reactions in breast cancer for TAXOTERE 100 mg/m² in combination with trastuzumab

MedDRA System Organ classes Very common adverse reactions Common adverse reactions

Investigations Weight increased

Cardiac disorders Cardiac failure

Blood and lymphatic system

disorders Neutropenia (G3/4: 32%);

Febrile neutropenia (includes

neutropenia associated with fever

and antibiotic use) or neutropenic

sepsis

Nervous system disorders Paresthesia; Headache; Dysgeusia;

Hypoaesthesia

Eye disorders Lacrimation increased; Conjunctivitis

Respiratory,thoracicandmediastinal

disorders Epistaxis; Pharyngolaryngeal pain;

Nasopharyngitis; Dyspnoea; Cough;

Rhinorrhoea

Gastrointestinal disorders Nausea; Diarrhoea; Vomiting;

Constipation; Stomatitis; Dyspepsia;

Abdominal pain

Skin and subcutaneous tissue

disorders Alopecia; Erythema; Rash; Nail

disorders

Musculoskeletal and connective

tissue disorders Myalgia; Arthralgia; Pain in

extremity; Bone pain; Back pain

Metabolism and nutrition disordersAnorexia

Vascular disorders Lymphoedema

General disorders and

administration site conditions Asthenia; Oedema peripheral;

Pyrexia; Fatigue; Mucosal

inflammation; Pain; Influenza like

illness; Chest pain; Chills Lethargy

Psychiatric disorders Insomnia

DescriptionofselectedadversereactionsinbreastcancerforTAXOTERE100mg/m²incombinationwith

trastuzumab

Cardiac disorders

Symptomaticcardiacfailurewasreportedin2.2%ofthepatientswhoreceiveddocetaxelplustrastuzumab

comparedto0%ofpatientsgivendocetaxelalone.Inthedocetaxelplustrastuzumabarm,64%hadreceiveda

prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm alone.

Blood and lymphatic system disorders

Verycommon:Haematologicaltoxicitywasincreasedinpatientsreceivingtrastuzumabanddocetaxel,compared

withdocetaxelalone(32%grade3/4neutropeniaversus22%,usingNCI‑CTCcriteria).Notethatthisislikelyto

beanunderestimatesincedocetaxelaloneatadoseof100mg/m 2 isknowntoresultinneutropeniain97%of

patients,76%grade4,basedonnadirbloodcounts.Theincidenceoffebrileneutropenia/neutropenicsepsis

wasalsoincreasedinpatientstreatedwithHerceptinplusdocetaxel(23%versus17%forpatientstreatedwith

docetaxel alone).

Tabulated list ofadverse reactions in breast cancer for TAXOTERE 75 mg/m² in combination with capecitabine

MedDRA System Organ classes Very common adverse reactions Common adverse reactions

Investigations Weight decreased;

G3/4 Blood bilirubin increased (9%)

Blood and lymphatic system

disorders Neutropenia (G3/4: 63%);

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

Nervous system disorders Dysgeusia (G3/4: <1%);

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

Headache (G3/4: <1%);

Neuropathy peripheral

Eye disorders Lacrimation increased

Respiratory,thoracicandmediastinal

disorders Pharyngolaryngeal pain (G3/4: 2%) Dyspnoea (G3/4: 1%);

Cough (G3/4: <1%);

Epistaxis (G3/4: <1%)

Gastrointestinal disorders Stomatitis (G3/4: 18%);

Diarrhoea (G3/4: 14%);

Nausea (G3/4: 6%);

Vomiting (G3/4: 4%);

Constipation (G3/4: 1%);

Abdominal pain (G3/4: 2%);

Dyspepsia Abdominal pain upper;

Dry mouth

Skin and subcutaneous tissue

disorders Hand‑foot syndrome (G3/4: 24%);

Alopecia (G3/4: 6%);

Nail disorders (G3/4: 2%) Dermatitis;

Rash erythematous (G3/4: <1%);

Nail discolouration;

Onycholysis (G3/4: 1%)

Musculoskeletal and connective

tissue disorders Myalgia (G3/4: 2%);

Arthralgia (G3/4: 1%) Pain in extremity (G3/4: <1%);

Back pain (G3/4: 1%)

Metabolism and nutrition disordersAnorexia (G3/4: 1%);

Decreased appetite Dehydration (G3/4: 2%)

Infections and infestations Oral candidiasis (G3/4: <1%)

General disorders and

administration site conditions Asthenia (G3/4: 3%);

Pyrexia (G3/4: 1%);

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

Oedema peripheral (G3/4: 1%) Lethargy;

Pain

TabulatedlistofadversereactionsinbreastcancerforTAXOTERE75mg/m²incombinationwithprednisoneor

prednisolone

MedDRA System Organ classes Very common adverse reactions Common adverse reactions

Cardiac disorders Cardiac left ventricular function

decrease (G3/4: 0.3%)

Blood and lymphatic system

disorders Neutropenia (G3/4: 32%);

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

Febrile neutropenia

Nervous system disorders Peripheral sensory neuropathy

(G3/4: 1.2%);

Dysgeusia (G3/4: 0%) Peripheral motor neuropathy

(G3/4: 0%)

Eye disorders Lacrimation increased (G3/4: 0.6%)

Respiratory,thoracicandmediastinal

disorders Epistaxis (G3/4: 0%);

Dyspnoea (G3/4: 0.6%);

Cough (G3/4: 0%)

Gastrointestinal disorders Nausea (G3/4: 2.4%);

Diarrhoea (G3/4: 1.2%);

Stomatitis/Pharyngitis (G3/4: 0.9%);

Vomiting (G3/4: 1.2%)

Skin and subcutaneous tissue

disorders Alopecia;

Nail disorders (no severe) Exfoliative rash (G3/4: 0.3%)

Musculoskeletal and connective

bone disorders Arthralgia (G3/4: 0.3%);

Myalgia (G3/4: 0.3%)

Metabolism and nutrition disordersAnorexia (G3/4: 0.6%)

Infections and infestations Infection (G3/4: 3.3%)

General disorders and

administration site conditions Fatigue (G3/4: 3.9%);

Fluid retention (severe: 0.6%)

Immune system disorders Hypersensitivity (G3/4: 0.6%)

TabulatedlistofadversereactionsinbreastcancerforadjuvanttherapywithTAXOTERE75mg/m²incombination

withdoxorubicinandcyclophosphamideinpatientswithnode‑positive(TAX316)andnode‑negative(GEICAM

9805) breast cancer‑pooled data

MedDRA System

Organ classes Very common adverse

reactions Common adverse

reactions Uncommon adverse

reactions

Investigations Weight increased (G3/4: 0%);

Weight decreased

(G3/4: 0.2%)

Cardiac disorders Arrhythmia (G3/4: 0.2%)

Blood and lymphatic

system disorders Anaemia (G3/4: 3%);

Neutropenia (G3/4: 59.2%);

Thrombocytopenia (G3/4:

1.6%);

Febrile neutropenia (G3/4:

Nervous system

disorders Dysgeusia (G3/4: 0.6%);

Peripheral sensory

neuropathy (G3/4: <0.1%) Peripheral motor

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

Neurotoxicity (G3/4: 0%);

Somnolence (G3/4: 0%)

Eye disorders Conjunctivitis (G3/4: <0.1%)Lacrimation increased (G3/4:

<0.1%)

Respiratory, thoracic

and mediastinal

MedDRA System

Organ classes Very common adverse

reactions Common adverse

reactions Uncommon adverse

reactions

Gastrointestinal

disorders 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%) Abdominal pain (G3/4: 0.4%)

Skin and subcutaneous

tissue disorders Alopecia (G3/4: <0.1%);

Skin disorder (G3/4: 0.6%);

Nail disorders (G3/4: 0.4%)

Musculoskeletal and

connective tissue

disorders Myalgia (G3/4: 0.7%);

Arthralgia (G3/4: 0.2%)

Metabolism and

nutrition disorders Anorexia (G3/4: 1.5%)

Infections and

infestations Infection (G3/4: 2.4%);

Neutropenic infection (G3/4:

2.6%)

Vascular disorders Hot flush (G3/4: 0.5%) Hypotension (G3/4: 0%)

Phlebitis (G3/4: 0%) Lymphoedema (G3/4: 0%)

General disorders and

administration site

conditions Asthenia (G3/4: 10%);

Pyrexia (G3/4: NA);

Oedema peripheral (G3/4:

0.2%)

Immune system

disorders Hypersensitivity (G3/4: 0.6%)

Reproductive system

and breast disorders Amenorrhoea (G3/4: NA)

DescriptionofselectedadversereactionsforadjuvanttherapywithTAXOTERE75mg/m²incombinationwith

doxorubicinandcyclophosphamideinpatientswithnode‑positive(TAX316)andnode‑negative(GEICAM9805)

breast cancer

Cardiac disorders

In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive

heartfailure.AllexceptonepatientineacharmwerediagnosedwithCHFmorethan30daysafterthetreatment

period. Two patients in the TAC arm and 4 patients in the FAC arm died because ofcardiac failure.

Nervous system disorders

Peripheralsensoryneuropathywasobservedtobeongoingduringfollow‑upin10patientsoutofthe84patients

with peripheral sensory neuropathy at the end ofthe chemotherapy in study TAX316.

Skin and subcutaneous tissue disorders

InstudyTAX316,alopeciapersistingintothefollow‑upperiodaftertheendofchemotherapywasreportedin

687 TAC patients and 645 FAC patients.

Attheendofthefollow‑upperiod,alopeciawasobservedtobeongoingin29TACpatients(4.2%)and16FAC

patients (2.4%).

General disorders and administration site conditions

InstudyTAX316,peripheraloedemawasobservedtobeongoingin19patientsoutofthe119patientswith

peripheraloedemaintheTACarmand4patientsoutofthe23patientswithperipheraloedemaintheFAC

arm.

InstudyGEICAM9805,lymphoedemawasobservedtobeongoingin4ofthe5patientswithlymphoedemaat

the end ofthe chemotherapy.

Reproductive system and breast disorders

Amenorrhoeawasobservedtobeongoingduringfollow‑upin121patientsoutofthe202patientswith

amenorrhoea at the end ofthe chemotherapy in study TAX316.

Acute leukaemia / Myelodysplastic syndrome

After10yearsoffollow‑upinstudyTAX316,acuteleukaemiawasreportedin4of744TACpatientsandin1of736

FAC patients. Myelodysplastic syndrome was reported in 2 of744 TAC patients and in 1 of736 FAC patients.

Atamedianfollow‑uptimeof77months,acuteleukaemiaoccurredin1of532(0.2%)patientswhoreceived

docetaxel,doxorubicin,andcyclophosphamideintheGEICAM9805study.Nocaseswerereportedinpatients

whoreceivedfluorouracil,doxorubicinandcyclophosphamide.Nopatientwasdiagnosedwithmyelodysplastic

syndrome in either treatment groups.

Neutropenic complications

ThetablebelowshowsthattheincidenceofGrade4neutropenia,febrileneutropeniaandneutropenicinfection

wasdecreasedinpatientswhoreceivedprimaryG‑CSFprophylaxisafteritwasmademandatoryintheTAC

arm – GEICAM study.

Neutropenic complications in patients receiving TAC with or without primary G‑CSF prophylaxis (GEICAM 9805)

Without primary

G-CSF prophylaxis

(n = 111)

n (%) With primary

G-CSF prophylaxis

(n = 421)

n (%)

Neutropenia (Grade 4) 104 (93.7) 135 (32.1)

Febrile neutropenia 28 (25.2) 23 (5.5)

Neutropenic infection 14 (12.6) 21 (5.0)

Neutropenic infection (Grade 3‑4) 2 (1.8) 5 (1.2)

TabulatedlistofadversereactionsingastricadenocarcinomacancerforTAXOTERE75mg/m²incombination

with cisplatin and 5‑fluorouracil

MedDRA System Organ classes Very common adverse reactions Common adverse reactions

Cardiac disorders Arrhythmia (G3/4: 1.0%)

Blood and lymphatic system

disorders Anaemia (G3/4: 20.9%);

Neutropenia (G3/4: 83.2%);

Thrombocytopenia (G3/4: 8.8%);

Febrile neutropenia

Nervous system disorders Peripheral sensory neuropathy

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

Peripheral motor neuropathy (G3/4:

1.3%)

Eye disorders Lacrimation increased (G3/4: 0%)

Ear and labyrinth disorders Hearing impaired (G3/4: 0%)

Gastrointestinal disorders Diarrhoea (G3/4: 19.7%);

Nausea (G3/4: 16%);

Stomatitis (G3/4: 23.7%);

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

Gastrointestinal pain (G3/4: 1.0%);

Oesophagitis/dysphagia/

odynophagia (G3/4: 0.7%)

Skin and subcutaneous tissue

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

Nail disorders (G3/4: 0.7%);

Skin exfoliation (G3/4: 0%)

Metabolism and nutrition disordersAnorexia (G3/4: 11.7%)

Infections and infestations Neutropenic infection;

Infection (G3/4: 11.7%)

General disorders and

administration site conditions Lethargy (G3/4: 19.0%);

Fever (G3/4: 2.3%);

Fluid retention (severe/life‑

threatening: 1%)

Immune system disorders Hypersensitivity (G3/4: 1.7%)

DescriptionofselectedadversereactionsingastricadenocarcinomacancerforTAXOTERE75mg/m²incombination

with cisplatin and 5‑fluorouracil

Blood and lymphatic system disorders

Febrileneutropeniaandneutropenicinfectionoccurredin17.2%and13.5%ofpatientsrespectively,regardlessof

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

andneutropenicinfectionoccurredrespectivelyin12.1%and3.4%ofpatientswhenpatientsreceivedprophylactic

G‑CSF, in 15.6% and 12.9% ofpatients without prophylactic G‑CSF (see section 4.2).

TabulatedlistofadversereactionsinheadandneckcancerforTAXOTERE75mg/m²incombinationwithcisplatin

and 5‑fluorouracil

Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA System

Organ classes Very common adverse

reactions Common adverse reactionsUncommon adverse

reactions

Investigations Weight increased

Cardiac disorders Myocardial ischemia (G3/4:

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

Blood and lymphatic

system disorders Neutropenia (G3/4: 76.3%);

Anemia (G3/4: 9.2%);

Thrombocytopenia (G3/4:

5.2%) Febrile neutropenia a

Nervous system

disorders Dysgeusia/Parosmia;

Peripheral sensory

neuropathy (G3/4: 0.6%) Dizziness

Eye disorders Lacrimation increased;

Conjunctivitis

Ear and labyrinth

disorders Hearing impaired

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%);

Abdominal pain;

Dyspepsia;

Gastrointestinal

haemorrhage (G3/4: 0.6%)

Skin and subcutaneous

tissue disorders Alopecia (G3/4: 10.9%) Rash pruritic;

Dry skin;

Skin exfoliative (G3/4: 0.6%)

Musculoskeletal and

connective tissue

disorders Myalgia (G3/4: 0.6%)

Metabolism and

nutrition disorders Anorexia (G3/4: 0.6%)

Infections and

infestations Infection (G3/4: 6.3%);

Neutropenic infection

Neoplasms benign,

malignant and

unspecified (incl cysts

and polyps) Cancer pain (G3/4: 0.6%)

Vascular disorders Venous disorder (G3/4: 0.6%)

General disorders and

administration site

conditions Lethargy (G3/4: 3.4%);

Pyrexia (G3/4: 0.6%);

Fluid retention;

Oedema

Immune system

disorders Hypersensitivity (no severe)

Febrileneutropenia:grade≥2feverconcomittantwithgrade4neutropeniarequiringi.v.antibioticsand/or

hospitalization.

Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA System

Organ classes Very common adverse

reactions Common adverse reactionsUncommon adverse

reactions

Investigations Weight decreased Weight increased

Cardiac disorders Arrhythmia (G3/4: 2.0%) Ischemia myocardial

MedDRA System

Organ classes Very common adverse

reactions Common adverse reactionsUncommon adverse

reactions

Blood and lymphatic

system disorders Neutropenia (G3/4: 83.5%);

Anemia (G3/4: 12.4%);

Thrombocytopenia (G3/4:

4.0%);

Febrile neutropenia a

Nervous system

disorders Dysgeusia/Parosmia (G3/4:

0.4%);

Peripheral sensory

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

Peripheral motor

neuropathy (G3/4: 0.4%)

Eye disorders Lacrimation increased Conjunctivitis

Ear and labyrinth

disorders Hearing impaired (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: 0.4%) Dyspepsia (G3/4: 0.8%);

Gastrointestinal pain (G3/4:

1.2%);

Gastrointestinal

haemorrhage (G3/4: 0.4%)

Skin and subcutaneous

tissue disorders Alopecia (G3/4: 4.0%);

Rash pruritic Dry skin;

Desquamation

Musculoskeletal,

connective tissue bone

disorders Myalgia (G3/4: 0.4%)

Metabolism and

nutrition disorders Anorexia (G3/4: 12.0%)

Infections and

infestations Infection (G3/4: 3.6%) Neutropenic infection

Neoplasms benign,

malignant and

unspecified (incl cysts

and polyps) Cancer pain (G3/4: 1.2%)

Vascular disorders Venous disorder

General disorders and

administration site

conditions Lethargy (G3/4: 4.0%);

Pyrexia (G3/4: 3.6%);

Fluid retention (G3/4: 1.2%);

Oedema (G3/4: 1.2%)

Immune system

disorders Hypersensitivity

Febrileneutropenia:grade≥2feverconcomittantwithgrade4neutropeniarequiringi.v.antibioticsand/or

hospitalization.

CombinationtherapywithTAXOTEREforadjuvanttreatmentofpatientswithoperablebreastcancerwhose

tumours overexpress HER2 and who received either AC-TH or TCH

AdverseEvents(AEs)RelatedtoStudyTreatment,OccurringatAnyTimeDuringtheStudy:Safetypopulation

(incidence of≥5% for non-cardiac AEs; incidence of≥1% for cardiac AEs)

AC-TH

n = 1068 TCH

n = 1056

Adverse Event

(NCI-CTC term) Overall

n (%) Grade 3/4

n (%) Overall

n (%) Grade 3/4

n (%)

Alopecia 1047 (98.0) 0 1012 (95.8) 0

Haemoglobin a 1036 (97.0) 34 (3.2) 1017 (96.3) 61 (5.8)

Nausea 931 (87.2) 57 (5.3) 853 (80.8) 49 (4.6)

Leucocytes a 929 (87.0) 643 (60.2) 877 (83.0) 507 (48.0)

Neutrophils a 922 (86.3) 761 (71.3) 859 (81.3) 696 (65.9)

Fatigue 868 (81.3) 71 (6.6) 849 (80.4) 73 (6.9)

Stomatitis/pharyngitis694 (65.0) 32 (3.0) 547 (51.8) 15 (1.4)

Vomiting 591 (55.3) 68 (6.4) 416 (39.4) 32 (3.0)

SGPT (ALT) a 579 (54.2) 19 (1.8) 561 (53.1) 25 (2.4)

Fluid retention a,b 558 (52.2) 16 (1.5) 539 (51.0) 15 (1.4)

Myalgia 544 (50.9) 52 (4.9) 353 (33.4) 15 (1.4)

Diarrhoea 484 (45.3) 55 (5.1) 589 (55.8) 52 (4.9)

Neuropathy‑sensory 478 (44.8) 20 (1.9) 316 (29.9) 6 (0.6)

SGOT (AST) a 454 (42.5) 9 (0.8) 401 (38.0) 11 (1.0)

Arthralgia 424 (39.7) 32 (3.0) 230 (21.8) 11 (1.0)

Nail changes 423 (39.6) 0 246 (23.3) 0

Platelets a 350 (32.8) 13 (1.2) 667 (63.2) 57 (5.4)

Irregular menses 311 (29.1) 213 (19.9) 340 (32.2) 226 (21.4)

Taste disturbance 290 (27.2) 0 312 (29.5) 0

Constipation 289 (27.1) 10 (0.9) 232 (22.0) 6 (0.6)

Rash/desquamation 277 (25.9) 14 (1.3) 241 (22.8) 4 (0.4)

Hot flashes/flushes 230 (21.5) 0 192 (18.2) 0

Tearing 228 (21.3) 3 (0.3) 109 (10.3) 0

Alkaline phosphatase a 206 (19.3) 3 (0.3) 215 (20.4) 3 (0.3)

Anorexia 205 (19.2) 5 (0.5) 222 (21.0) 5 (0.5)

Dyspepsia/heartburn203 (19.0) 3 (0.3) 211 (20.0) 4 (0.4)

Headache 175 (16.4) 6 (0.6) 160 (15.2) 3 (0.3)

Dyspnea 166 (15.5) 16 (1.5) 157 (14.9) 18 (1.7)

Weight gain 159 (14.9) 3 (0.3) 154 (14.6) 2 (0.2)

Infection without

neutropenia 135 (12.6) 20 (1.9) 98 (9.3) 16 (1.5)

Abdominal pain or

cramping 132 (12.4) 4 (0.4) 141 (13.4) 5 (0.5)

Insomnia 119 (11.1) 1 (0.1) 93 (8.8) 0

Febrile neutropenia 116 (10.9) 116 (10.9) 103 (9.8) 103 (9.8)

Fever (without

neutropenia) 116 (10.9) 4 (0.4) 70 (6.6) 3 (0.3)

Allergic reaction/

hypersensitivity 105 (9.8) 15 (1.4) 139 (13.2) 26 (2.5)

Bone pain 104 (9.7) 4 (0.4) 67 (6.3) 1 (0.1)

Infection with Grade

3/4 neutropenia 98 (9.2) 98 (9.2) 81 (7.7) 81 (7.7)

Pain c 86 (8.1) 4 (0.4) 57 (5.4) 0

Conjunctivitis 86 (8.1) 0 35 (3.3) 0

Dizziness/

lightheadedness 78 (7.3) 7 (0.7) 70 (6.6) 4 (0.4)

Creatinine a 72 (6.7) 5 (0.5) 102 (9.7) 6 (0.6)

Hand‑foot skin

reaction 72 (6.7) 15 (1.4) 29 (2.7) 0

Epistaxis 72 (6.7) 0 104 (9.8) 4 (0.4)

Weight loss 71 (6.6) 0 56 (5.3) 1 (0.1)

Dry skin 69 (6.5) 0 41 (3.9) 0

Cough 66 (6.2) 2 (0.2) 36 (3.4) 0

Rhinitis c 64 (6.0) 1 (0.1) 47 (4.5) 0

Rigors, chills 63 (5.9) 0 54 (5.1) 0

Infection with

unknown ANC 59 (5.5) 59 (5.5) 38 (3.6) 38 (3.6)

Neuropathy‑motor 57 (5.3) 4 (0.4) 38 (3.6) 3 (0.3)

Bilirubin a 54 (5.1) 4 (0.4) 61 (5.8) 4 (0.4)

Injection site reaction50 (4.7) 1 (0.1) 61 (5.8) 2 (0.2)

Mouth dryness 43 (4.0) 0 29 (2.7) 0

Cardiac left ventricular

function 37 (3.5) 5 (0.5) 15 (1.4) 1 (0.1)

Palpitations 36 (3.4) 0 47 (4.5) 0

Sinus tachycardia 19 (1.8) 0 23 (2.2) 0

Hypotension 10 (0.9) 0 13 (1.2) 2 (0.2)

AC‑TH = doxorubicin and cyclophosphamide, followed by TAXOTERE in combination with trastuzumab.

TCH = TAXOTERE in combination with trastuzumab and carboplatin.

Regardless ofcausality

Fluid retention AEs are defined as “oedema only”, or “weight gain only”, or “lung oedema only”, or “oedema

and weight gain”, or “oedema and lung oedema”, or “oedema + weight gain + lung oedema”. “Fluid retention”

corresponds to the NCI‑CTC term “oedema”.

COSTART term

The3yearcumulativeincidenceofallsymptomaticcardiaceventswas2.36%and1.16%intheAC‑THandTCH

arms,respectively(versus0.52%intheAC‑Tcontrolarm,seeCLINICALTRIALSsection).The3yearcumulative

incidenceofCHFevents(Grade3or4)was1.9%and0.4%intheAC‑THandTCHarms,respectively(versus0.3%

in the AC‑T control arm).

Post‑marketing experience

Cardiac disorders

Rare cases ofmyocardial infarction have been reported.

Blood and lymphatic system disorders

Bonemarrowsuppressionandotherhaematologicadversereactionshavebeenreported.Disseminatedintravascular

coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported.

Nervous system disorders

Rarecasesofconvulsionortransientlossofconsciousnesshavebeenobservedwithdocetaxeladministration.

These reactions sometimes appear during the infusion ofthe medicinal product.

Eye disorders

Veryrarecasesoftransientvisualdisturbances(flashes,flashinglights,scotomata)typicallyoccurringduring

infusionofthemedicinalproductandinassociationwithhypersensitivityreactionshavebeenreported.These

werereversibleupondiscontinuationoftheinfusion.Casesoflacrimationwithorwithoutconjunctivitis,ascases

oflacrimal duct obstruction resulting in excessive tearing have been rarely reported.

Ear and labyrinth disorders

Rare cases ofototoxicity, hearing impaired and/or hearing loss have been reported.

Respiratory, thoracic and mediastinal disorders

Acuterespiratorydistresssyndrome,interstitialpneumonia/pneumonitis,interstitiallungdisease,pulmonary

fibrosis,respiratoryfailure,andradiationrecallphenomenahaverarelybeenreported,andmaybeassociated

withfataloutcome.Rarecasesofradiationpneumonitishavebeenreportedinpatientsreceivingconcomitant

radiotherapy.

Gastrointestinal disorders

Rareoccurrencesofdehydrationasaconsequenceofgastrointestinalevents,gastrointestinalperforation,colitis

ischaemic,colitisandneutropenicenterocolitishavebeenreported.Rarecasesofileusandintestinalobstruction

have been reported.

Skin and subcutaneous tissue disorders

Veryrarecasesofcutaneouslupuserythematosusandbullouseruptionssuchaserythemamultiforme,Stevens‑

Johnsonsyndrome,toxicepidermalnecrolysis,havebeenreportedwithdocetaxel.Insomecasesconcomitant

factorsmayhavecontributedtothedevelopmentoftheseeffects.Sclerodermal‑likechangesusuallyprecededby

peripheral lymphoedema have been reported with docetaxel. Cases ofpersisting alopecia have been reported.

Renal and urinary disorders

Renalinsufficiencyandrenalfailurehavebeenreported.Inabout20%ofthesecasestherewerenoriskfactorsfor

acute renal failure such as concomitant nephrotoxic medicinal products and gastro‑intestinal disorders.

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Casesofacutemyeloidleukaemiaandmyelodysplasticsyndromehavebeenreportedinassociationwithdocetaxel

Vascular disorders

Venous thromboembolic events have rarely been reported.

General disorders and administration site conditions

Radiation recall phenomena have rarely been reported.

Fluidretentionhasnotbeenaccompaniedbyacuteepisodesofoliguriaorhypotension.Dehydrationand

pulmonary oedema have rarely been reported.

Immune system disorders

Some cases ofanaphylactic shock, sometimes fatal, have been reported.

Hepatobiliary disorders

Veryrarecasesofhepatitis,sometimesfatalprimarilyinpatientswithpre‑existingliverdisorders,havebeen

reported.

4.9Overdose

Therewereafewreportsofoverdose.Thereisnoknownantidotefordocetaxeloverdose.Incaseofoverdose,the

patientshouldbekeptinaspecialisedunitandvitalfunctionscloselymonitored.Incasesofoverdose,exacerbation

ofadverseeventsmaybeexpected.Theprimaryanticipatedcomplicationsofoverdosewouldconsistofbone

marrowsuppression,peripheralneurotoxicityandmucositis.PatientsshouldreceivetherapeuticG‑CSFassoonas

possible after discovery ofoverdose. Other appropriate symptomatic measures should be taken, as needed.

5. PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmaco‑therapeutic group: Taxanes, ATC Code: L01CD 02

Mechanism ofaction

Docetaxelisanantineoplasticagentwhichactsbypromotingtheassemblyoftubulinintostablemicrotubules

andinhibitstheirdisassemblywhichleadstoamarkeddecreaseoffreetubulin.Thebindingofdocetaxelto

microtubules does not alter the number ofprotofilaments.

Docetaxelhasbeenshowninvitrotodisruptthemicrotubularnetworkincellswhichisessentialforvitalmitotic

and interphase cellular functions.

Pharmacodynamic effects

Docetaxelwasfoundtobecytotoxicinvitroagainstvariousmurineandhumantumourcelllinesandagainst

freshlyexcisedhumantumourcellsinclonogenicassays.Docetaxelachieveshighintracellularconcentrations

withalongcellresidencetime.Inaddition,docetaxelwasfoundtobeactiveonsomebutnotallcelllinesover

expressingthep‑glycoproteinwhichisencodedbythemultidrugresistancegene.Invivo,docetaxelisschedule

independentandhasabroadspectrumofexperimentalantitumouractivityagainstadvancedmurineand

human grafted tumours.

Clinical efficacy and safety

Breast cancer

TAXOTERE in combination with doxorubicin and cyclophosphamide: adjuvant therapy

Patients with operable node‑positive breast cancer (TAX 316)

Datafromamulticenteropen‑labelrandomizedstudysupporttheuseofdocetaxelfortheadjuvanttreatment

ofpatientswithoperablenode‑positivebreastcancerandKPS³80%,between18and70yearsofage.After

stratificationaccordingtothenumberofpositivelymphnodes(1‑3,4+),1491patientswererandomizedtoreceive

eitherTAXOTERE75mg/m 2 administered1‑hourafterdoxorubicin50mg/m 2 andcyclophosphamide500mg/m 2

(TACarm),ordoxorubicin50mg/m 2 followedbyfluorouracil500mg/m 2 andcyclophosphamide500mg/m 2 (FAC

arm).Bothregimenswereadministeredonceevery3weeksfor6cycles.Docetaxelwasadministeredasa1‑hour

infusion,allotherdrugsweregivenasIVbolusondayone.G‑CSFwasadministeredassecondaryprophylaxisto

patientswhoexperiencedcomplicatedneutropenia(febrileneutropenia,prolongedneutropenia,orinfection).

PatientsontheTACarmreceivedantibioticprophylaxiswithciprofloxacin500mgorallyb.i.d.for10daysstarting

onday5ofeachcycle,orequivalent.Inbotharms,afterthelastcycleofchemotherapy,patientswithpositive

estrogenand/orprogesteronereceptorsreceivedtamoxifen20mgdailyforupto5years.Adjuvantradiationtherapy

wasprescribedaccordingtoguidelinesinplaceatparticipatinginstitutionsandwasgivento69%ofpatientswho

receivedTACand72%ofpatientswhoreceivedFAC.Twointerimanalysesandonefinalanalysiswereperformed.

Thefirstinterimanalysiswasplanned3yearsafterthedatewhenhalfofstudyenrollmentwasdone.Thesecond

interimanalysiswasdoneafter400DFSeventshadbeenrecordedoverall,whichledtoamedianfollow‑upof55

months.Thefinalanalysiswasperformedwhenallpatientshadreachedtheir10‑yearfollow‑upvisit(unlessthey

hadaDFSeventorwerelosttofollow‑upbefore).Disease‑freesurvival(DFS)wastheprimaryefficacyendpoint

and Overall Survival (OS) was the secondary efficacy endpoint.

Afinalanalysiswasperformedwithanactualmedianfollow‑upof96months.Significantlylongerdisease‑free

survivalfortheTACarmcomparedtotheFACarmwasdemonstrated.Incidenceofrelapsesat10yearswasreduced

inpatientsreceivingTACcomparedtothosewhoreceivedFAC(39%versus45%,respectively)i.e.,anabsoluterisk

reductionby6%(p=0.0043).Overallsurvivalat10yearswasalsosignificantlyincreasedwithTACcomparedto

FAC(76%versus69%,respectively)i.e.,anabsolutereductionoftheriskofdeathby7%(p=0.002).Asthebenefit

observedinpatientwith4+nodeswasnotstatisticallysignificantonDFSandOS,thepositivebenefit/riskratio

for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis.

Overall, the study results demonstrate a positive benefit risk ratio for TAC compared to FAC.

TAC‑treated patient subsets according to prospectively defined major prognostic factors were analyzed:

Disease-free survival Overall survival

Patient subsetNumber of

patients Hazard

ratio* 95% CI P= Hazard

ratio* 95% CI P=

No. ofpositive

nodes

Overall 745 0.80 0.68‑0.93 0.0043 0.74 0.61‑0.90 0.0020

1‑3 467 0.72 0.58‑0.91 0.0047 0.62 0.46‑0.82 0.0008

0.87 0.70‑1.09 0.2290 0.87 0.67‑1.12 0.2746

* a hazard ratio ofless than 1 indicates that TAC is associated with a longer disease‑free survival and overall

survival compared to FAC

Patients with operable node‑negative breast cancer eligible to receive chemotherapy (GEICAM 9805)

Datafromamulticenteropen‑labelrandomizedtrialsupporttheuseofTAXOTEREfortheadjuvanttreatment

ofpatientswithoperablenode‑negativebreastcancereligibletoreceivechemotherapy.1060patientswere

randomizedtoreceiveeitherTAXOTERE75mg/m 2 administered1‑hourafterdoxorubicin50mg/m 2 and

cyclophosphamide500mg/m 2 (539patientsinTACarm),ordoxorubicin50mg/m 2 followedbyfluorouracil

500mg/m 2 andcyclophosphamide500mg/m 2 (521patientsinFACarm),asadjuvanttreatmentofoperable

node‑negativebreastcancerpatientswithhighriskofrelapseaccordingto1998St.Gallencriteria(tumoursize

>2cmand/ornegativeERandPRand/orhighhistological/nucleargrade(grade2to3)and/orage<35years).Both

regimenswereadministeredonceevery3weeksfor6cycles.TAXOTEREwasadministeredasa1‑hourinfusion,

allothermedicinalproductsweregivenintravenouslyonday1everythreeweeks.PrimaryprophylacticG‑CSF

wasmademandatoryinTACarmafter230patientswererandomized.TheincidenceofGrade4neutropenia,

febrileneutropeniaandneutropenicinfectionwasdecreasedinpatientswhoreceivedprimaryG‑CSFprophylaxis

(seesection4.8).Inbotharms,afterthelastcycleofchemotherapy,patientswithER+and/orPgR+tumours

receivedtamoxifen20mgonceadayforupto5years.Adjuvantradiationtherapywasadministeredaccording

toguidelinesinplaceatparticipatinginstitutionsandwasgivento57.3%ofpatientswhoreceivedTACand51.2%

ofpatients who received FAC.

Mediandurationoffollow‑upwas77months.Significantlylongerdisease‑freesurvivalfortheTACarmcompared

totheFACarmwasdemonstrated.TAC‑treatedpatientshada32%reductionintheriskofrelapsecomparedto

thosetreatedwithFAC(hazardratio=0.68,95%CI(0.49‑0.93),p=0.01).Overallsurvival(OS)wasalsolonger

intheTACarmwithTAC‑treatedpatientshavinga24%reductionintheriskofdeathcomparedtoFAC(hazard

ratio=0.76,95%CI(0.46‑1.26),p=0.29).However,thedistributionofOSwasnotsignificantlydifferentbetween

the 2 groups.

TAC‑treatedpatientsubsetsaccordingtoprospectivelydefinedmajorprognosticfactorswereanalyzed(see

table below):

Subset Analyses‑Adjuvant Therapy in Patients with Node‑negative Breast Cancer Study (Intent‑to‑Treat Analysis)

Disease-Free Survival

Patient subset Number ofpatients in

TAC group Hazard ratio* 95% CI

Overall 539 0.68 0.49‑0.93

Age category 1

<50 years

≥50 years 260

0.67

0.67 0.43‑1.05

0.43‑1.05

Age category 2

<35 years

≥35 years 42

0.31

0.73 0.11‑0.89

0.52‑1.01

Hormonal receptor status

Negative

Positive 195

0.62 0.45‑1.1

0.4‑0.97

Tumour size

£2 cm

>2 cm 285

0.69

0.68 0.43‑1.1

0.45‑1.04

Histological grade

Grade 1 (includes grade not

assessed)

Grade 2

Grade 3 64

0.79

0.77

0.59 0.24‑2.6

0.46‑1.3

0.39‑0.9

Menopausal status

Pre‑Menopausal

Post‑Menopausal 285

0.64

0.72 0.40‑1

0.47‑1.12

* a hazard ratio (TAC/FAC) ofless than 1 indicates that TAC is associated with a longer disease‑free survival

compared to FAC

Exploratorysubgroupanalysesfordisease‑freesurvivalforpatientswhomeetthe2009St.Gallenchemotherapy

criteria – (ITT population) were performed and presented here below:

Subgroups TAC

(n = 539) FAC

(n = 521) Hazard ratio

(TAC/FAC)

(95% CI) p-value

Meeting relative indication for

chemotherapy a

18/214

(8.4%) 26/227

(11.5%) 0.796 (0.434‑1.459) 0.4593

48/325

(14.8%) 69/294

(23.5%) 0.606 (0.42‑0.877) 0.0072

TAC = docetaxel, doxorubicin and cyclophosphamide

FAC = 5‑fluorouracil, doxorubicin and cyclophosphamide

CI = confidence interval; ER = estrogen receptor

PR = progesterone receptor

ER/PR‑negative or Grade 3 or tumor size >5 cm

The estimated hazard ratio was using Cox proportional hazard model with treatment group as the factor.

TAXOTERE as single agent

TworandomisedphaseIIIcomparativestudies,involvingatotalof326alkylatingor392anthracyclinefailure

metastaticbreastcancerpatients,havebeenperformedwithdocetaxelattherecommendeddoseandregimen

of100 mg/m² every 3 weeks.

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(three

cases offatal congestive heart failure).

Inanthracycline‑failurepatients,docetaxelwascomparedtothecombinationofMitomycinCandVinblastine

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

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

vs. 9 months, p = 0.01).

DuringthesetwophaseIIIstudies,thesafetyprofileofdocetaxelwasconsistentwiththesafetyprofileobserved

in phase II studies (see section 4.8).

Anopen‑label,multicenter,randomizedphaseIIIstudywasconductedtocompareTAXOTEREmonotherapyand

paclitaxelinthetreatmentofadvancedbreastcancerinpatientswhoseprevioustherapyshouldhaveincludedan

anthracycline.Atotalof449patientswererandomizedtoreceiveeitherTAXOTEREmonotherapy100mg/m²asa

Withoutaffectingtheprimaryendpoint,overallresponserate(32%vs.25%,p=0.10),docetaxelprolonged

mediantimetoprogression(24.6weeksvs.15.6weeks,p<0.01)andmediansurvival(15.3monthsvs.

12.7 months, p = 0.03).

Moregrade3/4adverseeventswereobservedforTAXOTEREmonotherapy(55.4%)comparedtopaclitaxel

(23.0%).

TAXOTERE in combination with doxorubicin

OnelargerandomizedphaseIIIstudy,involving429previouslyuntreatedpatientswithmetastaticdisease,hasbeen

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

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

day 1 every 3 weeks.

Time to progression (TTP) was significantly longer in the AT arm versus AC arm, p = 0.0138. The median TTP

was 37.3 weeks (95% CI: 33.4‑42.1) in AT arm and 31.9 weeks (95% CI: 27.4‑36.0) in AC arm.

Overall response rate (ORR) was significantly higher in the AT arm versus AC arm, p = 0.009. The ORR was 59.3%

(95% CI: 52.8‑65.9) in AT arm versus 46.5% (95% CI: 39.8‑53.2) in AC arm.

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%

versus8.5%)thanATarm,and,inaddition,ahigherincidenceofseverecardiactoxicity:congestiveheartfailure

(3.8%versus2.8%),absoluteLVEFdecrease³20%(13.1%versus6.1%),absoluteLVEFdecrease³30%(6.2%versus

1.1%).Toxicdeathsoccurredin1patientintheATarm(congestiveheartfailure)andin4patientsintheACarm

(1 due to septic shock and 3 due to congestive heart failure).

Inbotharms,qualityoflifemeasuredbytheEORTCquestionnairewascomparableandstableduringtreatment

and follow‑up.

TAXOTERE in combination with trastuzumab

TAXOTEREincombinationwithtrastuzumabwasstudiedforthetreatmentofpatientswithmetastaticbreastcancer

whosetumoursoverexpressHER2,andwhopreviouslyhadnotreceivedchemotherapyformetastaticdisease.

OnehundredeightysixpatientswererandomizedtoreceiveTAXOTERE(100mg/m 2 )withorwithouttrastuzumab;

60%ofpatientsreceivedprioranthracycline‑basedadjuvantchemotherapy.TAXOTEREplustrastuzumabwas

efficaciousinpatientswhetherornottheyhadreceivedprioradjuvantanthracyclines.Themaintestmethodused

todetermineHER2positivityinthispivotalstudywasimmunohistochemistry(IHC).Aminorityofpatientswere

testedusingfluorescencein-situhybridization(FISH).Inthisstudy,87%ofpatientshaddiseasethatwasIHC3+,

and95%ofpatientsenteredhaddiseasethatwasIHC3+and/orFISHpositive.Efficacyresultsaresummarized

in the following table:

Parameter TAXOTERE plus trastuzumab 1

n = 92 TAXOTERE 1

n = 94

Response rate

(95% CI) 61%

(50‑71) 34%

(25‑45)

Median duration ofresponse

(months)

(95% CI) 11.4

(9.2‑15.0) 5.1

(4.4‑6.2)

Median TTP (months)

(95% CI) 10.6

(7.6‑12.9) 5.7

(5.0‑6.5)

Median survival (months)

(95% CI) 30.5 2

(26.8‑ne) 22.1 2

(17.6‑28.9)

TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached.

1 Full analysis set (intent‑to‑treat)

Estimated median survival

TAXOTERE in combination with capecitabine

Datafromonemulticenter,randomised,controlledphaseIIIclinicalstudysupporttheuseofdocetaxelin

combinationwithcapecitabinefortreatmentofpatientswithlocallyadvancedormetastaticbreastcancer

afterfailureofcytotoxicchemotherapy,includingananthracycline.Inthisstudy,255patientswererandomised

totreatmentwithdocetaxel(75mg/m 2 asa1hourintravenousinfusionevery3weeks)andcapecitabine

(1250mg/m 2 twicedailyfor2weeksfollowedby1‑weekrestperiod).256patientswererandomisedtotreatment

withdocetaxelalone(100mg/m 2 asa1hourintravenousinfusionevery3weeks).Survivalwassuperiorinthe

docetaxel+capecitabinecombinationarm(p=0.0126).Mediansurvivalwas442days(docetaxel+capecitabine)

vs.352days(docetaxelalone).Theoverallobjectiveresponseratesintheall‑randomisedpopulation(investigator

assessment)were41.6%(docetaxel+capecitabine)vs.29.7%(docetaxelalone);p=0.0058.Timetoprogressive

diseasewassuperiorinthedocetaxel+capecitabinecombinationarm(p<0.0001).Themediantimetoprogression

was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).

DoxorubicinandCyclophosphamidefollowedbyTAXOTEREincombinationwithTrastuzumab(AC-TH),or

TAXOTERE in combination with Trastuzumab and Carboplatin (TCH)

TheefficacyandsafetyofTAXOTEREincombinationwithtrastuzumabwasstudiedfortheadjuvanttreatment

ofpatientswithoperablebreastcancerwhosetumoursoverexpressHER2(withnode‑positiveandhighrisk

node‑negative).Atotalof3,222womenwererandomisedinthestudy,and3,174weretreatedwitheither:AC‑T,

AC‑TH, or TCH.

AC-T:(controlarm):Doxorubicin60mg/m 2 IVincombinationwithcyclophosphamide600mg/m 2 IVonan

every3weekbasisfor4cycles,followedbyTAXOTERE100mg/m 2 asa1‑hourIVinfusiononanevery3week

basis for 4 cycles;

AC-TH:Doxorubicin60mg/m 2 IVincombinationwithcyclophosphamide600mg/m 2 IVonanevery3week

basisfor4cycles.ThreeweeksafterthelastcycleofAC,trastuzumab4mg/kgloadingdosebyIVinfusion

over90minutesonday1ofcycle5wasadministered,followedbytrastuzumab2mg/kgbyIVinfusionover

30‑minutesweeklystartingday8ofcycle5;andTAXOTERE100mg/m 2 administeredbyIVinfusionover1‑hour

onday2ofcycle5,thenonday1onanevery3weekbasisforallsubsequentcycles(total4cyclesofTAXOTERE).

Beginningthreeweeksafterthelastcycleofchemotherapy,trastuzumab6mg/kgbyIVinfusionover30minutes

was given every 3 weeks (for 1 year from the date offirst administration);

TCH:Trastuzumab4mg/kgloadingdosebyIVinfusionover90minutesonday1ofcycle1only,followed

bytrastuzumab2mg/kgbyIVinfusionover30minutesweeklystartingonday8untilthreeweeksafterthe

lastcycleofchemotherapy.TAXOTERE75mg/m 2 wasadministeredonday2ofcycle1,thenonday1ofall

subsequentcyclesbyIVinfusionover1‑hourfollowedbycarboplatin(AUC6mg/mL/min)asa30‑60minute

IVinfusion,foratotalofsixcyclesofTAXOTEREandcarboplatin.Beginningthreeweeksafterthelastcycleof

chemotherapy,trastuzumab6mg/kgbyIVinfusionover30minuteswasgivenevery3weeks(for1‑yearfrom

the date offirst administration).

The patients and disease characteristics at baseline were well balanced between the 3 treatment arms.

Disease‑Free Survival (DFS) was the primary endpoint, and Overall Survival (OS) was the secondary endpoint.

Resultsofthesecondinterimanalysis,performedwithamedianfollow‑upof36months,demonstrated

thatTAXOTEREandtrastuzumabgivenconcurrentlyaspartofeitherananthracycline‑based(AC‑TH)or

non‑anthracycline‑based(TCH)adjuvanttreatmentregimens,forpatientswithHER2‑positiveoperablebreast

cancer,statisticallyprolongedbothDFSandOScomparedwiththecontrolarm(AC‑T).Therelativereductionin

theriskofrelapsewas39%(p<0.0001)and33%(p=0.0003)fortheAC‑THandTCHarms,respectively,compared

withtheAC‑Tarm.Therelativereductionintheriskofdeathwas42%(p=0.0024)and34%(p=0.0182)forthe

AC‑THandTCHarms,respectively,comparedwiththeAC‑Tarm.Therewasnostatisticallysignificantdifference

betweenthetwotrastuzumab‑containingarmsAC‑THandTCHforDFSandOS.Efficacyresultsaresummarised

in the following table:

DoxorubicinandcyclophosphamidefollowedbyTAXOTEREincombinationwithtrastuzumab,orTAXOTERE

in combination with trastuzumab, and carboplatin (Intent to Treat Population)

Disease-Free Survival (DFS) Overall Survival (OS)

AC-T

n = 1073 AC-TH

n = 1074 TCH

n = 1075 AC-T

n = 1073 AC-TH

n = 1074 TCH

n = 1075

Stratified analysis

Hazard ratio a NA 0.61 0.67 NA 0.58 0.66

95% CI NA (0.49‑0.77) (0.54‑0.83) NA (0.40‑0.83) (0.47‑0.93)

p‑value b NA <0.0001 0.0003 NA 0.0024 0.0182

Percent event free at

3 years (95% CI) 80.9%

(78.3‑83.5%) 86.7%

(84.4‑89.0%) 85.5%

(83.2‑87.9%) 93.0%

(91.2‑94.8%) 95.5%

(94.0‑96.9%) 95.2%

(93.7‑96.6%)

Absolute benefit c 5.8% 4.6% 2.5% 2.2%

AC‑T = doxorubicin plus cyclophosphamide, followed by TAXOTERE; AC‑TH = doxorubicin plus cyclophosphamide,

followed by TAXOTERE in combination with trastuzumab; TCH = TAXOTERE in combination with trastuzumab and

carboplatin

CI = confidence interval; NA = not applicable

= Relative to AC‑T. Estimated using Cox regression stratified by number ofnodes and hormonal receptor status

= Stratified log‑rank p‑value

= Absolute benefit in percent event free compared with AC‑T

Therewere29%ofpatientswithhighrisknode‑negativediseaseincludedinthestudy.Thebenefitobservedfor

the overall population was irrespective ofthe nodal status.

Disease-Free Survival (Intent to Treat Population) according to Nodal Status:

High risk node-negative patients Node-positive patients

AC-T

n = 309 AC-TH

n = 306 TCH

n = 307 AC-T

n = 764 AC-TH

n = 768 TCH

n = 768

Stratified analysis

Hazard ratio a NA 0.36 0.52 NA 0.67 0.70

95% CI NA (0.19‑0.68) (0.30‑0.92) NA (0.53‑0.85) (0.56‑0.89)

p‑value b NA 0.0010 0.0209 NA 0.0008 0.0029

Percent event free at 3

years (95% CI) 88.0%

(84.1‑91.9%) 94.8%

(91.9‑97.8%) 93.0%

(89.9‑96.2%) 78.1%

(74.9‑81.3%) 83.6%

(80.7‑86.5%) 82.6%

(79.6‑85.6%)

Absolute benefit c 6.8% 5.1% 5.5% 4.6%

AC‑T = doxorubicin plus cyclophosphamide, followed by TAXOTERE; AC‑TH = doxorubicin plus cyclophosphamide,

followed by TAXOTERE in combination with trastuzumab; TCH = TAXOTERE in combination with trastuzumab and

carboplatin

CI = confidence interval; NA = not applicable

= Relative to AC‑T. Estimated using Cox regression stratified by number ofnodes and hormonal receptor status

= Stratified log‑rank p‑value

= Absolute benefit in percent event free compared with AC‑T

Non-Small Cell Lung Cancer

Patients previously treated with chemotherapy with or without radiotherapy

InaphaseIIIstudy,inpreviouslytreatedpatients,timetoprogression(12.3weeksversus7weeks)andoverall

survivalweresignificantlylongerfordocetaxelat75mg/m²comparedtoBestSupportiveCare.The1‑yearsurvival

rate was also significantly longer in docetaxel (40%) versus BSC (16%).

Therewaslessuseofmorphinicanalgesic(p<0.01),non‑morphinicanalgesics(p<0.01),otherdisease‑related

medicinalproducts(p=0.06)andradiotherapy(p<0.01)inpatientstreatedwithdocetaxelat75mg/m²compared

to those with BSC.

Theoverallresponseratewas6.8%intheevaluablepatients,andthemediandurationofresponsewas

26.1 weeks.

TAXOTERE in combination with platinum agents in chemotherapy-naïve patients

InaPhaseIIIstudy,1218patientswithunresectablestageIIIBorIVNSCLC,withKPSof70%orgreater,andwho

didnotreceivepreviouschemotherapyforthiscondition,wererandomisedtoeitherTAXOTERE(T)75mg/m 2 asa

1hourinfusionimmediatelyfollowedbycisplatin(Cis)75mg/m 2 over30‑60minutesevery3weeks(TCis),TAXOTERE

75mg/m 2 asa1hourinfusionincombinationwithcarboplatin(AUC6mg/ml min)over30‑60minutesevery

3weeks,orvinorelbine(V)25mg/m 2 administeredover6‑10minutesondays1,8,15,22followedbycisplatin

100 mg/m 2 administered on day 1 ofcycles repeated every 4 weeks (VCis).

Survivaldata,mediantimetoprogressionandresponseratesfortwoarmsofthestudyareillustratedinthe

following table:

TCis

n = 408 VCis

n = 404 Statistical analysis

Overall survival

(Primary end‑point):

Median Survival (months) 11.3 10.1 Hazard Ratio: 1.122

[97.2% CI: 0.937; 1.342]*

1‑year Survival (%) 46 41 Treatment difference: 5.4%

[95% CI:‑1.1; 12.0]

2‑year Survival (%) 21 14 Treatment difference: 6.2%

[95% CI: 0.2; 12.3]

Median time to progression

(weeks): 22.0 23.0 Hazard Ratio: 1.032

[95% CI: 0.876; 1.216]

Overall response rate (%): 31.6 24.5 Treatment difference: 7.1%

[95% CI: 0.7; 13.5]

* Corrected for multiple comparisons and adjusted for stratification factors (stage ofdisease and region of

Secondaryend‑pointsincludedchangeofpain,globalratingofqualityoflifebyEuroQoL‑5D,LungCancer

SymptomScale,andchangesinKarnofskyperformancestatus.Resultsontheseend‑pointsweresupportiveof

the primary end‑points results.

ForTAXOTERE/Carboplatincombination,neitherequivalentnornon‑inferiorefficacycouldbeprovencompared

to the reference treatment combination VCis.

Prostate Cancer

ThesafetyandefficacyofTAXOTEREincombinationwithprednisoneorprednisoloneinpatientswithhormone

refractory metastatic prostate cancer were evaluated in a randomized multicenter Phase III study.

A total of1006 patients with KPS³60 were randomized to the following treatment groups:

TAXOTERE 75 mg/m 2 every 3 weeks for 10 cycles.

TAXOTERE 30 mg/m 2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.

Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles.

All3regimenswereadministeredincombinationwithprednisoneorprednisolone5mgtwicedaily,

continuously.

Patientswhoreceiveddocetaxeleverythreeweeksdemonstratedsignificantlylongeroverallsurvivalcompared

tothosetreatedwithmitoxantrone.Theincreaseinsurvivalseeninthedocetaxelweeklyarmwasnotstatistically

significantcomparedtothemitoxantronecontrolarm.EfficacyendpointsfortheTAXOTEREarmsversusthecontrol

arm are summarized in the following table:

Endpoint Docetaxel

every 3 weeks Docetaxel

every week Mitoxantrone

every 3 weeks

Number ofpatients

Median survival (months)

95% CI

Hazard ratio

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)

‑‑

‑‑

‑‑

Number ofpatients

PSA** response rate (%)

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)

‑‑

Number ofpatients

Pain response rate (%)

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)

‑‑

Number ofpatients

Tumour response rate (%)

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)

‑‑

Stratified log‑rank test

* Threshold for statistical significance = 0.0175

** PSA: Prostate‑Specific Antigen

GiventhefactthatTAXOTEREeveryweekpresentedaslightlybettersafetyprofilethanTAXOTEREevery3weeks,

it is possible that certain patients may benefit from TAXOTERE every week.

No statistical differences were observed between treatment groups for Global Quality ofLife.

Ovarian Cancer

Supportive clinical data

TAXOTEREwasstudiedinfivephaseIIclinicaltrialsinpatientswhowerediagnosedwithadvancedepithelial

ovariancancerandwhofailedaprevioustreatmentwithcisplatinand/ortocarboplatin.Thesepatients

(n = 281) received TAXOTERE 100 mg/m² every three weeks as a one‑hour infusion.

Overall response rate was 26.7% with a 5.7% complete response rate.

The median survival ranged from 11.2 to 11.9 months.

The adverse reaction profile from these 281 patients is similar to larger populations studied for metastatic breast

cancer (see Adverse Reactions section).

Ovarian first line treatment in combination with platinum

TAXOTEREwasstudiedintwomajorphaseIIstudieswith241patientswithstage1c‑IVovariancarcinoma.

Overallresponse rate inthese two studies ranged from66%‑69% (42%complete response rate in onestudy) with

17monthsprogressionfreesurvival.Asignificantfindingfromthisstudiedwasthelowrateofneurotoxicity

observed with TAXOTERE.

TAXOTEREwasstudiedinanothermajorphaseIIIstudythatconductedheadtoheadcomparisonofpaclitaxel

175mg/m 2 /carboplatinAUC5vs.TAXOTERE75mg/m 2 /carboplatinAUC5.Theresultsindicatedasignificantdifference

oftoxicityandmorespecificallyinneurotoxicityleadingtotreatmentdiscontinuation,32patientswithdrewfrom

study in paclitaxel group vs. 4 only in TAXOTERE group.

78%ofpatientsexperiencedsensoryneurotoxicityinpaclitaxelgroupvs.45%onlyinTAXOTEREgroupand18%

experiencedgrade1‑4motorneurotoxicityinpaclitaxelvs.8%onlyinTAXOTEREgroup.Efficacyresponserate

was 65% in TAXOTERE group vs. 62% in paclitaxel group.

There was a higher occurrence ofmyelotoxicity and neutropenia in the paclitaxel group.

Gastric Adenocarcinoma

Amulticenter,open‑label,randomizedstudy,wasconductedtoevaluatethesafetyandefficacyofTAXOTEREforthe

treatmentofpatientswithmetastaticgastricadenocarcinoma,includingadenocarcinomaofthegastroesophageal

junction,whohadnotreceivedpriorchemotherapyformetastaticdisease.Atotalof445patientswithKPS>70

weretreatedwitheitherTAXOTERE(T)(75mg/m 2 onday1)incombinationwithcisplatin(C)(75mg/m 2 onday

1)and5‑fluorouracil(F)(750mg/m 2 perdayfor5days)orcisplatin(100mg/m 2 onday1)and5‑fluorouracil

(1000mg/m 2 perdayfor5days).Thelengthofatreatmentcyclewas3weeksfortheTCFarmand4weeksfor

theCFarm.Themediannumberofcyclesadministeredperpatientwas6(witharangeof1‑16)fortheTCFarm

comparedto4(witharangeof1‑12)fortheCFarm.Timetoprogression(TTP)wastheprimaryendpoint.Therisk

reductionofprogressionwas32.1%andwasassociatedwithasignificantlylongerTTP(p=0.0004)infavorofthe

TCFarm.Overallsurvivalwasalsosignificantlylonger(p=0.0201)infavoroftheTCFarmwithariskreduction

ofmortality of22.7%. Efficacy results are summarized in the following table:

Efficacy ofTAXOTERE in the treatment ofpatients with gastric adenocarcinoma

Endpoint TCF

n = 221 CF

n = 224

Median TTP (months)

(95% CI)

Hazard ratio

(95% CI)

*p‑value 5.6

(4.86‑5.91) 3.7

(3.45‑4.47)

1.473

(1.189‑1.825)

0.0004

Median survival (months)

(95% CI)

2‑year estimate (%) 9.2

(8.38‑10.58)

18.4 8.6

(7.16‑9.46)

Hazard ratio

(95% CI)

*p‑value 1.293

(1.041‑1.606)

0.0201

Overall response rate (CR+PR) (%) 36.7 25.4

p‑value 0.0106

Progressive disease as best overall response

16.7 25.9

* Unstratified log‑rank test

Subgroup analyses across age, gender and race consistently favored the TCF arm compared to the CF arm.

Asurvivalupdateanalysisconductedwithamedianfollow‑uptimeof41.6monthsnolongershowedastatistically

significantdifferencealthoughalwaysinfavouroftheTCFregimenandshowedthatthebenefitofTCFoverCFis

clearly observed between 18 and 30 months offollow‑up.

Overall,qualityoflife(QoL)andclinicalbenefitresultsconsistentlyindicatedimprovementinfavoroftheTCF

arm.PatientstreatedwithTCFhadalongertimeto5%definitivedeteriorationofglobalhealthstatusonthe

QLQ‑C30questionnaire(p=0.0121)andalongertimetodefinitiveworseningofKarnofskyperformancestatus

(p = 0.0088) compared to patients treated with CF.

Head and neck cancer

Induction chemotherapy followed by radiotherapy (TAX323)

Thesafetyandefficacyofdocetaxelintheinductiontreatmentofpatientswithsquamouscellcarcinomaofthe

headandneck(SCCHN)wasevaluatedinaphaseIII,multicenter,open‑label,randomizedtrial(TAX323).Inthis

study,358patientswithinoperablelocallyadvancedSCCHN,andWHOperformancestatus0or1,wererandomized

tooneoftwotreatmentarms.Patientsonthedocetaxelarmreceiveddocetaxel(T)75mg/m 2 followedbycisplatin

(P)75mg/m 2 followedby5‑fluorouracil(F)750mg/m 2 perdayasacontinuousinfusionfor5days.Thisregimenwas

administeredeverythreeweeksfor4cyclesincaseatleastaminorresponse(≥25%reductioninbidimensionally

measuredtumoursize)wasobservedafter2cycles.Attheendofchemotherapy,withaminimalintervalof

4weeksandamaximalintervalof7weeks,patientswhosediseasedidnotprogressreceivedradiotherapy(RT)

accordingtoinstitutionalguidelinesfor7weeks(TPF/RT).Patientsonthecomparatorarmreceivedcisplatin(P)

100mg/m 2 followedby5‑fluorouracil(F)1000mg/m 2 perdayfor5days.Thisregimenwasadministeredevery

threeweeksfor4cyclesincaseatleastaminorresponse(≥25%reductioninbidimensionallymeasuredtumour

size)wasobservedafter2cycles.Attheendofchemotherapy,withaminimalintervalof4weeksandamaximal

intervalof7weeks,patientswhosediseasedidnotprogressreceivedradiotherapy(RT)accordingtoinstitutional

guidelinesfor7weeks(PF/RT).Locoregionaltherapywithradiationwasdeliveredeitherwithaconventionalfraction

(1.8Gy‑2.0Gyonceaday,5daysperweekforatotaldoseof66to70Gy),oraccelerated/hyperfractionated

regimensofradiationtherapy(twiceaday,withaminimuminterfractionintervalof6hours,5daysperweek).

Atotalof70Gywasrecommendedforacceleratedregimensand74Gyforhyperfractionatedschemes.Surgical

resectionwasallowedfollowingchemotherapy,beforeorafterradiotherapy.PatientsontheTPFarmreceived

antibioticprophylaxiswithciprofloxacin500mgorallytwicedailyfor10daysstartingonday5ofeachcycle,or

equivalent.Theprimaryendpointinthisstudy,progression‑freesurvival(PFS),wassignificantlylongerintheTPF

armcomparedtothePFarm,p=0.0042(medianPFS:11.4vs.8.3monthsrespectively)withanoverallmedian

follow‑uptimeof33.7months.MedianoverallsurvivalwasalsosignificantlylongerinfavoroftheTPFarm

comparedtothePFarm(medianOS:18.6vs.14.5monthsrespectively)witha28%riskreductionofmortality,

p = 0.0128. Efficacy results are presented in the table below:

EfficacyofdocetaxelintheinductiontreatmentofpatientswithinoperablelocallyadvancedSCCHN(Intent‑to‑

Treat Analysis)

Endpoint Docetaxel +

Cis + 5-FU

n = 177 Cis + 5-FU

n = 181

Median progression free survival (months)

(95% CI)

Adjusted hazard ratio

(95% CI)

*p‑value 11.4

(10.1‑14.0) 8.3

(7.4‑9.1)

0.70

(0.55‑0.89)

Median survival (months)

(95% CI) 18.6

(15.7‑24.0) 14.5

(11.6‑18.7)

Hazard ratio

(95% CI)

**p‑value 0.72

(0.56‑0.93)

0.0128

Best overall response to chemotherapy (%)

(95% CI)

***p‑value 67.8

(60.4‑74.6) 53.6

(46.0‑61.0)

0.006

Best overall response to study treatment

[chemotherapy +/‑radiotherapy] (%)

(95% CI) 72.3

(65.1‑78.8) 58.6

(51.0‑65.8)

***p‑value 0.006

Median duration ofresponse to

chemotherapy ± radiotherapy (months)

(95% CI) n = 128

15.7

(13.4‑24.6) n = 106

11.7

(10.2‑17.4)

Hazard ratio

(95% CI)

**p‑value 0.72

(0.52‑0.99)

0.0457

A hazard ratio ofless than 1 favors docetaxel + cisplatin + 5‑FU

* Cox model (adjustment for Primary tumour site, T and N clinical stages and PSWHO)

** Log‑rank test

*** Chi‑square test

Quality oflife parameters

PatientstreatedwithTPFexperiencedsignificantlylessdeteriorationoftheirGlobalhealthscorecomparedto

those treated with PF (p = 0.01, using the EORTC QLQ‑C30 scale).

Clinical benefit parameters

Theperformancestatusscale,forheadandneck(PSS‑HN)subscalesdesignedtomeasureunderstandabilityof

speech, ability to eat in public, and normalcy ofdiet, was significantly in favor ofTPF as compared to PF.

MediantimetofirstdeteriorationofWHOperformancestatuswassignificantlylongerintheTPFarmcomparedto

PF. Pain intensity score improved during treatment in both groups indicating adequate pain management.

Induction chemotherapy followed by chemoradiotherapy (TAX324)

Thesafetyandefficacyofdocetaxelintheinductiontreatmentofpatientswithlocallyadvancedsquamouscell

carcinomaoftheheadandneck(SCCHN)wasevaluatedinarandomized,multicenteropen‑label,phaseIII,study

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

randomizedtooneoftwoarms.Thestudypopulationcomprisedpatientswithtechnicallyunresectabledisease,

patientswithlowprobabilityofsurgicalcureandpatientsaimingatorganpreservation.Theefficacyandsafety

evaluationsolelyaddressedsurvivalendpointsandthesuccessoforganpreservationwasnotformallyaddressed.

Patientsonthedocetaxelarmreceiveddocetaxel(T)75mg/m²byintravenousinfusiononday1followedby

cisplatin(P)100mg/m²administeredasa30‑minutetothree‑hourintravenousinfusion,followedbythecontinuous

intravenousinfusionof5‑fluorouracil(F)1000mg/m²/dayfromday1today4.Thecycleswererepeatedevery

3weeksfor3cycles.Allpatientswhodidnothaveprogressivediseaseweretoreceivechemoradiotherapy(CRT)

asperprotocol(TPF/CRT).Patientsonthecomparatorarmreceivedcisplatin(P)100mg/m²asa30‑minuteto

three‑hourintravenousinfusiononday1followedbythecontinuousintravenousinfusionof5‑fluorouracil(F)

1000mg/m²/dayfromday1today5.Thecycleswererepeatedevery3weeksfor3cycles.Allpatientswhodid

not have progressive disease were to receive CRT as per protocol (PF/CRT).

Patientsinbothtreatmentarmsweretoreceive7weeksofCRTfollowinginductionchemotherapywithaminimum

intervalof3weeksandnolaterthan8weeksafterstartofthelastcycle(day22today56oflastcycle).During

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

Radiationwasdeliveredwithmegavoltageequipmentusingoncedailyfractionation(2Gyperday,5daysperweek

for7weeks,foratotaldoseof70‑72Gy).Surgeryontheprimarysiteofdiseaseand/orneckcouldbeconsideredat

anytimefollowingcompletionofCRT.Allpatientsonthedocetaxel‑containingarmofthestudyreceivedprophylactic

antibiotics.Theprimaryefficacyendpointinthisstudy,overallsurvival(OS)wassignificantlylonger(log‑ranktest,

p=0.0058)withthedocetaxel‑containingregimencomparedtoPF(medianOS:70.6versus30.1months

respectively),witha30%riskreductioninmortalitycomparedtoPF(hazardratio(HR)=0.70,95%confidenceinterval

(CI)=0.54‑0.90)withanoverallmedianfollow‑uptimeof41.9months.Thesecondaryendpoint,PFS,demonstrated

a29%riskreductionofprogressionordeathanda22monthimprovementinmedianPFS(35.5monthsfor

TPFand13.1forPF).ThiswasalsostatisticallysignificantwithanHRof0.71;95%CI0.56‑0.90;log‑ranktest

p = 0.004. Efficacy results are presented in the table below:

EfficacyofdocetaxelintheinductiontreatmentofpatientswithlocallyadvancedSCCHN(Intent‑to‑Treat

Analysis)

Endpoint Docetaxel + Cis + 5-FU

n = 255 Cis + 5-FU

n = 246

Median overall survival (months)

(95% CI) 70.6

(49.0‑NA) 30.1

(20.9‑51.5)

Hazard ratio:

(95% CI)

*p‑value 0.70

(0.54‑0.90)

0.0058

Median PFS (months)

(95% CI) 35.5

(19.3‑NA) 13.1

(10.6‑20.2)

Hazard ratio:

(95% CI)

**p‑value 0.71

(0.56‑0.90)

0.004

Best overall response (CR + PR) to

chemotherapy (%)

(95% CI)

***p‑value 71.8

(65.8‑77.2) 64.2

(57.9‑70.2)

0.070

Best overall response (CR + PR) to

study treatment [chemotherapy +/‑

chemoradiotherapy] (%)

(95% CI)

***p‑value 76.5

(70.8‑81.5) 71.5

(65.5‑77.1)

0.209

A hazard ratio ofless than 1 favors docetaxel + cisplatin + fluorouracil

* un‑adjusted log‑rank test

** un‑adjusted log‑rank test, not adjusted for multiple comparisons

*** Chi square test, not adjusted for multiple comparisons

NA = not applicable

Paediatric population

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithTAXOTEREinall

subsetsofthepaediatricpopulationinbreastcancer,non‑smallcelllungcancer,prostatecancer,gastriccarcinoma

andheadandneckcancer,notincludingtypeIIandIIIlessdifferentiatednasopharyngealcarcinoma(seesection

4.2 for information on paediatric use).

5.2Pharmacokinetic Properties

Absorption

Thepharmacokineticsofdocetaxelhavebeenevaluatedincancerpatientsafteradministrationof20‑115mg/m 2

inPhaseIstudies.Thekineticprofileofdocetaxelisdoseindependentandconsistentwithathree‑compartment

pharmacokineticmodelwithhalflivesforthea,bandgphasesof4min,36minand11.1h,respectively.The

late phase is due, in part, to a relatively slow efflux ofdocetaxel from the peripheral compartment.

Distribution

Followingtheadministrationofa100mg/m 2 dosegivenasaone‑hourinfusionameanpeakplasmalevelof

3.7µg/mlwasobtainedwithacorrespondingAUCof4.6h µg/ml.Meanvaluesfortotalbodyclearanceand

steady‑statevolumeofdistributionwere21l/h/m 2 and113l,respectively.Interindividualvariationintotalbody

clearance was approximately 50%. Docetaxel is more than 95% bound to plasma proteins.

Elimination

Astudyof 14 C‑docetaxelhasbeenconductedinthreecancerpatients.Docetaxelwaseliminatedinboththe

urineandfaecesfollowingcytochromeP450‑mediatedoxidativemetabolismofthetert‑butylestergroup,within

sevendays,theurinaryandfaecalexcretionaccountedforabout6%and75%oftheadministeredradioactivity,

respectively.About80%oftheradioactivityrecoveredinfaecesisexcretedduringthefirst48hoursasonemajor

inactive metabolite and 3 minor inactive metabolites and very low amounts ofunchanged drug.

Special population

Age and gender

Apopulationpharmacokineticanalysishasbeenperformedwithdocetaxelin577patients.Pharmacokinetic

parametersestimatedbythemodelwereveryclosetothoseestimatedfromPhaseIstudies.Thepharmacokinetics

ofdocetaxel were not altered by the age or sex ofthe patient.

Hepatic impairment

Inasmallnumberofpatients(n=23)withclinicalchemistrydatasuggestiveofmildtomoderateliverfunction

impairment(ALT,AST³1.5timestheULNassociatedwithalkalinephosphatase³2.5timestheULN),totalclearance

was lowered by 27% on average (see section 4.2).

Fluid retention

Docetaxelclearancewasnotmodifiedinpatientswithmildtomoderatefluidretentionandtherearenodata

available in patients with severe fluid retention.

Combination therapy

Doxorubicin

Whenusedincombination,docetaxeldoesnotinfluencetheclearanceofdoxorubicinandtheplasmalevelsof

doxorubicinol(adoxorubicinmetabolite).Thepharmacokineticsofdocetaxel,doxorubicinandcyclophosphamide

were not influenced by their co‑administration.

Capecitabine

PhaseIstudyevaluatingtheeffectofcapecitabineonthepharmacokineticsofdocetaxelandviceversashowed

noeffectbycapecitabineonthepharmacokineticsofdocetaxel(C max andAUC)andnoeffectbydocetaxelonthe

pharmacokinetics ofa relevant capecitabine metabolite 5’‑DFUR.

Cisplatin

Clearanceofdocetaxelincombinationtherapywithcisplatinwassimilartothatobservedfollowingmonotherapy.

ThepharmacokineticprofileofcisplatinadministeredshortlyafterTAXOTEREinfusionissimilartothatobserved

with cisplatin alone.

Cisplatin and 5-fluorouracil

Thecombinedadministrationofdocetaxel,cisplatinand5‑fluorouracilin12patientswithsolidtumourshadno

influence on the pharmacokinetics ofeach individual drug.

Prednisone and dexamethasone

Theeffectofprednisoneonthepharmacokineticsofdocetaxeladministeredwithstandarddexamethasone

Prednisone

No effect ofprednisone on the pharmacokinetics ofdocetaxel was observed.

5.3Preclinical safety data

The carcinogenic potential ofdocetaxel has not been studied.

Docetaxelhasbeenshowntobemutagenicintheinvitromicronucleusandchromosomeaberrationtestin

CHO‑K1cellsandintheinvivomicronucleustestinthemouse.However,itdidnotinducemutagenicityinthe

AmestestortheCHO/HGPRTgenemutationassay.Theseresultsareconsistentwiththepharmacologicalactivity

ofdocetaxel.

Undesirableeffectsonthetestisobservedinrodenttoxicitystudiessuggestthatdocetaxelmayimpairmale

fertility.

6. PHARMACEUTICAL PARTICULARS

6.1List ofexcipients

Polysorbate 80

Ethanol anhydrous

Citric acid

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection

6.6.

6.3Shelf-life

Unopened vial

2 years for a pack size of20 mg/1 ml.

3 years for a pack size of80 mg/4 ml.

After opening ofthe vial

Eachvialisforsingleuseandshouldbeusedimmediatelyafteropening.Ifnotusedimmediately,in‑usestorage

times and conditions are the responsibility ofthe user.

Once added to the infusion bag

Fromamicrobiologicalpointofview,reconstitution/dilutionmusttakeplaceincontrolledandasepticconditions

andthemedicinalproductshouldbeusedimmediately.Ifnotusedimmediately,in‑usestoragetimesand

conditions are the responsibility ofthe user.

Onceaddedasrecommendedintotheinfusionbag,thedocetaxelinfusionsolution,ifstoredbelow25°C,isstable

for 6 hours. It should be used within 6 hours (including the one hour infusion intravenous administration).

Inaddition,physicalandchemicalin‑usestabilityoftheinfusionsolutionpreparedasrecommendedhasbeen

demonstrated in non‑PVC bags up to 48 hours when stored between 2 to 8°C.

Docetaxelinfusionsolutionissupersaturated,thereforemaycrystallizeovertime.Ifcrystalsappear,thesolution

must no longer be used and shall be discarded.

6.4Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from light.

For storage conditions ofthe diluted medicinal product, see section 6.3.

6.5Nature and contents ofcontainer

TAXOTERE20mg/1mlconcentrateforsolutionforinfusion‑7mlclearglass(typeI)vialwithagreenaluminium

seal and a green plastic flip‑offcap containing 1 ml ofconcentrate.

TAXOTERE80mg/4mlconcentrateforsolutionforinfusion‑7mlclearglass(typeI)vialwitharedaluminium

seal and a magenta plastic flip‑offcap containing 4 ml ofconcentrate.

Each box contains one vial.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

TAXOTEREisanantineoplasticagentand,aswithotherpotentiallytoxiccompounds,cautionshouldbeexercised

when handling it and preparing TAXOTERE solutions. The use ofgloves is recommended.

IfTAXOTEREconcentrateorinfusionsolutionshouldcomeintocontactwithskin,washimmediatelyandthoroughly

withsoapandwater.IfTAXOTEREconcentrateorinfusionsolutionshouldcomeintocontactwithmucous

membranes, wash immediately and thoroughly with water.

Preparation for the intravenous administration

Preparation ofthe infusion solution

DONOTuseotherdocetaxelmedicinalproductsconsistingof2vials(concentrateandsolvent)withthis

medicinalproduct(TAXOTERE20mg/1mlor80mg/4mlconcentrateforsolutionforinfusion,which

contains only 1 vial).

TAXOTERE20mg/1mlor80mg/4mlconcentrateforsolutionforinfusionrequiresNOpriordilutionwith

a solvent and is ready to add to the infusion solution.

Each vial is ofsingle use and should be used immediately.

Ifthevialsarestoredunderrefrigeration,allowtherequirednumberofboxesofTAXOTEREconcentrateforsolution

for infusion to stand below 25°C for 5 minutes before use.

MorethanonevialofTAXOTEREconcentrateforsolutionforinfusionmaybenecessarytoobtaintherequired

doseforthepatient.AsepticallywithdrawtherequiredamountofTAXOTEREconcentrateforsolutionforinfusion

using a calibrated syringe fitted with a 21G needle.

In TAXOTERE 20 mg/1 ml or 80 mg/4 ml vial the concentration ofdocetaxel is 20 mg/ml.

TherequiredvolumeofTAXOTEREconcentrateforsolutionforinfusionmustbeinjectedviaasingleinjection

(oneshot)intoa250mlinfusionbagorbottlecontainingeither5%glucosesolutionorsodiumchloride

9 mg/ml (0.9%) solution for infusion.

Ifadosegreaterthan190mgofdocetaxelisrequired,usealargervolumeoftheinfusionvehiclesothata

concentration of0.74 mg/ml docetaxel is not exceeded.

Mix the infusion bag or bottle manually using a rocking motion.

Theinfusionbagsolutionshouldbeusedwithin6hoursbelow25°Cincludingtheonehourinfusiontothe

patient.

Aswithallparenteralproducts,TAXOTEREinfusionsolutionshouldbevisuallyinspectedpriortouse,solutions

containing a precipitate should be discarded.

Any unused medicinal product or waste material should be disposed ofin accordance with local requirements.

Seebelow‑PREPARATIONGUIDEFORUSEWITHTAXOTERE20mg/1mlor80mg/4mlCONCENTRATEFOR

SOLUTION FOR INFUSION

7. MARKETING AUTHORISATION HOLDER

sanofi‑aventis Israel ltd., P.O. Box 8090, Netanya 42504

8. MANUFACTURER

Sanofi‑Aventis Deutschland GmbH, D‑65926 Frankfurt am Main, Germany

PREPARATIONGUIDEFORUSEWITHTAXOTERE20mg/1mlor80mg/4mlCONCENTRATEFORSOLUTION

FOR INFUSION

ItisimportantthatyoureadtheentirecontentsofthisguidepriortothepreparationoftheTAXOTEREinfusion

solution.

Recommendations for safe handling:

Docetaxelisanantineoplasticagentand,aswithotherpotentiallytoxiccompounds,cautionshouldbeexercised

when handling it and preparing its solutions. The use ofgloves is recommended.

IfTAXOTEREconcentrateorinfusionsolutionshouldcomeintocontactwithskin,washimmediatelyandthoroughly

withsoapandwater.Ifitshouldcomeintocontactwithmucousmembranes,washimmediatelyandthoroughly

with water.

Preparation ofthe intravenous administration

Preparation ofthe infusion solution

DONOTuseotherdocetaxelmedicinalproductsconsistingof2vials(concentrateandsolvent)withthis

medicinalproduct(TAXOTERE20mg/1mlor80mg/4mlconcentrateforsolutionforinfusion,which

contains only 1 vial).

TAXOTERE20 mg/1 ml or 80 mg/4 mlconcentrate for solution for infusion requires NO prior dilution with

a solvent and is ready to add to the infusion solution.

Each vial is for single use and should be used immediately after opening. If not used immediately, in‑use storage

timesandconditionsaretheresponsibilityoftheuser.Morethanonevialofconcentrateforsolutionforinfusion

maybenecessarytoobtaintherequireddoseforthepatient.Forexample,adoseof140mgdocetaxelwould

require 7 ml docetaxel concentrate for solution.

Aseptically withdraw the required amount of concentrate for solution for infusion with a calibrated syringe.

In TAXOTERE20 mg/1 ml or 80 mg/4 mlvial the concentration ofdocetaxel is 20 mg/ml.

Then, inject via a single injection (one shot) into a 250 ml infusion bag or bottle containing either 5% glucose

solutionorsodiumchloride9mg/ml(0.9%)solutionforinfusion.Ifadosegreaterthan190mgofdocetaxel

isrequired,usealargervolumeoftheinfusionvehiclesothataconcentrationof0.74mg/mldocetaxelisnot

exceeded.

Mix the infusion bag or bottle manually using a rocking motion.

From a microbiological point of view, reconstitution/dilution must take place in controlled and aseptic conditions

andtheinfusionsolutionshouldbeusedimmediately.Ifnotusedimmediately,in‑usestoragetimesand

conditions are the responsibility ofthe user.

Onceaddedasrecommendedintotheinfusionbag,thedocetaxelinfusionsolution,ifstoredbelow25°C,isstable

for 6 hours. It should be used within 6 hours (including the one hour infusion intravenous administration).

Inaddition,physicalandchemicalin‑usestabilityoftheinfusionsolutionpreparedasrecommendedhasbeen

demonstrated in non‑PVC bags up to 48 hours when stored between 2°C to 8°C.

Docetaxelinfusionsolutionissupersaturated,thereforemaycrystallizeovertime.Ifcrystalsappear,thesolution

must no longer be used and shall be discarded.

As with all parenteral products, infusion solution should be visually inspected prior to use, solutions containing

a precipitate should be discarded.

Disposal:

Allmaterialsthathavebeenutilisedfordilutionandadministrationshouldbedisposedofaccordingtostandard

procedures.

The format ofthis leaflet was determined by the Ministry ofHealth

and its content was checked and approved in September 2012.

TAXO RTU INF PHY SH 051212

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