DOCETAXEL ACCORD 160mg / 8ml perfusive solution concentrate medication leaflet

Docetaxel Accord 20 mg/1 ml concentrate for solution for infusion

Docetaxel Accord 80 mg/4 ml concentrate for solution for infusion

Docetaxel Accord 160 mg/8 ml concentrate for solution for infusion

Each ml of concentrate contains 20 mg docetaxel.

Docetaxel Accord 20 mg/1 ml concentrate for solution for infusion

One vial of 1 ml of concentrate contains 20 mg of docetaxel.

Docetaxel Accord 80 mg/4 ml concentrate for solution for infusion

One vial of 4 ml of concentrate contains 80 mg of docetaxel.

Docetaxel Accord 160 mg/8 ml concentrate for solution for infusion

One vial of 8 ml of concentrate contains 160 mg of docetaxel.

Docetaxel Accord 20 mg/1 ml concentrate for solution for infusion

Each vial of 1ml of concentrate contains 0.5 ml of ethanol anhydrous (395 mg).

Docetaxel Accord 80 mg/4 ml concentrate for solution for infusion

Each vial of 4ml of concentrate contains 2 ml of ethanol anhydrous (1.58 g).

Docetaxel Accord 160 mg/8 ml concentrate for solution for infusion

Each vial of 8ml of concentrate contains 4 ml of ethanol anhydrous (3.16 g).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

The concentrate is a clear pale yellow to brownish-yellow solution.

Breast cancer

Docetaxel Accord in combination with doxorubicin and cyclophosphamide is indicated for theadjuvant treatment of patients with:

* operable node-positive breast cancer

* operable node-negative breast cancer .

For patients with operable node-negative breast cancer, adjuvant treatment should be restricted topatients eligible to receive chemotherapy according to internationally established criteria for primarytherapy of early breast cancer (see section 5.1).

Docetaxel Accord in combination with doxorubicin is indicated for the treatment of patients withlocally advanced or metastatic breast cancer who have not previously received cytotoxic therapy forthis condition.

Docetaxel Accord monotherapy is indicated for the treatment of patients with locally advanced ormetastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should haveincluded an anthracycline or an alkylating agent.

Docetaxel Accord in combination with trastuzumab is indicated for the treatment of patients withmetastatic breast cancer whose tumours over express HER2 and who previously have not receivedchemotherapy for metastatic disease.

Docetaxel Accord in combination with capecitabine is indicated for the treatment of patients withlocally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapyshould have included an anthracycline.

Docetaxel Accord is indicated for the treatment of patients with locally advanced or metastaticnon-small cell lung cancer after failure of prior chemotherapy.

Docetaxel Accord in combination with cisplatin is indicated for the treatment of patients withunresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have notpreviously received chemotherapy for this condition.

Prostate cancer

Docetaxel Accord in combination with prednisone or prednisolone is indicated for the treatment ofpatients with metastatic castration-resistant prostate cancer.

Docetaxel Accord in combination with androgen-deprivation therapy (ADT), with or withoutprednisone or prednisolone, is indicated for the treatment of patients with metastatic hormone-sensitiveprostate cancer.

Gastric adenocarcinoma

Docetaxel Accord in combination with cisplatin and 5-fluorouracil is indicated for the treatment ofpatients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophagealjunction, who have not received prior chemotherapy for metastatic disease.

Head and neck cancer

Docetaxel Accord in combination with cisplatin and 5-fluorouracil is indicated for the inductiontreatment of patients with locally advanced squamous cell carcinoma of the head and neck.

The use of docetaxel should be confined to units specialised in the administration of cytotoxicchemotherapy and it should only be administered under the supervision of a physician qualified in theuse of anticancer chemotherapy (see section 6.6).

For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oralcorticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days starting 1 dayprior to docetaxel administration, unless contraindicated, can be used (see section 4.4).

For metastatic castration-resistant prostate cancer, given the concurrent use of prednisone orprednisolone the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hoursand 1 hour before the docetaxel infusion (see section 4.4).

For metastatic hormone-sensitive prostate cancer, irrespective of the concurrent use of prednisone orprednisolone, the recommended premedication regimen is oral dexamethasone 8 mg 12 hours, 3 hours,and 1 hour before docetaxel infusion (see section 4.4).

Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.

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

Breast cancer

In the adjuvant treatment of operable node-positive and node-negative breast cancer, the recommendeddose of docetaxel is 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide500 mg/m2 every 3 weeks for 6 cycles (TAC regimen) (see also Dose adjustments during treatment).

For the treatment of patients with locally advanced or metastatic breast cancer, the recommended doseof docetaxel is 100 mg/m2 in monotherapy. In first-line treatment, docetaxel 75 mg/m2 is given incombination therapy with doxorubicin (50 mg/m2).

In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m2 every three weeks,with trastuzumab administered weekly. In the pivotal study the initial docetaxel infusion was startedthe day following the first dose of trastuzumab. The subsequent docetaxel doses were administeredimmediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab waswell tolerated. For trastuzumab dose and administration, see trastuzumab summary of productcharacteristics.

In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m2 every three weeks,combined with capecitabine at 1250 mg/m2 twice daily (within 30 minutes after a meal) for 2 weeksfollowed by a 1-week rest period. For capecitabine dose calculation according to body surface area,see capecitabine summary of product characteristics.

In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimenis docetaxel 75 mg/m2 immediately followed by cisplatin 75 mg/m2 over 30-60 minutes. For treatmentafter failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m2 as a singleagent.

Prostate cancer

Metastatic castration-resistant prostate cancer

The recommended dose of docetaxel is 75 mg/m2. Prednisone or prednisolone 5 mg orally twice dailyis administered continuously (see section 5.1).

Metastatic hormone-sensitive prostate cancer

The recommended dose of docetaxel is 75 mg/m2 every 3 weeks for 6 cycles. Prednisone or prednisolone5 mg orally twice daily may be administered continuously.

Gastric adenocarcinoma

The recommended dose of docetaxel is 75 mg/m2 as a 1-hour infusion, followed by cisplatin75 mg/m2, as a 1- to 3-hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m2 perday given as a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion.

Treatment is repeated every three weeks. Patients must receive premedication with antiemetics andappropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate therisk of haematological toxicities (see also Dose adjustments during treatment).

Head and neck cancer

Patients must receive premedication with antiemetics and appropriate hydration (prior to and aftercisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of haematologicaltoxicities. All patients on the docetaxel-containing arm of the TAX 323 and TAX 324 studies, receivedprophylactic antibiotics.

* Induction chemotherapy followed by radiotherapy (TAX 323)

For the induction treatment of inoperable locally advanced squamous cell carcinoma of the headand neck (SCCHN), the recommended dose of docetaxel is 75 mg/m2 as a 1 hour infusionfollowed by cisplatin 75 mg/m2 over 1 hour, on day one, followed by 5-fluorouracil as acontinuous infusion at 750 mg/m2 per day for five days. This regimen is administered every3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.

* Induction chemotherapy followed by chemoradiotherapy (TAX 324)

For the induction treatment of patients with locally advanced (technically unresectable, lowprobability of surgical cure, and aiming at organ preservation) squamous cell carcinoma of thehead and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m2 as a 1 hour intravenousinfusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3-hourinfusion, followed by 5-fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4.

This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients shouldreceive chemoradiotherapy.

For cisplatin and 5-fluorouracil dose modifications, see the corresponding summary of productcharacteristics.

Docetaxel should be administered when the neutrophil count is ≥ 1,500 cells/mm3. In patients whoexperienced either febrile neutropenia, neutrophil count < 500 cells/mm3 for more than one week,severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, thedose of docetaxel should be reduced from 100 mg/m2 to 75 mg/m2 and/or from 75 to 60 mg/m2. If thepatient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.

Adjuvant therapy for breast cancer

Primary G-CSF prophylaxis should be considered in patients who receive docetaxel, doxorubicin andcyclophosphamide (TAC) adjuvant therapy for breast cancer. Patients who experience febrileneutropenia and/or neutropenic infection should have their docetaxel dose reduced to 60 mg/m2 in allsubsequent cycles (see sections 4.4 and 4.8). Patients who experience Grade 3 or 4 stomatitis shouldhave their dose decreased to 60 mg/m2.

In combination with cisplatin

For patients who are dosed initially at docetaxel 75 mg/m2 in combination with cisplatin and whosenadir of platelet count during the previous course of therapy is < 25,000 cells/mm3, or in patients whoexperience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxeldose in subsequent cycles should be reduced to 65 mg/m2. For cisplatin dose adjustments, see thecorresponding summary of product characteristics.

In combination with capecitabine

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

* For patients developing the first appearance of Grade 2 toxicity, which persists at the time of thenext docetaxel/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at100% of the original dose.

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

Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to

Grade 0-1 and then resume treatment with docetaxel 55 mg/m2.

* For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the docetaxeldose.

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

In combination with cisplatin and 5-fluorouracil

If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite

G-CSF use, the docetaxel dose should be reduced from 75 to 60 mg/m2. If subsequent episodes ofcomplicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m2. In case of

Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m2. Patients shouldnot be retreated with subsequent cycles of docetaxel until neutrophils recover to a level> 1,500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3. Discontinue treatment if thesetoxicities persist (see section 4.4).

Recommended dose modifications for toxicities in patients treated with docetaxel in combination withcisplatin and 5-fluorouracil (5-FU):

Toxicity Dose adjustment

Diarrhoea grade 3 First episode: reduce 5-FU dose by 20%.

Second episode: then reduce docetaxel dose by 20%.

Diarrhoea grade 4 First episode: reduce docetaxel and 5-FU doses by 20%.

Second episode: discontinue treatment.

Stomatitis/mucositis First episode: reduce 5-FU dose by 20%.

grade 3 Second episode: stop 5-FU only, at all subsequent cycles.

Third episode: reduce docetaxel dose by 20%.

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

grade 4 Second episode: reduce docetaxel dose by 20%.

For cisplatin and 5-fluorouracil dose adjustments, see the corresponding summary of productcharacteristics.

In the pivotal SCCHN studies patients who experienced complicated neutropenia (including prolongedneutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provideprophylactic coverage (eg, day 6-15) in all subsequent cycles.

Based on pharmacokinetic data with docetaxel at 100 mg/m2 as single agent, patients who have bothelevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normalrange (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose ofdocetaxel is 75 mg/m2 (see sections 4.4 and 5.2). For those patients with serum bilirubin > ULN and/or

ALT and AST > 3.5 times the ULN associated with alkaline phosphatase > 6 times the ULN, nodose-reduction can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastricadenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULNassociated with alkaline phosphatase > 2.5 × ULN, and bilirubin > 1 x ULN; for these patients, nodose-reductions can be recommended and docetaxel should not be used unless strictly indicated. Nodata are available in patients with hepatic impairment treated by docetaxel in combination in the otherindications.

The safety and efficacy of docetaxel in nasopharyngeal carcinoma in children aged 1 month to lessthan 18 years have not yet been established.

There is no relevant use of docetaxel in the paediatric population in the indications breast cancer,non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not includingtype II and III less differentiated nasopharyngeal carcinoma.

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

In combination with capecitabine, for patients 60 years of age or more, a starting dose reduction ofcapecitabine to 75% is recommended (see capecitabine summary of product characteristics).

For instructions on preparation and administration of the product, see section 6.6.

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

Patients with baseline neutrophil count of < 1,500 cells/mm3.

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

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

For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such asdexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days starting 1 day prior to docetaxeladministration, unless contraindicated, can reduce the incidence and severity of fluid retention as wellas the severity of hypersensitivity reactions. For prostate cancer, the premedication is oraldexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).

Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a medianof 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring ofcomplete blood counts should be conducted on all patients receiving docetaxel. Patients should beretreated with docetaxel when neutrophils recover to a level ≥ 1,500 cells/mm3 (see section 4.2).

In the case of severe neutropenia (< 500 cells/mm3 for seven days or more) during a course ofdocetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriatesymptomatic measures are recommended (see section 4.2).

In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrileneutropenia and neutropenic infection occurred at lower rates when patients received prophylactic

G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk ofcomplicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection).

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

In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC),febrile neutropenia and/or neutropenic infection occurred at lower rates when patients receivedprimary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receiveadjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrileneutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should beclosely monitored (see sections 4.2 and 4.8).

Gastrointestinal reactions

Caution is recommended for patients with neutropenia, particularly at risk for developinggastrointestinal complications. Although majority of cases occurred during the first or second cycle ofdocetaxel containing regimen, enterocolitis could develop at any time, and could lead to death as earlyas on the first day of onset. Patients should be closely monitored for early manifestations of seriousgastrointestinal toxicity (see sections 4.2, pct. 4.4 Haematology, and 4.8).

Patients should be observed closely for hypersensitivity reactions especially during the first and secondinfusions. Hypersensitivity reactions may occur within a few minutes following the initiation of theinfusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should beavailable. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneousreactions do not require interruption of therapy. However, severe reactions, such as severehypotension, bronchospasm or generalised rash/erythema require immediate discontinuation ofdocetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactionsshould not be re-challenged with docetaxel. Patients who have previously experienced ahypersensitivity reaction to paclitaxel may be at risk to develop hypersensitivity reaction to docetaxel,including more severe hypersensitivity reaction. These patients should be closely monitored duringinitiation of docetaxel therapy.

Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedemafollowed by desquamation has been observed. Severe symptoms such as eruptions followed bydesquamation which lead to interruption or discontinuation of docetaxel treatment were reported (seesection 4.2).

Severe Cutaneous Adverse Reactions (SCARs) such as Stevens-Johnson Syndrome (SJS), Toxic

Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have beenreported with docetaxel treatment. Patients should be informed about the signs and symptoms of seriousskin manifestations and closely monitored. If signs and symptoms suggestive of these reactions appeardiscontinuation of docetaxel should be considered.

Fluid retention

Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should bemonitored closely.

Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease,pulmonary fibrosis and respiratory failure have been reported and may be associated with fataloutcome. Cases of radiation pneumonitis have been reported in patients receiving concomitantradiotherapy.

If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptlyinvestigated, and appropriately treated. Interruption of docetaxel therapy is recommended untildiagnosis is available. Early use of supportive care measures may help improve the condition. Thebenefit of resuming docetaxel treatment must be carefully evaluated.

Patients with liver impairment

In patients treated with docetaxel at 100 mg/m2 as single agent who have serum transaminase levels(ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levelsgreater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such astoxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia,infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxelin those patients with elevated liver function test (LFTs) is 75 mg/m2 and LFTs should be measured atbaseline and before each cycle (see section 4.2).

For patients with serum bilirubin levels > ULN and/or ALT and AST > 3.5 times the ULN concurrentwith serum alkaline phosphatase levels > 6 times the ULN, no dose-reduction can be recommendedand docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastricadenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULNassociated with alkaline phosphatase > 2.5 × ULN, and bilirubin > 1 x ULN; for these patients, nodose-reductions can be recommended and docetaxel should not be used unless strictly indicated. Nodata are available in patients with hepatic impairment treated by docetaxel in combination in the otherindications.

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

Nervous system

The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).

Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab,particularly following anthracycline (doxorubicin or epirubicin) -containing chemotherapy. This maybe moderate to severe and has been associated with death (see section 4.8).

When patients are candidates for treatment with docetaxel in combination with trastuzumab, theyshould undergo baseline cardiac assessment. Cardiac function should be further monitored duringtreatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. Formore details see summary of product characteristics of trastuzumab.

Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported inpatients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/ orcyclophosphamide (see section 4.8).

Baseline cardiac assessment is recommended.

Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel. Patients withimpaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO isdiagnosed, docetaxel treatment should be discontinued and appropriate treatment initiated (see section4.8).

Second primary malignancies

Second primary malignancies have been reported when docetaxel was given in combination withanticancer treatments known to be associated with second primary malignancies. Second primarymalignancies (including acute myeloid leukemia, myelodysplastic syndrome and non-Hodgkinlymphoma) may occur several months or years after docetaxel-containing therapy. Patients should bemonitored for second primary malignancies (see section 4.8).

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported with docetaxel after the first or the second cycle (see section4.8). Patients at risk of tumour lysis syndrome (e.g. with renal impairment, hyperuricemia, bulkytumour, rapid progression) should be closely monitored. Correction of dehydration and treatment ofhigh uric acid levels are recommended prior to initiation of treatment.

Women of childbearing potential must use contraceptive measures during treatment and for 2 monthsafter cessation of treatment with docetaxel. Men must use contraceptive measures during treatment andfor 4 months after cessation of treatment with docetaxel (see section 4.6).

The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole,clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin andvoriconazole) should be avoided (see section 4.5).

Additional cautions for use in adjuvant treatment of breast cancer

Complicated neutropenia

For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia orinfection), G-CSF and dose reduction should be considered (see section 4.2).

Gastrointestinal reactions

Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia,may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treatedpromptly.

Congestive heart failure (CHF)

Patients should be monitored for symptoms of congestive heart failure during therapy and during thefollow up period. In patients treated with the TAC regimen for node positive breast cancer, the risk of

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

Patients with 4+ nodes

As the benefit observed in patient with 4+ nodes was not statistically significant on disease-freesurvival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC in patients with4+ nodes was not fully demonstrated at the final analysis (see section 5.1).

Cautions for use in adjuvant treatment of breast cancer

There are limited data available in patients > 70 years of age on docetaxel use in combination withdoxorubicin and cyclophosphamide.

Cautions for use in castration-resistant prostate cancer

Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study, 209 patientswere 65 years of age or greater and 68 patients were older than 75 years. In patients treated withdocetaxel every three weeks, the incidence of related nail changes occurred at a rate ≥ 10% higher inpatients who were 65 years of age or greater compared to younger patients. The incidence of relatedfever, diarrhoea, anorexia, and peripheral oedema occurred at rates ≥ 10% higher in patients who were75 years of age or greater versus less than 65 years.

Cautions for use in hormone-sensitive prostate cancer

Of the 545 patients treated with docetaxel every 3 weeks in a hormone-sensitive prostate cancer study(STAMPEDE), 296 patients were 65 years of age or older, and 48 patients were 75 years of age orolder. More patients aged ≥65 years in the docetaxel arm reported hypersensitivity reaction,neutropenia, anaemia, fluid retention, dyspnea, and nail changes when compared to the patients agedless than 65 years. None of these increases in frequency reached 10% difference with the control arm.

In patients who were 75 years of age or older, when compared to younger patients, neutropenia,anaemia, diarrhea, dyspnea and upper respiratory tract infection were reported with a greater incidence(at least 10% higher).

Cautions for use in gastric adenocarcinoma cancer

Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part)patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancerstudy, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence ofserious adverse events was higher in elderly compared to younger patients. The incidence of thefollowing adverse events (all grades): lethargy, stomatitis, neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderlytreated with TCF should be closely monitored.

Docetaxel Accord 20 mg/1 ml concentratecontains 50 vol % ethanol anhydrous (alcohol), i.e. up to 395 mg ethanol anhydrous per vial,equivalent to 10 ml of beer or 4 ml wine.

Docetaxel Accord 80 mg/4 ml concentratecontains 50 vol % ethanol anhydrous (alcohol), i.e. up to 1.58 g ethanol anhydrous per vial, equivalentto 40 ml of beer or 16 ml wine.

Docetaxel Accord 160 mg/8 ml concentratecontains 50 vol % ethanol anhydrous (alcohol), i.e. up to 3.16 g ethanol anhydrous per vial, equivalentto 79 ml of beer or 32 ml wine.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such aspatients with liver disease, or epilepsy.

Consideration should be given to possible effects on the central nervous system.

The amount of alcohol in this medicinal product may alter the effects of other medicinal products.

In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitantadministration of compounds which induce, inhibit or are metabolised by (and thus may inhibit theenzyme competitively) cytochrome P450-3A such as ciclosporine, ketoconazole, erythromycin. As aresult, caution should be exercised when treating patients with these medicinal products asconcomitant therapy since there is a potential for a significant interaction.

In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel adverse reactions mayincrease, as a result of reduced metabolism. If the concomitant use of a strong CYP3A4 inhibitor (e.g.,ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,telithromycin and voriconazole) cannot be avoided, a close clinical surveillance is warranted and adose-adjustment of docetaxel may be suitable during the treatment with the strong CYP3A4 inhibitor(see section 4.4). In a pharmacokinetic study with 7 patients, the co-administration of docetaxel withthe strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in docetaxel clearance by49%.

Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastaticprostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4.

No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.

Docetaxel is highly protein bound (> 95%). Although the possible in vivo interaction of docetaxel withconcomitantly administered medicinal product has not been investigated formally, in vitro interactionswith tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone,phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding ofdocetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did notinfluence the binding of digitoxin.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by theirco-administration. Limited data from a single uncontrolled study were suggestive of an interactionbetween docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin wasabout 50% higher than values previously reported for carboplatin monotherapy.

Women of childbearing potential and men receiving docetaxel should be advised to avoid becomingpregnant, and not to father a child and to inform the treating physician immediately should this occur.

Due to the genotoxic risk of docetaxel (see section 5.3), women of childbearing potential must useeffective method of contraception during treatment and for 2 months after cessation of treatment withdocetaxel. Men must use effective method of contraception during treatment and for 4 months aftercessation of treatment with docetaxel.

There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to beboth embryotoxic and foetotoxic in rabbits and rats. As with other cytotoxic medicinal products,docetaxel may cause foetal harm when administered to pregnant women. Therefore, docetaxel mustnot be used during pregnancy unless clearly indicated.

Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk.

Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must bediscontinued for the duration of docetaxel therapy.

Studies in animals have shown that docetaxel may alter male fertility (see section 5.3). Therefore,males being treated with docetaxel must seek advice on conservation of sperm prior to treatment.

No studies on the effects on the ability to drive and use machines have been performed. The amountof alcohol in this medicinal product and the side effects of the product may impair the ability to driveor use machines (see sections 4.4 and 4.8). Therefore, patients should be warned of the potentialimpact of the amount of alcohol and the side effects of this medicinal product on the ability to drive oruse machines, and be advised not to drive or use machines if they experience these side effects duringtreatment.

Summary of the safety profile for all indications

The adverse reactions considered to be possibly or probably related to the administration of docetaxelhave been obtained in:

* 1,312 and 121 patients who received 100 mg/m2 and 75 mg/m2 of docetaxel as a single agentrespectively.

* 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 (TAX327) who received docetaxel in combination with prednisone or prednisolone(clinically important treatment related adverse events are presented).

* 1,276 patients (744 and 532 in TAX 316 and GEICAM 9,805 respectively) who receiveddocetaxel in combination with doxorubicin and cyclophosphamide (clinically important treatmentrelated adverse events are presented).

* 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patientsin the phase II part) who received docetaxel in combination with cisplatin and 5-fluorouracil(clinically important treatment related adverse events are presented).

* 174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatinand 5-fluorouracil (clinically important treatment related adverse events are presented).

* 545 patients (STAMPEDE study) who received docetaxel in combination with prednisone orprednisolone and ADT.

These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3;grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA terms. Frequencies are defined as:

very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from availabledata).

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

The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which wasreversible and not cumulative; the median day to nadir was 7 days and the median duration of severeneutropenia (< 500 cells/mm3) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoeaand asthenia. The severity of adverse events of docetaxel may be increased when docetaxel is given incombination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are displayed. Therewas an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in thetrastuzumab combination arm compared to docetaxel monotherapy.

For combination with capecitabine, the most frequent treatment-related undesirable effects (≥ 5%)reported in a phase III study in breast cancer patients failing anthracycline treatment are presented (seecapecitabine summary of product characteristics).

For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse eventsoccurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in thedocetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE gradingscale.

The following adverse reactions are frequently observed with docetaxel:

Hypersensitivity reactions have generally occurred within a few minutes following the start of theinfusion of docetaxel and were usually mild to moderate. The most frequently reported symptoms wereflushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and fever or chills. Severereactions were characterised by hypotension and/or bronchospasm or generalized rash/erythema (seesection 4.4).

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthesia or painincluding burning. Neuro-motor events are mainly characterised by weakness.

Reversible cutaneous reactions have been observed and were generally considered as mild tomoderate. Reactions were characterised by a rash including localised eruptions mainly on the feet andhands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequentlyassociated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.

Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead tointerruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severenail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation,redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.

Fluid retention includes events such as peripheral oedema and less frequently pleural effusion,pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lowerextremities and may become generalised with a weight gain of 3 kg or more. Fluid retention iscumulative in incidence and severity (see section 4.4).

Tabulated list of adverse reactions in breast cancer for docetaxel 100 mg/m2 single agent

MedDRA system Very common adverse Common adverse Uncommonorgan classes reactions reactions adversereactions

Infections and infestations Infections (G3/4: 5.7%; Infection associated with G4including sepsis and neutropenia (G3/4: 4.6%)pneumonia, fatal in 1.7%)

Blood and lymphatic Neutropenia (G4: 76.4%); Thrombocytopenia (G4:

system disorders Anaemia (G3/4: 8.9%); 0.2%)

Immune system disorders Hypersensitivity (G3/4:

5.3%)

Metabolism and nutrition Anorexiadisorders

Nervous system disorders Peripheral sensoryneuropathy (G3: 4.1%);

Peripheral motorneuropathy (G3/4: 4%);

Dysgeusia (severe: 0.07%)

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

Vascular disorders Hypotension;

Hypertension;

Respiratory, thoracic and Dyspnoea (severe: 2.7%)mediastinal disorders

Gastrointestinal disorders Stomatitis (G3/4: 5.3%); Constipation (severe: 0.2%); Oesophagitis

Diarrhoea (G3/4: 4%); Abdominal pain (severe: 1%); (severe: 0.4%)

Nausea (G3/4: 4%); Gastrointestinal haemorrhage

Vomiting (G3/4: 3%) (severe: 0.3%)

Skin and subcutaneous Alopecia;tissue disorders Skin reaction (G3/4: 5.9%);

Nail disorders (severe:

2.6%)

Musculoskeletal and Myalgia (severe: 1.4%) Arthralgiaconnective tissue disorders

General disorders and Fluid retention (severe: Infusion site reaction;administration site 6.5%); Non-cardiac chest painconditions Asthenia (severe: 11.2%); (severe: 0.4%)

MedDRA system Very common adverse Common adverse Uncommonorgan classes reactions reactions adversereactions

Investigations G3/4 Blood bilirubinincreased (< 5%);

G3/4 Blood alkalinephosphatase increased (<4%);

G3/4 AST increased (< 3%);

G3/4 ALT increased (< 2%)

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m2 single agent

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

Reversibility data are available among 35.3% of patients who developed neurotoxicity followingdocetaxel treatment at 100 mg/m² as single agent. The events were spontaneously reversible within3 months.

Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactionswere reversible within 21 days.

The median cumulative dose to treatment discontinuation was more than 1,000 mg/m2 and the mediantime to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset of moderate andsevere retention is delayed (median cumulative dose: 818.9 mg/m2) in patients with premedicationcompared with patients without premedication (median cumulative dose: 489.7 mg/m2); however, ithas been reported in some patients during the early courses of therapy.

Tabulated list of adverse reactions in non-small cell lung cancer for docetaxel 75 mg/m2 single agent

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

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

Blood and lymphatic system Neutropenia (G4: 54.2%); Febrile neutropeniadisorders Anaemia (G3/4: 10.8%);

Thrombocytopenia (G4: 1.7%)

Immune system disorders Hypersensitivity (no severe)

Metabolism and nutrition Anorexiadisorders

Nervous system disorders Peripheral sensory neuropathy Peripheral motor neuropathy(G3/4: 0.8%) (G3/4: 2.5%)

Cardiac disorders Arrhythmia (no severe)

Vascular disorders Hypotension

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

Stomatitis (G3/4: 1.7%);

Vomiting (G3/4: 0.8%);

Diarrhoea (G3/4: 1.7%)

Skin and subcutaneous tissue Alopecia; Nail disorders (severe: 0.8%)disorders Skin reaction (G3/4: 0.8%)

Musculoskeletal and connective Myalgiatissue disorders

General disorders and Asthenia (severe: 12.4%);

MedDRA system organ Very common adverse Common adverse reactionsclasses reactionsadministration site conditions Fluid retention (severe: 0.8%);

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

Tabulated list of adverse reactions in breast cancer for docetaxel 75 mg/m2 in combination withdoxorubicin

MedDRA system Very common adverse Common adverse Uncommon adverseorgan classes reactions reactions reactions

Infections and Infection (G3/4: 7.8%)infestations

Blood and lymphatic Neutropenia (G4:

system disorders 91.7%);

Anaemia (G3/4: 9.4%);

Febrile neutropenia;

Thrombocytopenia(G4: 0.8%)

Immune system Hypersensitivity (G3/4:

disorders 1.2%)

Metabolism and Anorexianutrition disorders

Nervous system Peripheral sensory Peripheral motordisorders neuropathy (G3: 0.4%) neuropathy (G3/4:

0.4%)

Cardiac disorders Cardiac failure;

Arrhythmia (no severe)

Vascular disorders Hypotension

Gastrointestinal Nausea (G3/4: 5%);disorders Stomatitis (G3/4:

7.8%);

Diarrhoea (G3/4:

6.2%);

Vomiting (G3/4: 5%);

Skin and subcutaneous Alopecia;tissue disorders Nail disorders (severe:

0.4%);

Skin reaction (nosevere)

Musculoskeletal and Myalgiaconnective tissuedisorders

General disorders and Asthenia (severe: Infusion site reactionadministration site 8.1%);conditions Fluid retention (severe:

1.2%);

Investigations G3/4 Blood bilirubin G3/4 AST increasedincreased (< 2.5%); (< 1%);

G3/4 Blood alkaline G3/4 ALT increasedphosphatase increased (< 1%)(< 2.5%)

Tabulated list of adverse reactions in non-small cell lung cancer for docetaxel 75 mg/m2 incombination with cisplatin

MedDRA system Very common adverse Common adverse Uncommon adverseorgan classes reactions reactions reactions

Infections and Infection (G3/4: 5.7%)infestations

Blood and lymphatic Neutropenia (G4: Febrile neutropeniasystem disorders 51.5%);

Anaemia (G3/4: 6.9%);

Thrombocytopenia(G4: 0.5%)

Immune system Hypersensitivity (G3/4:

disorders 2.5%)

Metabolism and Anorexianutrition disorders

Nervous system Peripheral sensorydisorders neuropathy (G3: 3.7%);

Peripheral motorneuropathy (G3/4: 2%)

Cardiac disorders Arrhythmia (G3/4: Cardiac failure0.7%)

Vascular disorders Hypotension (G3/4:

0.7%)

Gastrointestinal Nausea (G3/4: 9.6%); Constipationdisorders Vomiting (G3/4:

7.6%);

Diarrhoea (G3/4:

6.4%);

Stomatitis (G3/4: 2%)

Skin and subcutaneous Alopecia;tissue disorders Nail disorders (severe:

0.7%);

Skin reaction (G3/4:

0.2%)

Musculoskeletal and Myalgia (severe: 0.5%)connective tissuedisorders

General disorders and Asthenia (severe: Infusion site reaction;administration site 9.9%); Painconditions Fluid retention (severe:

0.7%);

Fever (G3/4: 1.2%)

Investigations G3/4 Blood bilirubin G3/4 AST increasedincreased (2.1%); (0.5%);

G3/4 ALT increased G3/4 Blood alkaline(1.3%) phosphatase increased(0.3%)

Tabulated list of adverse reactions in breast cancer for docetaxel 100 mg/m2 in combination withtrastuzumab

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

Blood and lymphatic system Neutropenia (G3/4: 32%);disorders Febrile neutropenia (includes

MedDRA system organ Very common adverse Common adverse reactionsclasses reactionsneutropenia associated withfever and antibiotic use) orneutropenic sepsis

Metabolism and nutrition Anorexiadisorders

Psychiatric disorders Insomnia

Nervous system disorders Paraesthesia; Headache;

Dysgeusia; Hypoaesthesia

Eye disorders Lacrimation increased;

Conjunctivitis

Cardiac disorders Cardiac failure

Vascular disorders Lymphoedema

Respiratory, thoracic and Epistaxis; Pharyngolaryngealmediastinal disorders pain; Nasopharyngitis;

Dyspnoea;

Cough; Rhinorrhoea

Gastrointestinal disorders Nausea; Diarrhoea; Vomiting;

Constipation; Stomatitis;

Dyspepsia; Abdominal pain

Skin and subcutaneous tissue Alopecia; Erythema; Rash; Naildisorders disorders

Musculoskeletal and connective Myalgia; Arthralgia; Pain intissue disorders extremity; Bone pain; Back pain

General disorders and Asthenia; Oedema peripheral; Lethargyadministration site conditions Pyrexia; Fatigue; Mucosalinflammation; Pain; Influenzalike illness; Chest pain; Chills

Investigations Weight increased

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m2 in combinationwith trastuzumab

Very common: Haematological toxicity was increased in patients receiving trastuzumab and docetaxel,compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria).

Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m2 is known toresult in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The incidence offebrile neutropenia/neutropenic sepsis was also increased in patients treated with Herceptin plusdocetaxel (23% versus 17% for patients treated with docetaxel alone).

Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plustrastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm,64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel armalone.

Tabulated list of adverse reactions in breast cancer for docetaxel 75 mg/m2 in combination withcapecitabine

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

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

Blood and lymphatic system Neutropenia (G3/4: 63%); Thrombocytopenia (G3/4: 3%)disorders Anaemia (G3/4: 10%)

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

Metabolism and nutrition Anorexia (G3/4: 1%); Dehydration (G3/4: 2%)disorders Decreased appetite

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

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

Neuropathy peripheral

Eye disorders Lacrimation increased

Respiratory, thoracic and Pharyngolaryngeal pain (G3/4: Dyspnoea (G3/4: 1%);mediastinal disorders 2%) Cough (G3/4: < 1%);

Epistaxis (G3/4: < 1%)

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

Diarrhoea (G3/4: 14%); Dry mouth

Nausea (G3/4: 6%);

Vomiting (G3/4: 4%);

Constipation (G3/4: 1%);

Abdominal pain (G3/4: 2%);

Dyspepsia

Skin and subcutaneous tissue Hand-foot syndrome (G3/4: Dermatitis;disorders 24%); Rash erythematous (G3/4:

Alopecia (G3/4: 6%); < 1%);

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

Onycholysis (G3/4: 1%)

Musculoskeletal and connective Myalgia (G3/4: 2%); Pain in extremity (G3/4: < 1%);tissue disorders Arthralgia (G3/4: 1%) Back pain (G3/4: 1%)

General disorders and Asthenia (G3/4: 3%); Lethargy;administration site conditions Pyrexia (G3/4: 1%); Pain

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

Oedema peripheral (G3/4: 1%)

Investigations Weight decreased;

G3/4 Blood bilirubin increased(9%)

Tabulated list of adverse reactions in metastatic castration-resistant prostate cancer for docetaxel 75mg/m2 in combination with prednisone or prednisolone

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

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

Blood and lymphatic system Neutropenia (G3/4: 32%); Thrombocytopenia (G3/4:

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

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

Metabolism and nutrition Anorexia (G3/4: 0.6%)disorders

Nervous system disorders Peripheral sensory neuropathy Peripheral motor neuropathy(G3/4: 1.2%); (G3/4: 0%)

Dysgeusia (G3/4: 0%)

Eye disorders Lacrimation increased (G3/4:

0.6%)

Cardiac disorders Cardiac left ventricular functiondecrease (G3/4: 0.3%)

Respiratory, thoracic and Epistaxis (G3/4: 0%);mediastinal disorders Dyspnoea (G3/4: 0.6%);

Cough (G3/4: 0%)

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

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

Diarrhoea (G3/4: 1.2%);

Stomatitis/Pharyngitis (G3/4:

0.9%);

Vomiting (G3/4: 1.2%)

Skin and subcutaneous tissue Alopecia; Exfoliative rash (G3/4: 0.3%)disorders Nail disorders (no severe)

Musculoskeletal and connective Arthralgia (G3/4: 0.3%);bone disorders Myalgia (G3/4: 0.3%)

General disorders and Fatigue (G3/4: 3.9%);administration site conditions Fluid retention (severe: 0.6%)

Tabulated list of adverse reactions in high-risk locally advanced or metastatic hormone-sensitiveprostate cancer for Docetaxel 75 mg/m² in combination with prednisone or prednisolone and ADT(STAMPEDE study)

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

Blood and lymphatic system Neutropenia (G3-4: 12 %)disorders Anaemia

Febrile neutropenia (G3-4: 15%)

Immune system disorders Hypersensitivity (G3-4: 1%)

Endocrine disorders Diabetes (G3-4: 1%)

Metabolism and nutrition Anorexiadisorders

Psychiatric disorders Insomnia (G3: 1%)

Nervous system disorders Peripheral sensory neuropathy Dizziness(≥G3: 2%)a

Eye disorders Blurred vision

Cardiac disorders Hypotension (G3: 0%)

Respiratory, thoracic and Dyspnea (G3: 1%) Pharyngitis (G3: 0%)mediastinal disorders Coughing (G3: 0%)

Upper respiratory tract infection(G3: 1%)

Gastrointestinal disorders Diarrhea (G3: 3%) Vomiting (G3: 1%)

Stomatitis (G3: 0%)

Constipation (G3: 0%)

Nausea (G3: 1%)

Dyspepsia

Abdominal pain (G3: 0%)

Flatulence

Skin and subcutaneous tissue Alopecia (G3: 3%)a Rashdisorders Nail changes (G3: 1%)

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

Musculoskeletal and Myalgiaconnective tissue disorders

General disorders and Lethargy (G3-4: 2%) Fever (G3: 1%)administration site conditions Flu-like symptoms (G3: 0%) Oral candidiasis

Asthenia (G3: 0%) Hypocalcaemia (G3: 0%)

Fluid retention Hypophosphataemia (G3-4: 1%)

Hypokalaemia (G3: 0%)a From the GETUG AFU15 study

Tabulated list of adverse reactions in breast cancer for adjuvant therapy with docetaxel 75 mg/m2 incombination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) andnode-negative (GEICAM 9805) breast cancer - pooled data

MedDRA System Very common adverse Common adverse Uncommon adverse

Organ classes reactions reactions reactions

Infections and Infection (G3/4: 2.4%);infestations Neutropenic infection(G3/4: 2.6%)

Blood and lymphatic Anaemia (G3/4: 3%);system disorders Neutropenia (G3/4:

59.2%);

Thrombocytopenia(G3/4: 1.6%);

Febrile neutropenia(G3/4: NA)

Immune system Hypersensitivity (G3/4:

disorders 0.6%)

Metabolism and Anorexia (G3/4: 1.5%)nutrition disorders

Nervous system Dysgeusia (G3/4: Peripheral motor Syncope (G3/4: 0%);disorders 0.6%); neuropathy (G3/4: 0%) Neurotoxicity (G3/4:

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

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

Cardiac disorders Arrhythmia (G3/4:

0.2%)

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

0%); 0%)

Phlebitis (G3/4: 0%)

Respiratory, thoracic Cough (G3/4: 0%)and mediastinaldisorders

Gastrointestinal Nausea (G3/4: 5.0%); Abdominal pain (G3/4:

disorders Stomatitis (G3/4: 0.4%)6.0%);

Vomiting (G3/4:

4.2%);

Diarrhoea (G3/4:

3.4%);

Constipation (G3/4:

0.5%)

Skin and subcutaneous Alopecia ( persisting:

tissue disorders <3%);

Skin disorder (G3/4:

0.6%);

Nail disorders (G3/4:

0.4%)

Musculoskeletal and Myalgia (G3/4: 0.7%);connective tissue Arthralgia (G3/4:

disorders 0.2%)

Reproductive system Amenorrhoea (G3/4:

and breast disorders NA)

General disorders and Asthenia (G3/4:

administration site 10.0%);conditions Pyrexia (G3/4: NA);

Oedema peripheral(G3/4: 0.2%)

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

Weight decreased(G3/4: 0.2%)

Description of selected adverse reactions for adjuvant therapy with docetaxel 75 mg/m² incombination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) andnode-negative (GEICAM 9805) breast cancer

In study TAX316 peripheral sensory neuropathy started during the treatment period and persisted intothe follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2 %) in FAC arm. At the endof the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy wasobserved to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

In GEICAM 9805 study peripheral sensory neuropathy that started during the treatment periodpersisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8 %) in FACarm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheralsensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient(0.2%) in FAC arm.

In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC armexperienced congestive heart failure. All except one patient in each arm were diagnosed with CHFmore than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FACarm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developedcongestive heart failure during the follow-up period. At the end of the follow-up period (actual medianfollow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC armdied because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in

FAC arm.

In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy wasreported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%).

At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed tobe ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study alopecia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in

FAC arm. Alopecia related to study drug started or worsened during the follow-up period in42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm. At the end of the follow-upperiod (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

In TAX316 amenorrhoea that started during the treatment period and persisted into the follow-upperiod after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736

FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period(median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

In GEICAM 9805 study amenorrhoea that started during the treatment period and persisted into thefollow-up period was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %)in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months),amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in

FAC arm.

In study TAX316 peripheral oedema that started during the treatment period and persisted into thefollow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8years), peripheral oedema was ongoing in19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316 lymphoedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736

FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years),lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX316 asthenia that started during the treatment period and persisted into the follow-upperiod after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736

FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years),asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805 peripheral oedema that started during the treatment period persisted into thefollow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end ofthe follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC armhad peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm.

Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients(0.9%) in TAC arm and 2 patients (0.4 %) in FAC arm. At the end of the follow-up period,lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in

FAC arm.

Asthenia that started during the treatment period and persisted into the follow-up period was observedto be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of thefollow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2patients (0.4%) in FAC arm.

Acute leukaemia/Myelodysplastic syndrome

After 10 years of follow up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients(0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) dieddue to AML during the follow-up period (median follow-up time of 8 years). Myelodysplasticsyndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%). After10 years of follow-up in GEICAM 9805 study acute leukaemia occurred in 1 of 532 (0.2%) patients in

TAC arm No cases were reported in patients in FAC arm No patient was diagnosed withmyelodysplastic syndrome in either treatment groups.

Neutropenic complications

Table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenicinfection was decreased in patients who received primary G-CSF prophylaxis after it was mademandatory in the TAC arm-GEICAM study.

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

Without primary With primary

G-CSF prophylaxis G-CSF prophylaxis(n = 111) (n = 421)n (%) 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 2 (1.8) 5 (1.2)(Grade 3-4)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for docetaxel 75 mg/m2 incombination with cisplatin and 5-fluorouracil

MedDRA system organ Very common adverse Common adverse reactionsclasses reactions

Infections and infestations Neutropenic infection;

Infection (G3/4: 11.7%)

Blood and lymphatic system Anaemia (G3/4: 20.9%);disorders Neutropenia (G3/4: 83.2%);

Thrombocytopenia (G3/4:

8.8%);

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

Metabolism and nutrition Anorexia (G3/4: 11.7%)disorders

Nervous system disorders Peripheral sensory neuropathy Dizziness (G3/4: 2.3%);(G3/4: 8.7%) Peripheral motor neuropathy(G3/4: 1.3%)

Eye disorders Lacrimation increased (G3/4:

0%)

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

Cardiac disorders Arrhythmia (G3/4: 1.0%)

Gastrointestinal disorders Diarrhoea (G3/4: 19.7%); Constipation (G3/4: 1.0%);

Nausea (G3/4: 16%); Gastrointestinal pain (G3/4:

Stomatitis (G3/4: 23.7%); 1.0%);

Vomiting (G3/4: 14.3%) Oesophagitis/dysphagia/odynophagia (G3/4: 0.7%)

Skin and subcutaneous tissue Alopecia (G3/4: 4.0%) Rash pruritus (G3/4: 0.7%);disorders Nail disorders (G3/4: 0.7%);

Skin exfoliation (G3/4: 0%)

General disorders and Lethargy (G3/4: 19.0%);administration site conditions Fever (G3/4: 2.3%);

Fluid retention(severe/life- threatening: 1%)

Description of selected adverse reactions in gastric adenocarcinoma cancer for docetaxel 75 mg/m2 incombination with cisplatin and 5-fluorouracil

Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively,regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% ofthe cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% ofpatients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients withoutprophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for docetaxel 75 mg/m2 in combinationwith cisplatin and 5-fluorouracil

* Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA system Very common adverse Common adverse Uncommon adverseorgan classes reactions reactions reactions

Infections and Infection (G3/4: 6.3%);infestations Neutropenic infection

Neoplasms benign, Cancer pain (G3/4: 0.6%)malignant andunspecified (incl cysts

MedDRA system Very common adverse Common adverse Uncommon adverseorgan classes reactions reactions reactionsand polyps)

Blood and lymphatic Neutropenia (G3/4: 76.3%); Febrile neutropeniasystem disorders Anaemia (G3/4: 9.2%);

Thrombocytopenia (G3/4:

5.2%)

Immune system Hypersensitivity (nodisorders severe)

Metabolism and Anorexia (G3/4: 0.6%)nutrition disorders

Nervous system Dysgeusia/Parosmia; Dizzinessdisorders Peripheral sensoryneuropathy (G3/4: 0.6%)

Eye disorders Lacrimation increased;

Conjunctivitis

Ear and labyrinth Hearing impaireddisorders

Cardiac disorders Myocardial ischemia Arrhythmia (G3/4:

(G3/4:1.7%) 0.6%)

Vascular disorders Venous disorder (G3/4:

0.6%)

Gastrointestinal Nausea (G3/4: 0.6%); Constipation;disorders Stomatitis (G3/4: 4.0%); Esophagitis/dysphagia/

Diarrhoea (G3/4: 2.9%); odynophagia (G3/4:

Vomiting (G3/4: 0.6%) 0.6%);

Abdominal pain;

Dyspepsia;

Gastrointestinalhaemorrhage (G3/4:

0.6%)

Skin and subcutaneous Alopecia (G3/4: 10.9%) Rash pruritic;tissue disorders Dry skin;

Skin exfoliative (G3/4:

0.6%)

Musculoskeletal and Myalgia (G3/4: 0.6%)connective tissuedisorders

General disorders and Lethargy (G3/4: 3.4%);administration site Pyrexia (G3/4: 0.6%);conditions Fluid retention;

Oedema

Investigations Weight increased

* Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system Very common adverse Common adverse Uncommon adverseorgan classes reactions reactions reactions

Infections and Infection (G3/4: 3.6%) Neutropenic infectioninfestations

Neoplasms benign, Cancer pain (G3/4:

malignant and 1.2%)unspecified (incl cystsand polyps)

Blood and lymphatic Neutropenia (G3/4:

system disorders 83.5%);

MedDRA system Very common adverse Common adverse Uncommon adverseorgan classes reactions reactions reactions

Anaemia (G3/4:

12.4%);

Thrombocytopenia(G3/4: 4.0%);

Immune system Hypersensitivitydisorders

Metabolism and Anorexia (G3/4:

nutrition disorders 12.0%)

Nervous system Dysgeusia/Parosmia Dizziness (G3/4:

disorders (G3/4: 0.4%); 2.0%);

Peripheral sensory Peripheral motorneuropathy (G3/4: neuropathy (G3/4:

1.2%) 0.4%)

Eye disorders Lacrimation increased Conjunctivitis

Ear and labyrinth Hearing impaireddisorders (G3/4: 1.2%)

Cardiac disorders Arrhythmia (G3/4: Ischemia myocardial2.0%)

Vascular disorders Venous disorder

Gastrointestinal Nausea (G3/4: 13.9%); Dyspepsia (G3/4:

disorders Stomatitis (G3/4: 0.8%);20.7%); Gastrointestinal pain

Vomiting (G3/4: 8.4%); (G3/4: 1.2%);

Diarrhoea (G3/4: Gastrointestinal6.8%); haemorrhage (G3/4:

Esophagitis/dysphagia/ 0.4%)odynophagia (G3/4:

12.0%);

Constipation (G3/4:

0.4%)

Skin and subcutaneous Alopecia (G3/4: 4.0%); Dry skin;tissue disorders Rash pruritic Desquamation

Musculoskeletal, Myalgia (G3/4: 0.4%)connective tissue bonedisorders

General disorders and Lethargy (G3/4: 4.0%);administration site Pyrexia (G3/4: 3.6%);conditions Fluid retention (G3/4:

1.2%);

Oedema (G3/4: 1.2%)

Investigations Weight decreased Weight increased

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

Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have beenreported in association with docetaxel when used in combination with other anticancer treatmentsknown to be associated with second primary malignancies. Acute myeloid leukemia andmyelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies inbreast cancer with TAC regimen.

Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminatedintravascular coagulation (DIC), often in association with sepsis or multi-organ failure, has beenreported.

Some cases of anaphylactic shock, sometimes fatal, have been reported.

Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients whopreviously experienced hypersensitivity reactions to paclitaxel.

Rare cases of convulsion or transient loss of consciousness have been observed with docetaxeladministration. These reactions sometimes appear during the infusion of the medicinal product.

Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurringduring infusion of the medicinal product and in association with hypersensitivity reactions have beenreported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with orwithout conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have beenrarely reported. Cases of cystoid macular oedema (CMO) have been reported in patients treated withdocetaxel.

Ear and labyrinth disorders

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

Rare cases of myocardial infarction have been reported.

Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, hasbeen reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/ or cyclophosphamide.

Venous thromboembolic events have rarely been reported.

Acute respiratory distress syndrome and cases of interstitial pneumonia/ pneumonitis, interstitial lungdisease, pulmonary fibrosis and respiratory failure sometimes fatal have rarely been reported. Rarecases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have beenreported with a potential fatal outcome (frequency not known).Rare occurrences of dehydration havebeen reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinalperforation.

Rare cases of ileus and intestinal obstruction have been reported.

Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders,have been reported.

Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severecutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis(TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel.

Scleroderma-like changes usually preceded by peripheral lymphoedema have been reported withdocetaxel. Cases of permanent alopecia (frequency not known) have been reported.

Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no riskfactors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro-intestinaldisorders.

Radiation recall phenomena have rarely been reported.

Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation followingadministration of docetaxel at a different site) has been observed at the site of previous extravasation(frequency not known).

Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydrationand pulmonary oedema have rarely been reported.

Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostlyassociated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, andhypocalcaemia were observed, usually in association with gastrointestinal disorders and in particularwith diarrhoea. Tumour lysis syndrome, potentially fatal, has been reported (frequency not known).

Musculoskeletal disorder

Myositis has been reported with docetaxel (frequency not known).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case ofoverdose, the patient should be kept in a specialised unit and vital functions closely monitored. Incases of overdose, exacerbation of adverse events may be expected. The primary anticipatedcomplications of overdose would consist of bone marrow suppression, peripheral neurotoxicity andmucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose.

Other appropriate symptomatic measures should be taken, as needed.

Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, Taxanes,

ATC Code: L01CD02

Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stablemicrotubules and inhibits their disassembly which leads to a marked decrease of free tubulin. Thebinding of docetaxel to microtubules does not alter the number of protofilaments.

Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential forvital mitotic and interphase cellular functions.

Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines andagainst freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellularconcentrations with a long cell residence time. In addition, docetaxel was found to be active on somebut not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistancegene. In vivo, docetaxel is schedule independent and has a broad spectrum of experimental anti-tumouractivity against advanced murine and human grafted tumours.

Breast cancer

Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy

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

Data from a multicentre open-label randomised study support the use of docetaxel for the adjuvanttreatment of patients with operable node-positive breast cancer and KPS ≥ 80%, between 18 and 70years of age. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491patients were randomised to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed byfluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens wereadministered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, allother medicinal products were given as intravenous bolus on day one. G-CSF was administered assecondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia,prolonged neutropenia, or infection). Patients on the TAC arm received antibiotic prophylaxis withciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. Inboth arms, after the last cycle of chemotherapy, patients with positive oestrogen and/or progesteronereceptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribedaccording to guidelines in place at participating institutions and was given to 69% of patients whoreceived TAC and 72% of patients who received FAC. Two interim analyses and one final analysiswere performed. The first interim analysis was planned 3 years after the date when half of studyenrolment was done. The second interim analysis was done after 400 DFS events had been recordedoverall, which led to a median follow-up of 55 months. The final analysis was performed when allpatients had reached their 10-year follow-up visit (unless they had a DFS event or were lost tofollow-up before). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival(OS) was the secondary efficacy endpoint.

A final analysis was performed with an actual median follow up of 96 months. Significantly longerdisease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidenceof relapses at 10 years was reduced in patients receiving TAC compared to those whoreceived FAC (39% versus 45%, respectively) i.e. an absolute risk reduction by 6% (p =0.0043). Overall survival at 10 years was also significantly increased with TAC compared to

FAC (76% versus 69%, respectively) i.e. an absolute reduction of the risk of death by 7% (p =0.002). As the benefit observed in patients with 4+ nodes was not statistically significant on DFS and

OS, the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at thefinal 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 wereanalysed:

Disease free survival Overall survival

Patient Number Hazard 95% CI p = Hazard 95% CI p =subset of ratio* ratio*patients

No of positivenodes

Overall 745 0.80 0.68-0.93 0.0043 0.74 0.61-0.90 0.00201-3 467 0.72 0.58-0.91 0.0047 0.62 0.46-0.82 0.00084+ 278 0.87 0.70-1.09 0.2290 0.87 0.67-1.12 0.2746

*a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival andoverall survival compared to FAC

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

Data from a multicentre open-label randomised trial support the use of docetaxel for the adjuvanttreatment of patients with operable node-negative breast cancer eligible to receive chemotherapy. 1060patients were randomised to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin50 mg/m2 and cyclophosphamide 500 mg/m2 (539 patients in TAC arm), or doxorubicin 50 mg/m2followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (521 patients in FAC arm), asadjuvant treatment of operable node-negative breast cancer patients with high risk of relapse accordingto 1998 St. Gallen criteria (tumour size >2 cm and/or negative ER and PR and/or highhistological/nuclear grade (grade 2 to 3) and /or age <35 years).). Both regimens were administeredonce every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinalproducts were given intravenously on day 1 every three weeks. Primary prophylactic G-CSF was mademandatory in TAC arm after 230 patients were randomised. The incidence of Grade 4 neutropenia,febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSFprophylaxis (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant radiationtherapy was administered according to guidelines in place at participating institutions and was given to57.3% of patients who received TAC and 51.2% of patients who received FAC.

One primary analysis and one updated analysis were performed. The primary analysis was done whenall patients had a follow-up of greater than 5 years (median follow-up time of 77 months). The updatedanalysis was performed when all patients had reached their 10-year (median follow up time of 10years and 5 months) follow-up visit (unless they had a DFS event or were lost to follow-uppreviously). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS)was the secondary efficacy endpoint.

At the median follow-up time of 77 months significantly longer disease-free survival for the TACarm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in therisk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93), p = 0.01).

At the median follow up time of 10 years and 5 months, TAC-treated patients had a 16.5% reductionin the risk of relapse compared to those treated with FAC (hazard ratio = 0.84, 95% CI (0.65-1.08),p=0.1646). DFS data were not statistically significant but were still associated with a positive trend infavour of TAC.

At the median follow-up time of 77 months, overall survival (OS) was longer in the TAC arm with

TAC-treated patients having a 24% reduction in the risk of death compared to FAC (hazard ratio =0.76, 95% CI (0.46-1.26, p = 0.29). However, the distribution of OS was not significantly differentbetween the 2 groups.

At the median follow up time of 10 years and 5 months, TAC-treated patients had a 9% reduction inthe risk of death compared to FAC-treated patients (hazard ratio = 0.91, 95% CI (0.63-1.32)).

The survival rate was 93.7% in the TAC arm and 91.4 % in the FAC arm, at the 8-year follow-up timepoint, and 91.3 % in the TAC arm and 89 % in the FAC arm, at the 10-year follow-up time point.

The positive benefit risk ratio for TAC compared to FAC remained unchanged.

TAC-treated patient subsets according to prospectively defined major prognostic factors were analysedin the primary analysis (at the median follow-up time of 77 months) (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 of patients Hazard ratio* 95% CIin TAC group

Overall 539 0.68 0.49-0.93

Age category 1<50 years 260 0.67 0.43-1.05≥50 years 279 0.67 0.43-1.05

Age category 2<35 years 42 0.31 0.11-0.89≥35 years 497 0.73 0.52-1.01

Hormonal receptorstatus

Negative 195 0.7 0.45-1.1

Positive 344 0.62 0.4-0.97

Tumour size≤ 2 cm 285 0.69 0.43-1.1>2 cm 254 0.68 0.45-1.04

Histological grade

Grade1 (includes grade 64 0.79 0.24-2.6not assessed)

Grade 2 216 0.77 0.46-1.3

Grade 3 259 0.59 0.39-0.9

Menopausal status

Pre-Menopausal 285 0.64 0.40-1

Post-Menopausal 254 0.72 0.47-1.12

*a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer disease free survivalcompared to FAC.

Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallenchemotherapy criteria - (ITT population) were performed and presented here below:

Hazard ratio

TAC FAC (TAC/FAC)

Subgroups (n=539) (n=521) (95% CI) p-value

Meeting relative indicationfor chemotherapy a

No 18/214 26/227 0.796 (0.434 - 1.459) 0.4593(8.4%) (11.5%)

Yes 48/325 69/294 0.606 (0.42 - 0.877) 0.0072(14.8%) (23.5%)

TAC = docetaxel, doxorubicin and cyclophosphamide

FAC = 5-fluorouracil, doxorubicin and cyclophospamide

CI = confidence interval; ER = oestrogen receptor

PR = progesterone receptora

ER/PR-negative or Grade 3 or tumour size >5 cm

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

Docetaxel as single agent

Two randomised phase III comparative studies, involving a total of 326 alkylating or392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at therecommended dose and regimen of 100 mg/m2 every 3 weeks.

In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m2 every 3 weeks).

Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p = 0.38) ortime to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p = 0.54), docetaxel increasedresponse rate (52% vs. 37%, p = 0.01) and shortened time to response (12 weeks vs. 23 weeks,p = 0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heartfailure).

In anthracycline-failure patients, docetaxel was compared to the combination of mitomycin C andvinblastine (12 mg/m2 every 6 weeks and 6 mg/m2 every 3 weeks). Docetaxel increased response rate(33% vs. 12%, p < 0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p = 0.0004) andprolonged overall survival (11 months vs. 9 months, p = 0.01).

During these two phase III studies, the safety profile of docetaxel was consistent with the safety profileobserved in phase II studies (see section 4.8).

An open-label, multicentre, randomised phase III study was conducted to compare docetaxelmonotherapy and paclitaxel in the treatment of advanced breast cancer in patients whose previoustherapy should have included an anthracycline. A total of 449 patients were randomised to receiveeither docetaxel monotherapy 100 mg/m2 as a 1 hour infusion or paclitaxel 175 mg/m2 as a 3 hourinfusion. Both regimens were administered every 3 weeks.

Without affecting the primary endpoint, overall response rate (32% vs 25%, p = 0.10), docetaxelprolonged median time to progression (24.6 weeks vs 15.6 weeks; p < 0.01) and median survival(15.3 months vs 12.7 months; p = 0.03).

More grade 3/4 adverse events were observed for docetaxel monotherapy (55.4%) compared topaclitaxel (23.0%).

Docetaxel in combination with doxorubicin

One large randomised phase III study, involving 429 previously untreated patients with metastaticdisease, has been performed with doxorubicin (50 mg/m2) in combination with docetaxel (75 mg/m2)(AT arm) versus doxorubicin (60 mg/m2) in combination with cyclophosphamide (600 mg/m2)(AC arm). Both regimens were administered on day 1 every 3 weeks.

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

In this study, AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrileneutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhoea (7.5% versus 1.4%), asthenia(8.5% versus 2.4%), and pain (2.8% versus 0%) than AC arm. On the other hand, AC arm showed ahigher incidence of severe anaemia (15.8% versus 8.5%) than AT arm, and, in addition, a higherincidence of severe cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEFdecrease ≥ 20% (13.1% versus 6.1%), absolute LVEF decrease ≥ 30% (6.2% versus 1.1%). Toxicdeaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1due to septic shock and 3 due to congestive heart failure).

In both arms, quality of life measured by the EORTC questionnaire was comparable and stable duringtreatment and follow-up.

Docetaxel in combination with trastuzumab

Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastaticbreast cancer whose tumours overexpress HER2, and who previously had not received chemotherapyfor metastatic disease. One hundred eighty six patients were randomised to receive docetaxel (100mg/m2) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvantchemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they hadreceived prior adjuvant anthracyclines. The main test method used to determine HER2 positivity inthis pivotal study was immunohistochemistry (IHC). A minority of patients were tested usingfluorescence in-situ hybridization (FISH). In this study, 87% of patients had disease that was IHC 3+,and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results aresummarized in the following table:

Parameter Docetaxel plus trastuzumab1 Docetaxel1n = 92 n = 94

Response rate 61% 34%(95% CI) (50-71) (25-45)

Median duration of response(months) 11.4 5.1(95% CI) (9.2-15.0) (4.4-6.2)

Median TTP (months) 10.6 5.7(95% CI) (7.6-12.9) (5.0-6.5)

Median survival (months) 30.52 22.12(95% CI) (26.8-ne) (17.6-28.9)

TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached.1Full analysis set (intent-to-treat)2Estimated median survival

Docetaxel in combination with capecitabine

Data from one multicentre, randomised, controlled phase III clinical study support the use of docetaxelin combination with capecitabine for treatment of patients with locally advanced or metastatic breastcancer after failure of cytotoxic chemotherapy, including an anthracycline. In this study, 255 patientswere randomised to treatment with docetaxel (75 mg/m2 as a 1 hour intravenous infusion every 3weeks) and capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). 256patients were randomised to treatment with docetaxel alone (100 mg/m2 as a 1 hour intravenousinfusion every 3 weeks). Survival was superior in the docetaxel + capecitabine combination arm (p =0.0126). Median survival was 442 days (docetaxel + capecitabine) vs. 352 days (docetaxel alone). Theoverall objective response rates in the all-randomised population (investigator assessment) were 41.6%(docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease wassuperior in the docetaxel + capecitabine combination arm (p < 0.0001). The median time toprogression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).

Patients previously treated with chemotherapy with or without radiotherapy

In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks)and overall survival were significantly longer for docetaxel at 75 mg/m2 compared to Best Supportive

Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).

There was less use of morphinic analgesic (p < 0.01), non-morphinic analgesics (p < 0.01), otherdisease-related medicinal products (p = 0.06) and radiotherapy (p < 0.01) in patients treated withdocetaxel at 75 mg/m2 compared to those with BSC.

The overall response rate was 6.8% in the evaluable patients, and the median duration of response was26.1 weeks.

Docetaxel in combination with platinum agents in chemotherapy-naïve patients

In a phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% orgreater, and who did not receive previous chemotherapy for this condition, were randomised to eitherdocetaxel (T) 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m2 over30-60 minutes every 3 weeks (TCis), docetaxel 75 mg/m2 as a 1 hour infusion in combination withcarboplatin (AUC 6 mg/ml.min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m2administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered onday 1 of cycles repeated every 4 weeks (VCis).

Survival data, median time to progression and response rates for two arms of the study are illustratedin the following table:

TCis VCis Statistical analysisn = 408 n = 404

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 of disease andregion of treatment), based on evaluable patient population.

Secondary end-points included change of pain, global rating of quality of life by EuroQoL-5D, Lung

Cancer Symptom Scale, and changes in Karnosfky performance status. Results on these end-pointswere supportive of the primary end-points results.

For docetaxel/carboplatin combination, neither equivalent nor non-inferior efficacy could be provencompared to the reference treatment combination VCis.

Prostate cancer

Metastatic castration-resistant prostate cancer

The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients withmetastatic castration-resistant prostate cancer were evaluated in a randomised multicentre phase IIIstudy(TAX 327). A total of 1006 patients with KPS ≥ 60 were randomised to the following treatmentgroups:

* Docetaxel 75 mg/m2 every 3 weeks for 10 cycles.

* Docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.

* Mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles.

All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily,continuously.

Patients who received docetaxel every three weeks demonstrated significantly longer overall survivalcompared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weeklyarm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints forthe docetaxel arms versus the control arm are summarized in the following table:

Endpoint Docetaxel Docetaxel Mitoxantroneevery 3 weeks every week every 3 weeks

Number of patients 335 334 337

Median survival (months) 18.9 17.4 16.595% CI (17.0-21.2) (15.7-19.0) (14.4-18.6)

Hazard ratio 0.761 0.912 --95% CI (0.619-0.936) (0.747-1.113) --p-value†* 0.0094 0.3624 --

Number of patients 291 282 300

PSA** response rate (%) 45.4 47.9 31.795% CI (39.5-51.3) (41.9-53.9) (26.4-37.3)p-value* 0.0005 <0.0001 --

Number of patients 153 154 157

Pain response rate (%) 34.6 31.2 21.795% CI (27.1-42.7) (24.0-39.1) (15.5-28.9)p-value* 0.0107 0.0798 --

Number of patients 141 134 137

Tumour response rate (%) 12.1 8.2 6.695% CI (7.2-18.6) (4.2-14.2) (3.0-12.1)p-value* 0.1112 0.5853 --†Stratified log-rank test

*Threshold for statistical significance = 0.0175

**PSA: Prostate-Specific Antigen

Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every3 weeks, it is possible that certain patients may benefit from docetaxel every week.

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

Metastatic hormone-sensitive prostate cancer

STAMPEDE study

The safety and efficacy of docetaxel administered concomitantly with standard of care (ADT) inpatients with high-risk locally advanced or metastatic hormone-sensitive prostate cancer wereevaluated in a randomised multi-centre, multi-arm multi-stage (MAMS) study with a seamless phase

II/III design (STAMPEDE - MRC PR08). A total of 1776 male patients were allocated to thetreatment arms of interest:

* Standard of care + docetaxel 75 mg/m², administered every 3 weeks for 6 cycles

* Standard of care alone

Docetaxel regimen was administered in combination with prednisone or prednisolone 5 mg twice dailycontinuously.

Among the 1776 randomised patients 1086 (61%) had metastatic disease, 362 were randomised todocetaxel in combination with standard of care, 724 received standard of care alone.

In these metastatic prostate cancer patients, the median overall survival was significantly longer indocetaxel treatment groups than in the standard of care alone group, with a median overall survival 19months longer with the addition of docetaxel to standard of care (HR = 0.76, 95% CI = 0.62-0.92,p=0.005).

Efficacy results in metastatic prostate cancer patients for docetaxel arm versus control arm aresummarized in the following table:

Efficacy of docetaxel in combination with prednisone or prednisolone and standard of care in thetreatment of patients with metastatic hormone-sensitive prostate cancer (STAMPEDE)

Endpoint Docetaxel + standard of care Standard of care alone

Number of metastatic prostate 362 724cancer patients

Median overall survival (months) 62 4395% CI 51-73 40-48

Adjusted hazard ratio 0.7695% CI (0.62-0.92)p-valuea 0.005

Failure-Free survivalb

Median (months) 20.4 1295% CI 16.8-25.2 9.6-12

Adjusted hazard ratio 0.6695% CI (0.57-0.76)p-valuea < 0.001a p-value calculated from the likelihood ratio test and adjusted for all stratification factors(except center and planned hormone therapy) and stratified by trial periodb Failure-free survival: time from randomization to first evidence of at least one of: biochemicalfailure (defined as a rise in PSA of 50% above the within-24-week nadir and above 4 ng/mLand confirmed by retest or treatment); progression either locally, in lymph nodes, or in distantmetastases; skeletal-related event; or death from prostate cancer.

CHAARTED study

The safety and efficacy of docetaxel administered at the beginning of androgen-deprivation therapy(ADT) in patients with metastatic hormone-sensitive prostate cancer were evaluated in a randomised

Phase III multi-centre study (CHAARTED). A total of 790 male patients were allocated to the 2treatment groups.

* ADT + docetaxel 75 mg/m² given at the beginning of ADT, administered every 3 weeksfor 6 cycles

* ADT alone

The median overall survival was significantly longer in docetaxel treatment group than in the ADTalone group, with a median overall survival 13.6 months longer with the addition of docetaxel to ADT(hazard ratio (HR) = 0.61, 95% confidence interval (CI) = 0.47-0.80, p=0.0003).

Efficacy results or the docetaxel arm versus the control arm are summarized in the following table:

Efficacy of docetaxel and ADT in the treatment of patients with metastatic hormone-sensitive prostatecancer (CHAARTED)

Endpoint Docetaxel +ADT ADT alone

Number of patients 397 393

Median overall survival (months)

All patients 57.6 44.095% CI 49.1-72.8 34.4-49.1

Adjusted hazard ratio 0.61 --95% CI (0.47-0.80) --p-valuea 0.0003 --

Progression Free Survival

Median (months) 19.8 11.695% CI 16.7-22.8 10.8-14.3

Adjusted hazard ratio 0.60 --95% CI 0.51-0.72 --p-value* P<0.0001 --

PSA response** at 6 months - N(%) 127 (32.0) 77 (19.6)p-valuea* <0.0001 --

PSA response** at 12 months - N(%) 110 (27.7) 66 (16.8)p-valuea* <0.0001 --

Time to castration-resistant prostate cancerb

Median (months) 20.2 11.795% CI (17.2-23.6) (10.8-14.7)

Adjusted hazard ratio 0.61 --95% CI (0.51-0.72) --p-valuea* <0.0001 --

Time to clinical progressionc

Median (months) 33.0 19.895% CI (27.3-41.2) (17.9-22.8)

Adjusted hazard ratio 0.61 --95% CI (0.50-0.75) --p-valuea* <0.0001 --a Time to event variables: Stratified log-rank test.

Response rate variables: Fisher's Exact test

* p-value for descriptive purpose.

** PSA response: Prostate-Specific Antigen response: PSA level <0.2 ng/mL measured for twoconsecutive measurements at least 4 weeks apart.

b Time to castration-resistant prostate cancer = time from randomization to PSA progression orclinical progression (i.e., increasing symptomatic bone metastases, progression per Response

Evaluation Criteria in Solid Tumours (RECIST) criteria, or clinical deterioration due to cancer perthe Investigator’s opinion), whichever occurred first.c The time to clinical progression = the time from randomization until clinical progression (i.e.,increased symptoms of bone metastases; progression according to RECIST; or clinical deteriorationdue to cancer according to the investigator’s opinion).

Gastric adenocarcinoma

A multicentre, open-label, randomised study was conducted to evaluate the safety and efficacy ofdocetaxel for the treatment of patients with metastatic gastric adenocarcinoma, includingadenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy formetastatic disease. A total of 445 patients with KPS > 70 were treated with either docetaxel (T)(75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and 5-fluorouracil (F)(750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 perday for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CFarm. The median number of cycles administered per patient was 6 (with a range of 1-16) for the

TCF arm compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was theprimary endpoint. The risk reduction of progression was 32.1% and was associated with a significantlylonger TTP (p = 0.0004) in favour of the TCF arm. Overall survival was also significantly longer (p =0.0201) in favour of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results aresummarized in the following table:

Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma

Endpoint TCF CFn = 221 n = 224

Median TTP (months) 5.6 3.7(95% CI) (4.86-5.91) (3.45-4.47)

Hazard ratio 1.473(95% CI) (1.189-1.825)

*p-value 0.0004

Median survival (months) 9.2 8.6(95% CI) (8.38-10.58) (7.16-9.46)2-year estimate (%) 18.4 8.8

Hazard ratio 1.293(95% CI) (1.041-1.606)

*p-value 0.0201

Overall response rate (CR+PR) (%) 36.7 25.4p-value 0.0106

Progressive disease as best overall response (%) 16.7 25.9

*Unstratified logrank test

Subgroup analyses across age, gender and race consistently favoured the TCF arm compared to the

CF arm.

A survival update analysis conducted with a median follow-up time of 41.6 months no longer showeda statistically significant difference although always in favour of the TCF regimen and showed that thebenefit of TCF over CF is clearly observed between 18 and 30 months of follow up.

Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favourof the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of globalhealth status on the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive worsening of

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

Head and neck cancer

* Induction chemotherapy followed by radiotherapy (TAX323)

The safety and efficacy of docetaxel in the induction treatment of patients with squamous cellcarcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label,randomised study (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN,and WHO perfomance status 0 or 1, were randomised to one of two treatment arms. Patients on thedocetaxel arm received docetaxel (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 followed by5-fluorouracil (F) 750 mg/m2 per day as a continuous infusion for 5 days. This regimen wasadministered every three weeks for 4 cycles in case at least a minor response (≥ 25% reduction inbidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, witha minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did notprogress received radiotherapy (RT) according to institutional guidelines for 7 weeks (TPF/RT).

Patients on the comparator arm received cisplatin (P) 100 mg/m2 followed by 5-fluorouracil (F)1000 mg/m2 per day for 5 days. This regimen was administered every three weeks for 4 cycles in caseat least a minor response (≥ 25% reduction in bidimensionally measured tumour size) was observedafter 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal intervalof 7 weeks, patients whose disease did not progress received radiotherapy (RT) according toinstitutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered eitherwith a conventional fraction (1.8 Gy - 2.0 Gy once a day, 5 days per week for a total dose of 66 to70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a minimuminterfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for acceleratedregimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed followingchemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxiswith ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent.

The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the

TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 vs. 8.3 months respectively) with anoverall median follow up time of 33.7 months. Median overall survival was also significantly longer infavour of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with a28% risk reduction of mortality, p = 0.0128. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with inoperable locally advanced SCCHN(Intent-to-treat analysis)

Endpoint Docetaxel + Cis + 5-FU

Cis + 5-FUn = 177 n = 181

Median progression free survival (months) 11.4 8.3(95% CI) (10.1-14.0) (7.4-9.1)

Adjusted hazard ratio 0.70(95% CI) (0.55-0.89)

*p-value 0.0042

Median survival (months) 18.6 14.5(95% CI) (15.7-24.0) (11.6-18.7)

Hazard ratio 0.72(95% CI) (0.56-0.93)

**p-value 0.0128

Best overall response to chemotherapy (%) 67.8 53.6(95% CI) (60.4-74.6) (46.0-61.0)

***p-value 0.006

Best overall response to study treatment[chemotherapy +/- radiotherapy] (%) 72.3 58.6(95% CI) (65.1-78.8) (51.0-65.8)

***p-value 0.006

Median duration of response to chemotherapy  n = 128 n = 106radiotherapy (months) 15.7 11.7(95% CI) (13.4-24.6) (10.2-17.4)

Hazard ratio 0.72(95% CI) (0.52-0.99)

**p-value 0.0457

A hazard ratio of less than 1 favours docetaxel + cisplatin + 5-FU

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

**Logrank test

*** Chi-square test

Quality of life parameters

Patients treated with TPF experienced significantly less deterioration of their Global health scorecompared to those treated with PF (p = 0.01, using the EORTC QLQ-C30 scale).

Clinical benefit parameters

The performance status scale, for head and neck (PSS-HN) subscales designed to measureunderstandability of speech, ability to eat in public, and normalcy of diet, was significantly in favourof TPF as compared to PF.

Median time to first deterioration of WHO performance status was significantly longer in the TPF armcompared to PF. Pain intensity score improved during treatment in both groups indicating adequatepain management.

* Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of docetaxel in the induction treatment of patients with locally advancedsquamous cell carcinoma of the head and neck (SCCHN) was evaluated in a randomised, multicentreopen-label, phase III study (TAX324). In this study, 501 patients, with locally advanced SCCHN, anda WHO performance status of 0 or 1, were randomised to one of two arms. The study populationcomprised patients with technically unresectable disease, patients with low probability of surgical cureand patients aiming at organ preservation. The efficacy and safety evaluation solely addressed survivalendpoints and the success of organ preservation was not formally addressed. Patients on the docetaxelarm received docetaxel (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P) 100mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by the continuousintravenous infusion of 5-fluorouracil (F) 1000 mg/m²/day from day 1 to day 4. The cycles wererepeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receivechemoradiotherapy (CRT) as per protocol (TPF/CRT). Patients on the comparator arm receivedcisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous infusion on day 1 followed by thecontinuous intravenous infusion of 5-fluorouracil (F) 1000 mg/m²/day from day 1 to day 5. The cycleswere repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were toreceive CRT as per protocol (PF/CRT).

Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapywith a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 today 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hourintravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipmentusing once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytimefollowing completion of CRT. All patients on the docetaxel-containing arm of the study receivedprophylactic antibiotics. The primary efficacy endpoint in this study, overall survival (OS) wassignificantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to

PF (median OS: 70.6 versus 30.1 months respectively), with a 30% risk reduction in mortalitycompared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90) with an overallmedian follow up time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29% riskreduction of progression or death and a 22 month improvement in median PFS (35.5 months for TPFand 13.1 for PF). This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90;log-rank test p = 0.004. Efficacy results are presented in the table below:

Efficacy of docetaxel in the induction treatment of patients with locally advanced SCCHN(Intent-to-treat analysis)

Endpoint Docetaxel + Cis + 5-FU Cis + 5-FUn = 255 n = 246

Median overall survival (months) 70.6 30.1(95% CI) (49.0-NA) (20.9-51.5)

Hazard ratio: 0.70(95% CI) (0.54-0.90)

*p-value 0.0058

Median PFS (months) 35.5 13.1(95% CI) (19.3-NA) (10.6 - 20.2)

Hazard ratio: 0.71(95% CI) (0.56 - 0.90)

**p-value 0.004

Best overall response (CR + PR) to 71.8 64.2chemotherapy (%) (65.8-77.2) (57.9-70.2)(95% CI)

***p-value 0.070

Best overall response (CR + PR) to study 76.5 71.5treatment [chemotherapy (70.8-81.5) (65.5-77.1)+/- chemoradiotherapy] (%)(95%CI)

***p-value 0.209

A hazard ratio of less than 1 favours 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

The European Medicines Agency has waived the obligation to submit the results of studies with

Docetaxel Accord in all subsets of the paediatric population in breast cancer, non-small cell lungcancer, prostated cancer, gastric carcinoma and head and neck cancer, not including type II and III lessdifferentiated nasopharyngeal carcinoma (see section 4.2 for information on paediatric use).

The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of20-115 mg/m2 in phase I studies. The kinetic profile of docetaxel is dose independent and consistentwith a three-compartment pharmacokinetic model with half lives for the α, β and γ (terminal) phases of4 min, 36 min and between 11.1 h and 17.5 h, respectively, when sampled up to 24 hours. Anadditional study assessing the pharmacokinetics of docetaxel at similar doses (75 - 100 mg/m2) inpatients, but over a longer time interval (over 22 days) found a longer mean terminal elimination half-life between 91 and 120 hours. The late phase is due, in part, to a relatively slow efflux of docetaxelfrom the peripheral compartment.

Following the administration of a 100 mg/m2 dose given as a one-hour infusion a mean peak plasmalevel of 3.7 µg/ml was obtained with a corresponding AUC of 4.6 h.µg/ml. Mean values for total bodyclearance and steady-state volume of distribution were 21 l/h/m2 and 113 l, respectively. Interindividual variation in total body clearance was approximately 50%. Docetaxel is more than 95%bound to plasma proteins.

A study of 14C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated inboth the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butylester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% ofthe administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces isexcreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolitesand very low amounts of unchanged medicinal product.

Age and gender

A population pharmacokinetic analysis has been performed with docetaxel in 577 patients.

Pharmacokinetic parameters estimated by the model were very close to those estimated from phase Istudies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient.

In a small number of patients (n = 23) with clinical chemistry data suggestive of mild to moderate liverfunction impairment (ALT, AST ≥ 1.5 times the ULN associated with alkaline phosphatase ≥ 2.5 timesthe ULN), total clearance was lowered by 27% on average (see section 4.2).

Fluid retention

Docetaxel clearance was not modified in patients with mild to moderate fluid retention and there areno data available in patients with severe fluid retention.

Doxorubicin

When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasmalevels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicinand cyclophosphamide were not influenced by their co-administration.

Capecitabine

Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versashowed no effect by capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC) and noeffect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5’-DFUR.

Cisplatin

Clearance of docetaxel in combination therapy with cisplatin was similar to that observed followingmonotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion issimilar to that observed with cisplatin alone.

Cisplatin and 5-fluorouracil

The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solidtumours had no influence on the pharmacokinetics of each individual medicinal product.

Prednisone and dexamethasone

The effect of prednisone on the pharmacokinetics of docetaxel administered with standarddexamethasone premedication has been studied in 42 patients.

Prednisone

No effect of prednisone on the pharmacokinetics of docetaxel was observed.

The carcinogenic potential of docetaxel has not been studied.

Docetaxel has been shown to be genotoxic by an aneugenic mechanism in the in vitro micronucleusand chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in the mouse.

However, it did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay.

These results are consistent with the pharmacological activity of docetaxel.

Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel may impairmale fertility.

Polysorbate 80

Ethanol anhydrous

Citric acid anhydrous

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial2 years

After opening of the vial

Each vial is for single use and should be used immediately after opening. If not used immediately,in-use storage times and conditions are the responsibility of the user.

Once added to the infusion bag

From a microbiological point of view, dilution must take place in controlled and aseptic conditions andthe medicinal product should be used immediately. If not used immediately, in-use storage times andconditions are the responsibility of the user.

Once added as recommended into the infusion bag, the docetaxel infusion solution, if stored below25°C, is stable for 6 hours. It should be used within 6 hours (including the one hour infusionintravenous administration). The infusion solution must not be coupled to the infusion set for morethan 6 h at 25°C.

In addition, physical and chemical in-use stability of the infusion solution prepared as recommendedhas been demonstrated in non-PVC bags up to 48 hours when stored between 2°C to 8°C.

Do not store above 25°C.

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

For storage conditions of the diluted medicinal product, see section 6.3.

Docetaxel Accord 20 mg/1 ml concentrate for solution for infusion

Clear glass (type I) vial with fluorotec plus (ethylene tetrafluoroethylene film) rubber stopper andaluminium seal and an orange flip-off cap, containing 1 ml of concentrate.

Docetaxel Accord 80 mg/4 ml concentrate for solution for infusion

Clear glass (type I) vial with fluorotec plus (ethylene tetrafluoroethylene film) rubber stopper andaluminium seal and a red flip-off cap, containing 4 ml of concentrate.

Docetaxel Accord 160 mg/8 ml concentrate for solution for infusion

Clear glass (type I) vial with fluorotec plus (ethylene tetrafluoroethylene film) rubber stopper andaluminium seal and a red flip-off cap, containing 8 ml of concentrate.

Each box contains one vial.

Docetaxel is an antineoplastic agent and, as with other potentially toxic compounds, caution should beexercised when handling it and preparing Docetaxel Accord solutions. The use of gloves isrecommended.

If Docetaxel Accord concentrate or infusion solution should come into contact with skin, washimmediately and thoroughly with soap and water. If Docetaxel Accord concentrate or infusionsolution should come into contact with mucous membranes, wash immediately and thoroughly withwater.

Preparation for the intravenous administration

Preparation of the infusion solution

DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent)with this medicinal product which contains only 1 vial of concentrate. Docetaxel Accord 20 mg/1 mlconcentrate for solution for infusion requires NO prior dilution with a solvent and is ready to add tothe infusion solution.

Each vial is of single use and should be used immediately.

If the vials are stored under refrigeration, allow the required number of boxes of Docetaxel Accordconcentrate for solution for infusion to stand below 25°C for 5 minutes before use. More than one vialof Docetaxel Accord concentrate for solution for infusion may be necessary to obtain the requireddose for the patient. Aseptically withdraw the required amount of Docetaxel Accord concentrate forsolution for infusion using a calibrated syringe fitted with a 21G needle.

In Docetaxel Accord 20 mg/1 ml vial the concentration of docetaxel is 20 mg/ml.

The required volume of Docetaxel Accord concentrate for solution for infusion must be injected via asingle injection (one shot) into a 250 ml infusion bag containing either 5% glucose solution or sodiumchloride 9 mg/ml (0.9%) solution for infusion.

If a dose greater than 190 mg of docetaxel is required, use a larger volume of the infusion vehicle sothat a concentration of 0.74 mg/ml docetaxel is not exceeded.

Mix the infusion bag manually using a rocking motion.

The infusion bag solution should be used within 6 hours below 25°C including the one hour infusion tothe patient.

As with all parenteral products, Docetaxel Accord infusion solution should be visually inspected priorto use, solutions containing a precipitate should be discarded.

Docetaxel infusion solution is supersaturated and may therefore crystallize over time. If crystals appear,the solution must no longer be used and shall be discarded.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/12/769/001

EU/1/12/769/002

EU/1/12/769/003

Date of first authorisation: 22 May 2012

Date of latest renewal: 23rd February 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu