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• Docetaxel Seacross concentrate for solution for infusion SmPC
• Docetaxel Seacross concentrate for solution for infusion ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Docetaxel Seacross 20 mg/mlconcentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate contains 20 mg docetaxel anhydrous.

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

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

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

Excipients with known effect:

Each vial of 1 ml of concentrate contains 0.57 ml of ethanol 96% (0.46 g).

Each vial of 4 ml of concentrate contains 2.28 ml of ethanol 96% (1.83 g).

Each vial of 8 ml of concentrate contains 4.56 ml of ethanol 96% (3.66 g).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

The concentrate is a clear viscous, colourless to brownish-yellow sterile solution.

4. CLINICAL PARTICULARS

^{4.1 Therapeutic indications}

Breast cancer

Docetaxel Seacross in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with:

• operable node- positive breast cancer.

• operable node- negative breast cancer.

Forpatientswithoperablenode-negativebreastcancer,adjuvanttreatmentshouldberestrictedtopatients eligibletoreceivechemotherapyaccordingtointernationallyestablishedcriteriaforprimarytherapyofearly breastcancer(seesection5.1).

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

Docetaxel Seacross monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent.

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

Docetaxel Seacross in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.

Non-small cell lung cancer

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

Docetaxel Seacross in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not previously received chemotherapy for this condition.

Prostate cancer

Docetaxel Seacross in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer.

Gastric adenocarcinoma

Docetaxel Seacross in combination with cisplatin and 5‑fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for metastatic disease.

Head and neck cancer

Docetaxel Seacross in combination with cisplatin and 5‑fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck.

^{4.2 Posology and method of administration}

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

Recommended dose

For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see section 4.4). Prophylactic G‑CSF may be used to mitigate the risk of haematological toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.4).

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 recommended dose of docetaxel is 75 mg/m²administered 1‑hour after doxorubicin 50 mg/m²and cyclophosphamide 500 mg/m²every 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 dose of docetaxel is 100 mg/m²in monotherapy. In first-line treatment, docetaxel 75 mg/m² is given in combination therapy with doxorubicin(50 mg/m²).

In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m²every three weeks, with trastuzumab administered weekly. In the pivotal study the initial docetaxel infusion was started the day following the first dose of trastuzumab. The subsequent docetaxel doses were administered immediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab was well tolerated. For trastuzumab dose and administration, see trastuzumab summary of product characteristics.

In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m²every three weeks, combined with capecitabine at 1250 mg/m²twice daily (within 30 minutes after a meal) for 2 weeks followed by a 1‑week rest period. For capecitabine dose calculation according to body surface area, see capecitabine summary of product characteristics.

Non-small cell lung cancer

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

Prostate cancer

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

Gastric adenocarcinoma

The recommended dose of docetaxel is 75 mg/m²as a 1-hour infusion, followed by cisplatin 75 mg/m², as a 1- to 3-hour infusion (both on day 1 only), followed by 5‑fluorouracil 750 mg/m²per day 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 and appropriate hydration for cisplatin administration. Prophylactic G‑CSF should be used to mitigate the risk 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 after cisplatin administration). Prophylactic G‑CSF may be used to mitigate the risk of haematological toxicities. All patients on the docetaxel-containing arm of the TAX 323 and TAX 324 studies, received prophylactic antibiotics.

For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m²as a 1 hour infusion followed by cisplatin 75 mg/m²over 1 hour, on day one, followed by 5‑fluorouracil as a continuous infusion at 750 mg/m²per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.

For the induction treatment of patients with locally advanced (technically unresectable, low probability of surgical cure, and aiming at organ preservation) squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m²as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m² administered as a 30-minute to 3-hour infusion, 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 should receive chemoradiotherapy.

For cisplatin and 5‑fluorouracil dose modifications, see the corresponding summary of product characteristics.

Dose adjustments during treatment

General

Docetaxel should be administered when the neutrophil count is ³ 1,500 cells/mm³.

In patients who experienced either febrile neutropenia, neutrophil count < 500 cells/mm³for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 100 mg/m²to 75 mg/m²and/or from 75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.

Adjuvant therapy for breast cancer

Primary G-CSFprophylaxisshouldbeconsideredinpatientswhoreceivedocetaxel,doxorubicinand cyclophosphamide (TAC)adjuvanttherapyforbreastcancer.Patientswhoexperiencefebrile

neutropeniaand/orneutropenicinfectionshouldhavetheirdocetaxeldosereducedto60 mg/m² inall subsequentcycles(seesections4.4and4.8).PatientswhoexperienceGrade3or4stomatitisshouldhave their dosedecreasedto 60mg/m².

In combination with cisplatin

For patients who are dosed initially at docetaxel 75 mg/m²in combination with cisplatin and whose nadir of platelet count during the previous course of therapy is < 25,000 cells/mm³, orin patients who experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxel dose in subsequent cycles should be reduced to 65 mg/m². For cisplatin dose adjustments, see the corresponding summary of product characteristics.

In combination with capecitabine

• For patients developing the first appearance of Grade 2 toxicity, which persists at the time of the next docetaxel/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at 100% 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 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 of complicated 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 should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level > 1,500 cells/mm³and platelets recover to a level > 100,000 cells/mm³. Discontinue treatment if these toxicities persist (see section 4.4).

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

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

In the pivotal SCCHN studiespatients who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G‑CSF to provide prophylactic coverage (eg, day 6‑15) in all subsequent cycles.

Special populations

Patients with hepatic impairment

Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who have both elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel 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, no dose-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 gastric adenocarcinoma, the pivotal clinical studyexcluded patients with ALT and/orAST > 1.5 × ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin > 1 x ULN; for these patients,no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.

Paediatric population

Thesafetyandefficacyofdocetaxelinnasopharyngealcarcinomainchildrenaged1monthtolessthan 18yearshavenotyetbeenestablished.

Thereisnorelevantuseofdocetaxelinthepaediatricpopulationintheindicationsbreastcancer,non-small cell lungcancer,prostatecancer,gastriccarcinomaandheadandneckcancer,notincludingtype IIandIIIless differentiatednasopharyngealcarcinoma.

Elderly patients

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

^{4.3 Contraindications}

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

Docetaxel must not be used in patients with baseline neutrophil count of < 1,500 cells/mm³.

Docetaxel must not be used in patients with severe liver impairment since there is no data available (see sections 4.2 and 4.4).

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

^{4.4 Special warnings and precautions for use}

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

Haematology

Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pre‑treated patients. Frequent monitoring of complete blood counts should be conducted on all patients receiving docetaxel. Patients should be retreated with docetaxel when neutrophils recover to a level ³ 1,500 cells/mm3 (see section 4.2).

In the case of severe neutropenia (< 500 cells/mm³for seven days or more) during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are recommended (see section 4.2).

In patients treated with docetaxel in combination with cisplatin and 5‑fluorouracil (TCF), febrile neutropenia 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 of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored (see sections 4.2 and 4.8).

Inpatientstreatedwithdocetaxelincombination withdoxorubicinandcyclophosphamide(TAC),febrile neutropeniaand/orneutropenicinfectionoccurredat lowerrateswhenpatientsreceived

primaryG-CSFprophylaxis.PrimaryG-CSFprophylaxisshouldbeconsideredinpatientswhoreceiveadjuvant therapywithTACforbreastcancerto mitigatetheriskofcomplicated neutropenia(febrileneutropenia, prolonged neutropeniaorneutropenicinfection).PatientsreceivingTACshouldbe

closelymonitored(seesections4.2and4.8).

Hypersensitivity reactions

Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel.

Cutaneous reactions

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

Fluid retention

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

Respiratory disorders

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

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

Patients with liver impairment

In patients treated with docetaxel at 100 mg/m²as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in those patients with elevated liver function test (LFTs) is 75 mg/m²and LFTs should be measured at baseline 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 concurrent with serum alkaline phosphatase levels > 6 times the ULN, no dose-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 gastric adenocarcinoma, the pivotal clinical studyexcluded patients with ALT and/orAST > 1.5 × ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin > 1 x ULN; for these patients,no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.

Patients with renal impairment

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).

Cardiac toxicity

Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be 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, they should undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For more details see summary of product characteristics of trastuzumab.

Eye disorders

Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, docetaxel treatment should be discontinued and appropriate treatment initiated (see section 4.8).

Others

Contraceptive measures must be taken by both men and women during treatment and for men at least 6 months after cessation of therapy (see section 4.6).

The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) 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 or infection), 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 treated promptly.

Congestive heart failure (CHF)

Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow 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 section 4.8 and 5.1)

Leukaemia

In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow‑up.

Patients with 4+ nodes

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

Older people

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

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

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 cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse events was higher in the elderly patients compared to younger patients. The incidence of the following 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.

Elderly patients treated with TCF should be closely monitored.

Excipients

This medicinal product contains approximately 55 vol % ethanol (alcohol), i.e. up to 0.457 g (0.57 ml) ethanol 96 % per 1 ml vial, equivalent to 12 ml of beer or 5 ml wine per 1 ml vial, 1.828 g (2.28 ml) ethanol 96 % per 1 ml vial, equivalent to 48 ml of beer or 20 ml wine per 4 ml vial, or 3.66g (4.56 ml) ethanol 96 % per vial of 8 ml fill volume, equivalent to 96 ml beer or 40ml wine per 8 ml vial.

Harmful for those suffering from alcoholism.

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

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

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

^{4.5 Interaction with other medicinal products and other forms of interaction}

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

In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel adverse reactions may increase, 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 a dose-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 with the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in docetaxel clearance by 49%.

Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic prostate 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 vivointeraction of docetaxel with concomitantly administered medicinal product has not been investigated formally, in vitrointeractions with tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of digitoxin.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co‑administration. Limited data from a single uncontrolled study were suggestive of an interaction between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was about 50% higher than values previously reported for carboplatin monotherapy.

^{4.6 Fertility, pregnancy and lactation}

Pregnancy

There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.

Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.

Breast-feeding

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 be discontinued for the duration of docetaxel therapy.

Contraception in males and females

An effective method of contraception should be used during treatment.

Fertility

In non-clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3). Therefore, men being treated with docetaxel are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment.

^{4.7 Effects on ability to drive and use machines}

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

^{4.8 Undesirable effects}

Summary of the safety profile for all indications

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

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

• 258 patients who received docetaxel in combination with doxorubicin.

• 406 patients who received docetaxel in combination with cisplatin.

• 92 patients treated with docetaxel in combination with trastuzumab.

• 255 patients who received docetaxel in combination with capecitabine.

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

• 1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received docetaxel in combination with doxorubicin and cyclophosphamide (clinically important treatment related adverse events are presented).

• 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patients in the phase 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 cisplatin and 5‑fluorouracil (clinically important treatment related adverse events are presented).

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	≥ 1/1000 to < 1/100)
rare	(≥ 1/10,000 to < 1/1000)
very rare	(< 1/10000)
not known	(cannot be estimated from available data)

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 was reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe neutropenia (< 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 in combination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the trastuzumab 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 (see capecitabine summary of product characteristics).

The following adverse reactions are frequently observed with docetaxel:

Immune system disorders

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

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paresthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated 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 to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions

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 lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

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

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m²single agent

Blood and lymphatic system disorders

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

Nervous system disorders

Reversibility data are available among 35.3% of patients who developed neurotoxicity following docetaxel treatment at 100 mg/m² as single agent. The events were spontaneously reversible within 3 months.

Skin and subcutaneous tissue disorders

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

General disorders and administration site conditions

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

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

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions
Infections and infestations	Infections (G3/4: 5%)
Blood and lymphatic system disorders	Neutropenia (G4: 54.2%); Anaemia (G3/4: 10.8%); Thrombocytopenia (G4: 1.7%)	Febrile neutropenia
Immune system disorders		Hypersensitivity (no severe)
Metabolism and nutrition disorders	Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3/4: 0.8%)	Peripheral motor neuropathy (G3/4: 2.5%)
Cardiac disorders		Arrhythmia (no severe)
Vascular disorders		Hypotension
Gastrointestinal disorders	Nausea (G3/4: 3.3%); Stomatitis (G3/4: 1.7%); Vomiting (G3/4: 0.8%); Diarrhea (G3/4: 1.7%)	Constipation
Skin and subcutaneous tissue disorders	Alopecia; Skin reaction (G3/4: 0.8%)	Nail disorders (severe 0.8%)
Musculoskeletal and connective tissue disorders		Myalgia
General disorders and administration site conditions	Asthenia (severe 12.4%); Fluid retention (severe 0.8%); Pain
Investigations		G3/4 Blood bilirubin increased (<2%)

Tabulated list of adverse reactions in breast cancer for docetaxel 75mg/m² in combination with doxorubicin:

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 7.8%)
Blood and the lymphatic system disorders	Neutropenia (G4: 91.7%); Anaemia (G3/4: 9.4%); Febrile neutropenia; Thrombocytopenia (G4: 0.8 %)
Immune system disorders		Hypersensitivity (G3/4: 1.2 %)
Metabolism and nutrition disorders		Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3: 0.4%)	Peripheral motor neuropathy (G3/4: 0.4%)
Cardiac disorders		Cardiac failure; Arrhythmia (no severe)
Vascular disorders			Hypotension
Gastrointestinal disorders	Nausea (G3/4: 5%); Stomatitis (G3/4: 7.8%); Diarrhoea (G3/4: 6.2%); Vomiting (G3/4: 5%); Constipation
Skin and subcutaneous tissue disorders	Alopecia; Nail disorders (severe 0.4%); Skin reaction (no severe)
Musculoskeletal and connective tissue disorders		Myalgia
General disorders and administration site conditions	Asthenia (severe 8.1%); Fluid retention (severe 1.2%); Pain	Infusion site reaction
Investigations		G3/4 Blood bilirubin increased (< 2.5 %); G3/4 Blood alkaline phosphatase increased (< 2.5 %)	G3/4 AST increased (<1 %); G3/4 ALT increased (< 1 %)

Tabulated list of adverse reactions in non-small cell lungcancer for docetaxel 75 mg/m² in combination with cisplatin

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

Description of selected adverse reactions in breast cancer for docetaxel 100 mg/m²in combination with trastuzumab

Blood and lymphatic system disorders

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/m²is known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).

Cardiac disorders

Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus trastuzumab 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 arm alone.

Tabulated list of adverse reactions in breast cancer for docetaxel 75mg/m² in combination with capecitabine:

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions
Infections and infestations		Oral candidiasis (G3/4: <1%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 63%); Anaemia (G3/4: 10%)	Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition disorders	Anorexia (G3/4: 1%); Decreased appetite	Dehydration (G3/4: 2%);
Nervous system disorders	Dysgeusia (G3/4: <1%); Paraesthesia (G3/4: <1%)	Dizziness; Headache (G3/4: <1%); Neuropathy peripheral
Eye disorders	Lacrimation increased
Respiratory, thoracic and mediastinal disorders	Pharyngolaryngeal pain (G3/4: 2%)	Dyspnoea (G3/4: 1%); Cough (G3/4: <1%); Epistaxis (G3/4: <1%)
Gastrointestinal disorders	Stomatitis (G3/4: 18%); Diarrhoea (G3/4: 14%); Nausea (G3/4: 6%); Vomiting (G3/4: 4%); Constipation (G3/4: 1%); Abdominal pain (G3/4: 2%); Dyspepsia	Abdominal pain upper; Dry mouth
Skin and subcutaneous tissue disorders	Hand-foot syndrome (G3/4: 24%) Alopecia (G3/4: 6%); Nail disorders (G3/4: 2%)	Dermatitis; Rash erythematous (G3/4: <1%); Nail discolouration; Onycholysis (G3/4: 1%)
Musculoskeletal and connective tissue disorders	Myalgia (G3/4: 2%); Arthralgia (G3/4: 1%)	Pain in extremity (G3/4: <1%); Back pain (G3/4: 1%);
General disorders and administration site conditions	Asthenia (G3/4: 3%); Pyrexia (G3/4: 1%); Fatigue/ weakness (G3/4: 5%); Oedema peripheral (G3/4: 1%);	Lethargy; Pain
Investigations		Weight decreased; G3/4 Blood bilirubin increased (9%)

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

Tabulated list of adverse reactions in breast cancer for adjuvant therapywithdocetaxel 75 mg/m²in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX316) andnode-negative(GEICAM 9805)breast cancer -pooleddata

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

Nervous system disorders

Peripheral sensory neuropathy was observed to be ongoing during follow‑up in 10 patients out of the 84 patients with peripheral sensory neuropathy at the end of the chemotherapy in the node positive breast cancer study (TAX316)

Cardiac disorders

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

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed congestive heart failure during the follow-up period. One patient in TAC arm died because of dilated cardiomyopathy.

Skin and subcutaneous tissue disorders

In study TAX 316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients and 645 of 736 FAC patients

At the end of the follow-up period (actual median follow-up time of 96 months), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study, alopecia persisted into the follow-up period (median follow-up time of 10 years and 5 months) and 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 in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm.

Reproductive system and breast disorders

Amenorrhoea was observed to be ongoing during follow‑up in 121 patients out of the 202 patients with amenorrhoea at the end of the chemotherapy in study TAX316.

In GEICAM 9805 study, amenorrhoea persisted into the follow-up period (median follow-up time of 10 years and 5 months) and was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm.

General disorders and administration site conditions

In study TAX316, peripheral oedema was observed to be ongoing in 19 patients out of the 119 patients with peripheral oedema in the TAC arm and 4 patients out of the 23 patients with peripheral oedema in the FAC arm.

In study GEICAM 9805, lymphoedema was observed to be ongoing in 4 of the 5 patients in TAC arm and in 1 of the 2 patients in FAC arm at the end of the chemotherapy, and did not resolve during the follow-up period (median follow-up time of 10 years and 5 months). Asthenia persisted into the follow-up period (median follow-up time of 10 years and 5 months) and was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm.

Acute leukaemia / Myelodysplasticsyndrome.

After 10 years of follow up in study TAX316, acute leukaemia was reported in 4 of 744 TAC patients and in 1 of 736 FAC patients. Myelodysplastic syndrome was reported in 2 of 744 TAC patients and in 1 of 736 FAC patients.

After 10 years of follow-upin GEICAM 9805 study,acuteleukaemiaoccurredin1of532(0.2%)patientsin TAC arm. Nocaseswerereported inpatients in FAC arm.Nopatientwasdiagnosed withmyelodysplastic syndromeineithertreatmentgroups.

Neutropenic complications

TablebelowshowsthattheincidenceofGrade4 neutropenia,febrileneutropeniaandneutropenicinfection wasdecreasedinpatientswhoreceivedprimary G-CSFprophylaxisafterit wasmademandatoryintheTAC arm— GEICAMstudy.

Neutropenic complications in patients receiving TAC with or withoutprimaryG-CSF prophylaxis

_{(GEICAM 9805)}

	Without primary G-CSF prophylaxis (n = 111) n (%)	With primary G-CSF prophylaxis (n = 421) n (%)
Neutropenia (Grade 4)	104 (93.7)	135 (32.1)
Febrile neutropenia	28 (25.2)	23 (5.5)
Neutropenic infection	14 (12.6)	21 (5.0)
Neutropenic infection (Grade 3-4)	2 (1.8)	5 (1.2)

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

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions
Infections and infestations	Neutropenic infection; Infection (G3/4: 11.7%)
Blood and lymphatic system disorders	Anaemia (G3/4: 20.9%); Neutropenia (G3/4: 83.2%); Thrombocytopenia (G3/4: 8.8%); Febrile neutropenia
Immune system disorders	Hypersensitivity (G3/4: 1.7%)
Metabolism and nutrition disorders	Anorexia (G3/4: 11.7%)
Nervous system disorders	Peripheral sensory neuropathy (G3/4: 8.7%)	Dizziness (G3/4: 2.3%); Peripheral motor neuropathy (G3/4: 1.3%)
Eye disorders		Lacrimation increased (G3/4: 0%)
Ear and labyrinth disorders		Hearing impaired (G3/4: 0%)
Cardiac disorders		Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders	Diarrhoea (G3/4: 19.7%); Nausea (G3/4: 16%); Stomatitis (G3/4: 23.7%); Vomiting (G3/4: 14.3%)	Constipation (G3/4: 1.0%); Gastrointestinal pain (G3/4: 1.0%); Oesophagitis/dysphagia/odynophagia (G3/4: 0.7%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 4.0%)	Rash pruritus (G3/4: 0.7%); Nail disorders (G3/4: 0.7%); Skin exfoliation (G3/4: 0%)
General disorders and administration site conditions	Lethargy (G3/4: 19.0%); Fever (G3/4: 2.3%); Fluid retention (severe/life-threatening: 1%)

Description of selected adverse reactions in gastric adenocarcinoma cancer for docetaxel 75 mg/m²in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders

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% of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients when patients received prophylactic G‑CSF, in 15.6% and 12.9% of patients without prophylactic G‑CSF (see section 4.2).

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

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 6.3%); Neutropenic infection
Neoplasms benign, malignant and unspecified (incl cysts and polyps)		Cancer pain (G3/4: 0.6%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 76.3%); Anaemia (G3/4: 9.2%); Thrombocytopenia (G3/4: 5.2%)	Febrile neutropenia
Immune system disorders		Hypersensitivity (no severe)
Metabolism and nutrition disorders	Anorexia (G3/4: 0.6%)
Nervous system disorders	Dysgeusia/Parosmia; Peripheral sensory neuropathy (G3/4: 0.6%)	Dizziness
Eye disorders		Lacrimation increased; Conjunctivitis
Ear and labyrinth disorders		Hearing impaired
Cardiac disorders		Myocardial ischemia (G3/4:1.7%)	Arrhythmia (G3/4: 0.6%)
Vascular disorders		Venous disorder (G3/4: 0.6%)
Gastrointestinal disorders	Nausea (G3/4: 0.6%); Stomatitis (G3/4: 4.0%); Diarrhoea (G3/4: 2.9%); Vomiting (G3/4: 0.6%)	Constipation; Esophagitis/dysphagia/ odynophagia (G3/4: 0.6%); Abdominal pain; Dyspepsia; Gastrointestinal haemorrhage (G3/4: 0.6%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 10.9%)	Rash pruritic; Dry skin; Skin exfoliative (G3/4: 0.6%)
Musculoskeletal and connective tissue disorders		Myalgia (G3/4: 0.6%)
General disorders and administration site conditions	Lethargy (G3/4: 3.4%); Pyrexia (G3/4: 0.6%); Fluid retention; Oedema
Investigations		Weight increased

MedDRA system organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and infestations	Infection (G3/4: 3.6%)	Neutropenic infection
Neoplasms benign, malignant and unspecified (incl cysts and polyps)		Cancer pain (G3/4: 1.2%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 83.5%); Anaemia (G3/4: 12.4%); Thrombocytopenia (G3/4: 4.0%); Febrile neutropenia
Immune system disorders			Hypersensitivity
Metabolism and nutrition disorders	Anorexia (G3/4: 12.0%)
Nervous system disorders	Dysgeusia/Parosmia (G3/4: 0.4%); Peripheral sensory neuropathy (G3/4: 1.2%)	Dizziness (G3/4: 2.0%); Peripheral motor neuropathy (G3/4: 0.4%)
Eye disorders		Lacrimation increased	Conjunctivitis
Ear and labyrinth disorders	Hearing impaired (G3/4: 1.2%)
Cardiac disorders		Arrhythmia (G3/4: 2.0%)	Ischemia myocardial
Vascular disorders			Venous disorder
Gastrointestinal disorders	Nausea (G3/4: 13.9%); Stomatitis (G3/4: 20.7%); Vomiting (G3/4: 8.4%); Diarrhoea (G3/4: 6.8%); Esophagitis/dysphagia/ odynophagia (G3/4: 12.0%); Constipation (G3/4: 0.4%)	Dyspepsia (G3/4: 0.8%); Gastrointestinal pain (G3/4: 1.2%); Gastrointestinal haemorrhage (G3/4: 0.4%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 4.0%); Rash pruritic	Dry skin ; Desquamation
Musculoskeletal, connective tissue bone disorders		Myalgia (G3/4: 0.4%)
General disorders and administration site conditions	Lethargy (G3/4: 4.0%); Pyrexia (G3/4: 3.6%); Fluid retention (G3/4: 1.2%); Oedema (G3/4: 1.2%)
Investigations	Weight decreased		Weight increased

Post-marketing experience

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

Cases of acute myeloid leukaemiaand myelodysplastic syndromehave been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.

Blood and lymphatic system disorders

Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported.

Immune system disorders

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

Nervous system disorders

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

Eye disorders

Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been rarely reported. Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel.

Ear and labyrinth disorders

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

Cardiac disorders

Rare cases of myocardial infarction have been reported.

Vascular disorders

Venous thromboembolic events have rarely been reported.

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

Rare occurrences of dehydration as a consequence of gastrointestinal events, gastrointestinal perforation, colitis ischaemic, colitis and neutropenic enterocolitis have been reported. Rare cases of ileus and intestinal obstruction have been reported.

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some cases concomitant factors may have contributed to the development of these effects. Sclerodermal-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of persisting alopecia have been reported.

Renal and urinary disorders

Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastrointestinal disorders.

General disorders and administration site conditions

Radiation recall phenomena have rarely been reported.

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

Metabolism and nutrition disorders

Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

^{4.9 Overdose}

There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In cases of overdose, exacerbation of adverse events may be expected. The primary anticipated complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

5. PHARMACOLOGICAL PROPERTIES

^{5.1 Pharmacodynamic properties}

Pharmacotherapeutic group: Taxanes, ATC Code: L01CD02

Mechanism of action

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

Docetaxel has been shown in vitroto disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions.

Pharmacodynamic effects

Docetaxel was found to be cytotoxic in vitroagainst various murine and human tumour cell lines and against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular concentrations with a long cell residence time. In addition, docetaxel was found to be active on some but not all cell lines over expressing the p‑glycoprotein which is encoded by the multidrug resistance gene. In vivo, docetaxel is schedule independent and has a broad spectrum of experimental antitumour activity against advanced murine and human grafted tumours.

Clinical efficacy and safety

Breast cancer

Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy

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

Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant treatment of patients with operable node-positive breast cancer and KPS  80%, between 18 and 70 years of age. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m²administered 1-hour after doxorubicin 50 mg/m²and cyclophosphamide 500 mg/m²(TAC arm), or doxorubicin 50 mg/m²followed by fluorouracil 500 mg/m²and cyclosphosphamide 500 mg/m²(FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products were given as intravenous bolus on day one. G‑CSF was administered as secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection). Patients on the TAC arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.

Two interim analyses and one final analysis were performed. The first interim analysis was planned 3 years after the date when half of study enrolment was done. The second interim analysis was done after 400 DFS events had been recorded overall, which led to a median follow up of 55 months. The final analysis was performed when all patients had reached their 10-year follow-up visit (unless they had a DFS event or were lost to follow-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 longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of relapses at 10 years was reduced in patients receiving TAC compared to those who received 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 the final analysis.

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

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

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

Patients with operable node-negativebreast cancereligibleto receive chemotherapy (GEICAM 9805)

Data fromamulticenteropenlabelrandomizedtrial supporttheuseofdocetaxelfortheadjuvant _{treatmentofpatientswithoperablenode-negativebreastcancereligibletoreceivechemotherapy.}

1060patientswererandomizedtoreceiveeitherdocetaxel 75mg/m²administered 1-hourafterdoxorubicin 50 mg/m²andcyclophosphamide 500mg/m²(539patientsinTACarm),ordoxorubicin 50 mg/m²followedbyfluorouracil500mg/m²andcyclosphosphamide 500mg/m²(521patientsin FACarm),asadjuvanttreatmentofoperablenode-negativebreastcancerpatientswithhighriskofrelapse accordingto 1998St.Gallencriteria(tumoursize>2cmand/ornegativeERandPRand/orhighhistological/nucleargrade(grade2to3)and/orage<35years).Bothregimenswereadministeredonceevery3weeksfor6cycles.Docetaxel wasadministeredasa 1-hourinfusion,all other