Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion

Each single dose vial contains docetaxel 20 mg/ml

Each 1 ml single dose vial contains 20 mg docetaxel

Each 4 ml single dose vial contains 80 mg docetaxel

Each 7 ml single dose vial contains 140 mg docetaxel

Excipient: Ethanol absolute 400 mg/ml

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion

The concentrate is a clear, pale yellow solution.

Breast cancer

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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

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

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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 Actavis 20mg/ml Concentrate for Solution for Infusion 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 Actavis 20mg/ml Concentrate for Solution for Infusion 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 Actavis 20mg/ml Concentrate for Solution for Infusion 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 Actavis 20mg/ml Concentrate for Solution for Infusion is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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 Actavis 20mg/ml Concentrate for Solution for Infusion in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer.

Gastric Adenocarcinoma

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion 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 Actavis 20mg/ml Concentrate for Solution for Infusion 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.

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 dosage

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. 8mg 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 hematological toxicities.

For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premedication regimen is oral dexamethasone 8mg, 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 75mg/m² administered 1-hour after doxorubicin 50mg/m² and cyclophosphamide 500mg/m² every 3 weeks for 6 cycles (TAC regiment) (see also Dosage adjustments during treatment).

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

In combination with trastuzumab the recommended dose of docetaxel is 100mg/m² every 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 dosage and administration, see trastuzumab summary of product characteristics.

In combination with capecitabine, the recommended dose of docetaxel is 75mg/m² every three weeks, combined with capecitabine at 1250mg/m² twice daily (within 30 minutes after a meal) for 2 weeks followed by 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 75mg/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 75mg/m² as a single agent.

Prostate cancer

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

Gastric adenocarcinoma

The recommended dose of docetaxel is 75mg/m² as a 1 hour infusion, followed by cisplatin 75mg/m², as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750mg/m² per 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 Dosage 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.

- Induction chemotherapy followed by radiotherapy (TAX 323)

For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75mg/m² as a 1 hour infusion followed by cisplatin 75mg/m² over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750mg/m² per day for five days. This regimen is administered every 3 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, 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 75mg/m² as a 1 hour intravenous infusion on day 1, followed by cisplatin 100mg/m² administered as a 30-minute to 3 hour infusion, followed by 5-fluorouracil 1000mg/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 1,500cells/mm³. In patients who experienced either febrile neutropenia, neutrophil < 500cells/mm³ for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 100mg/m² to 75mg/m² and/or from 75 to 60mg/m². If the patient continues to experience these reactions at 60mg/m², the treatment should be discontinued.

Adjuvant therapy for breast cancer

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

In combination with cisplatin

For patients who are dosed initially at docetaxel 75mg/m² in combination with cisplatin and whose nadir of platelet count during the previous course of therapy is < 25,000cells/mm³, or in patients who experience febrile neutropenia, or in patients with serious non-hematologic toxicities, the docetaxel dosage in subsequent cycles should be reduced to 65mg/m². For cisplatin dosage adjustments, see manufacturer's 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 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 a Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1, then resume treatment with docetaxel 55mg/m².

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

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 60mg/m². If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45mg/m². In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60mg/m². Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level > 1,500cells/mm³ and platelets recover to a level > 100,000cells/mm³. Discontinue treatment if these toxicities persist. (See section 4.4).

Recommended dose modifications for gastrointestinal 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 studies patients 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 100mg/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 trial excluded patients with ALT and/or AST > 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.

This medicinal product contains 400 mg ethanol per ml concentrate. This has to be taken into account in high-risk groups such as patients with liver disease.

Paediatric population

The safety and efficacy of docetaxel in nasopharyngeal carcinoma in children aged 1 month to less than 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 including type II and III less differentiated nasopharyngeal carcinoma.

Elderly

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)

Hypersensitivity to the active substance or to any of the excipients.

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 as dexamethasone 16mg per day (e.g. 8mg 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 8mg, 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 1,500cells/mm³ (see section 4.2).

In the case of severe neutropenia (< 500cells/mm³ for 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).

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

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 localized 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.

Patients with liver impairment

In patients treated with docetaxel at 100mg/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 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 75mg/m² and 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 study excluded patients with ALT and/or AST > 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). Since Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion contains ethanol (400mg ethanol per ml concentrate), consideration should be given to possible central nervous system and other effects.

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.

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).

Ethanol

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion contains 400mg ethanol per ml concentrate. This may be harmful in patients suffering from alcoholism and should also be taken into consideration in children and high-risk groups such as patients with liver disease or other diseases affecting the central nervous system (e.g. epilepsy).

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

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

Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow up period.

Leuakemia

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

Patients with 4+ nodes

The benefit/risk ratio for TAC in patients with 4+ nodes was not defined fully at the interim analysis (see section 5.1).

Elderly

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 edema 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.

In vitro studies 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, terfenadine, ketoconazole, erythromycin and troleandomycin. 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.

Docetaxel is highly protein bound (> 95%). Although the possible in vivo interaction of docetaxel with concomitantly administered medication has not been investigated formally, in vitro interactions 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 coadministration. 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.

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 should be administered with caution in patients concomitantly receiving potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, azole antifungals like ketoconazole or itraconazole). A drug interaction study performed in patients receiving ketoconazole and docetaxel showed that the clearance of docetaxel was reduced by half by ketoconazole, probably because the metabolism of docetaxel involves CYP3A4 as a major (single) metabolic pathway. Reduced tolerance of docetaxel may occur, even at lower doses.

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion contains 400 mg ethanol per ml concentrate. In higher doses (7.5 ml concentrate (150 mg) contains 3 g ethanol) the amount of alcohol may alter the effects of other medicines.

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 potential/contraception:

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

An effective method of contraception should be used during treatment.

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.

Lactation:

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.

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

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion contains 400 mg ethanol per ml concentrate. In higher doses (7.5 ml concentrate (150 mg docetaxel) contains 3 g ethanol) the amount of alcohol may impair the ability to drive or use machines.

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 100mg/m² and 75mg/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; grade3-4 = G3/4; grade 4 = G4) the COSTART and the MEDRA terms. Frequencies are defined as: very common ( 1/10), common (1/100 to <1/10), uncommon (1/1000 to <1/100), rare ( 1/10000 to < 1/1000), very rare (<1/10000), not known (cannot be estimated from the 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 (< 500cells/mm³) was 7 days), anemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and 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:

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).

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).

Docetaxel 100 mg/m² single 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 100mg/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 1,000mg/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: 818.9mg/m²) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7mg/m²); however, it has been reported in some patients during the early courses of therapy.

Docetaxel 75mg/m² single agent:

Docetaxel 75mg/m² in combination with doxorubicin:

Docetaxel 75mg/m² in combination with cisplatin:

Docetaxel 100mg/m² in combination with trastuzumab:

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.

Blood and the 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 100mg/m² is 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).

Docetaxel 75mg/m² in combination with capecitabine:

Docetaxel 75mg/m² in combination with prednisone or prednisolone:

Advuvant therapy with docetaxel 75mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX316) and node negative (GEICAM9805) breast cancer – pooled data:

Cardiac disorders

Congestive Heart Failure (CHF) has also been reported in 18 of 1267 patients during the follow-up period. In the node positive study (TAC316). One patient in each treatment arm died due to cardiac failure.

Nervous system disorders

Peripheral sensory neuropathy was observed to be ongoing during follow-up in 12 patients out of the 83 patients with peripheral sensory neuropathy at the end of the chemotherapy.

Skin and subcutaneous tissue disorders

Alopecia was observed to be ongoing during follow-up in 25 patients out of the 736 patients with alopecia at the end of the chemotherapy.

General disorders and administration site condition

Peripheral oedema peripheral was observed to be ongoing during follow-up in 18 patients out of the 112 patients with peripheral oedema at the end of the chemotherapy in study TAX 316, whereas lymphoedema was observed to be ongoing in 4 of 5 patients with lymphoedema at the end of the chemotherapy in the study GEICAM 9805.

Reproductive system and breast disorders

Amenorrhoea was observed to be ongoing during follow-up time in 140 patients out of the 251 patients with amenorrhoea at the end of the chemotherapy.

Acute leukaemia / Myelodysplastic syndrome

At a median follow-up time of 77 months, acute leukaemia occurred in 1 of 532 (0.2%) patients who received docetaxel, doxorubicin and cyclophosphamide in the GEICAM 9805 study. No cases were reported in patients who received fluorouracil, doxorubicin and cyclophosphamide. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

Table below shows that the incidence of Grade 4 neutropenia, febrile nautropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis after it was made mandatory in the TAC arm – GEICAM study.

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

Docetaxel 75mg/m² in combination with cisplatin and 5-fluorouracil for gastric adenocarcinoma cancer:

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).

Docetaxel 75mg/m² in combination with cisplatin and 5-fluorouracil for Head and Neck cancer:

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

Post-Marketing Experience:

Cardiac disorders

Rare cases of myocardial infarction have been reported.

Blood and the lymphatic system disorders

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

Ear and labyrinth disorders

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

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome, interstitial pneumonia and pulmonary fibrosis 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.

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.

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

Very rare cases of acute myeloid leukaemia and myelodysplastic syndrome have been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.

Vascular disorders

Venous thromboembolic events have rarely been reported.

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

Immune system disorders

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

Hepato-biliary disorders

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

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.

Pharmaco-therapeutic group: Antineoplastic agents, ATC Code: L01CD 02

Preclinical data

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 vitro to disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions.

Docetaxel was found to be cytotoxic in vitro against 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 data

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/m² administered 1-hour after doxorubicin 50mg/m² and cyclophosphamide 500mg/m² (TAC arm), or doxorubicin 50mg/m² followed by fluorouracil 500mg/m² and cyclosphosphamide 500mg/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.

An interim analysis was performed with a median follow up of 55 months. Significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of relapses at 5 years was reduced in patients receiving TAC compared to those who received FAC (25% versus 32%, respectively) i.e. an absolute risk reduction by 7% (p=0.001). Overall survival at 5 years was also significantly increased with TAC compared to FAC (87% versus 81%, respectively) i.e. an absolute reduction of the risk of death by 6% (p=0.008). 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

The beneficial effect of TAC was not proven in patients with 4 and more positive nodes (37% of the population) at the interim analysis stage. The effect appears to be less pronounced than in patients with 1-3 positive nodes. The benefit/risk ratio was not defined fully in patients with 4 and more positive nodes at this analysis stage.

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

Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant treatment of patients with operable node-negative breast cancer eligible to receive chemotherapy. 1060 patients were randomized to receive either docetaxel 75mg/m² administered 1-hour after doxorubicin 50mg/m² and cyclophosphamide 500mg/m² (539 patients in TAC arm), or doxorubicin 50mg/m² followed by fluorouracil 500mg/m² and cyclosphosphamide 500mg/m² (521 patients in FAC arm), as adjuvant treatment of operable node-negative breast cancer patients with high risk of relapse according to 1998 St. Gallen criteria (tumour size >2 cm and/or negative ER and PR and/or high histological/nuclear grade (grade 2 to 3) and /or age <35 years). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other drugs were given intraveinously on day 1 every three weeks. Primary prophylactic G-CSF was made mandatory in TAC arm after 230 patients were randomized. The incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20mg once a day for up to 5 years. Adjuvant radiation therapy was administered according to guidelines in place at participating institutions and was given to 57.3% of patients who received TAC and 51.2% of patients who received FAC.

Median duration of follow-up was 77 months. Significantly longer disease-free survival for the TAC arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93), p = 0.01). Overall survival (OS) was also 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 different between the 2 groups.

TAC-treated patient subsets according to prospectively defined major prognostic factors were analyzed (see table below):

Subset analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study

(Intent-tp-Treat Analysis)

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

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

TAC = docetaxel, doxorubicin and cyclophosphamide

FAC = 5-fluorouracil, doxorubin and cyclophosphamide

CI = confidence interval; ER= estrogen receptor

PR = progesterone receptor

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

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

Docetaxel as single agent

Two randomised phase III comparative studies, involving a total of 326 alkylating or 392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the recommended dose and regimen of 100mg/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) or time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p=0.54), docetaxel increased response 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 15 doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart failure).

In anthracycline-failure patients, docetaxel was compared to the combination of Mitomycin C and Vinblastine (12 mg/m² every 6 weeks and 6mg/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) and prolonged 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 profile observed in phase II studies (see section 4.8).

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

Without affecting the primary endpoint, overall response rate (32% vs 25%, p=0.10), docetaxel prolonged 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 to paclitaxel (23.0%).

Docetaxel in combination with doxorubicin

One large randomized phase III study, involving 429 previously untreated patients with metastatic disease, has been performed with doxorubicin (50mg/m²) in combination with docetaxel (75mg/m²) (AT arm) versus doxorubicin (60mg/m²) in combination with cyclophosphamide (600mg/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. The median TTP was 37.3 weeks (95%CI :33.4 - 42.1) in AT arm and 31.9 weeks (95%CI : 27.4 - 36.0) in AC arm.

• Overall response rate (ORR) was significantly higher in the AT arm versus AC arm, p=0.009. The ORR was 59.3% (95%CI : 52.8 - 65.9) in AT arm versus 46.5% (95%CI : 39.8 - 53.2) in AC arm.

In this study, AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrile neutropenia (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 a higher incidence of severe anemia (15.8% versus 8.5%) than AT arm, and, in addition, a higher incidence of severe cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEF decrease 20% (13.1 % versus 6.1%), absolute LVEF decrease 30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due 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 during treatment and follow-up.

Docetaxel in combination with trastuzumab

Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2, and who previously had not received chemotherapy for metastatic disease. One hundred eighty six patients were randomized to receive docetaxel (100 mg/m²) with or without trastuzumab; 60% of patients received prior anthracycline based adjuvant chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in this pivotal trial was immunohistochemistry (IHC). A minority of patients were tested using fluorescence 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 are summarized in the following table:

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

¹Full analysis set (intent-to-treat)

² Estimated median survival

Docetaxel in combination with capecitabine

Data from one multicenter, randomised, controlled phase III clinical study support the use of docetaxel in combination with capecitabine for treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this study, 255 patients were randomised to treatment with docetaxel (75mg/m² as a 1 hour intravenous infusion every 3 weeks) and capecitabine (1250mg/m² twice daily for 2 weeks followed by 1-week rest period). 256 patients were randomised to treatment with docetaxel alone (100mg/ m² as a 1 hour intravenous infusion 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). The overall 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 was superior in the docetaxel + capecitabine combination arm (p < 0.0001). The median time to progression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).

Non-Small Cell Lung Cancer

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 75mg/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), other disease related medications (p=0.06) and radiotherapy (p < 0.01) in patients treated with docetaxel at 75mg/m² compared to those with BSC.

The overall response rate was 6.8% in the evaluable patients, and the median duration of response was 26.1 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% or greater, and who did not receive previous chemotherapy for this condition, were randomised to either docetaxel (T) 75mg/m² as a 1 hour infusion immediately followed by cisplatin (Cis) 75mg/ m² over 30-60 minutes every 3 weeks, docetaxel 75mg/ m² as a 1 hour infusion in combination with carboplatin (AUC 6 mg/ml•min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/ m² administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100mg/ m² administered on day 1 of cycles repeated every 4 weeks.

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

*: Corrected for multiple comparisons and adjusted for stratification factors (stage of disease and region 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-points were supportive of the primary end-points results.

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

Prostate cancer

The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients with hormone refractory metastatic prostate cancer were evaluated in a randomized multicenter Phase III study. A total of 1006 patients with KPS 60 were randomized to the following treatment groups:

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

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

• Mitoxantrone 12mg/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 survival compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for the docetaxel arms versus the control arm are summarized in the following table:

^† 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 every 3 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.

Gastric adenocarcinoma

A multicenter, open-label, randomized study, was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for metastatic disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75mg/m² on day 1) in combination with cisplatin (C) (75mg/m² on day 1) and 5-fluorouracil (F) (750mg/m² per day for 5 days) or cisplatin (100mg/m² on day 1) and 5-fluorouracil (1000mg/m² per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. 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 the primary endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer TTP (p=0.0004) in favor of the TCF arm. Overall survival was also significantly longer (p=0.0201) in favor of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized in the following table:

Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma

*Unstratified logrank test

Subgroup analyses across age, gender and race consistently favored 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 showed a statistically significant difference although always in favour of the TCF regimen and showed that the benefit 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 favor of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global health 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

The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO perfomance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75mg/m² followed by cisplatin (P) 75mg/m² followed by 5-fluorouracil (F) 750mg/m² per day as a continuous infusion for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response ( 25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress 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) 1000mg/m² per day for 5 days. This regimen was administered every three weeks for 4 cycles in case at least a minor response ( 25% reduction in bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered either with a conventional fraction (1.8 Gy - 2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxis with 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 an overall median follow up time of 33.7 months. Median overall survival was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with a 28% 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)

A Hazard ratio of less than 1 favors docetaxel+Cisplatin+5-FU

*Cox model (adjustment for Primary tumor 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 score compared 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 measure understandability of speech, ability to eat in public, and normalcy of diet, was significantly in favor of TPF as compared to PF.

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

• Induction chemotherapy followed by chemoradiotherapy (TAX324)

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

Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy with a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT. All patients on the docetaxel-containing arm of the study received prophylactic antibiotics. The primary efficacy endpoint in this study, overall survival (OS) was significantly 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 mortality compared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90) with an overall median follow up time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29% risk reduction of progression or death and a 22 month improvement in median PFS (35.5 months for TPF and 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)

A Hazard ratio of less than 1 favors docetaxel + cisplation + 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 pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20-115 mg/m² in Phase I studies. The kinetic profile of docetaxel is dose independent and consistent with a three-compartment pharmacokinetic model with half lives for the α, β and γ phases of 4 min, 36 min and 11.1 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Following the administration of a 100 mg/m² dose given as a one hour infusion a mean peak plasma level of 3.7 µg/ml was obtained with a corresponding AUC of 4.6 h.µg/ml. Mean values for total body clearance and steady-state volume of distribution were 21 l/h/m² and 113 l, respectively. Inter individual 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 in both the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl ester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites and very low amounts of unchanged medicinal product.

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 I studies. 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 liver function impairment (ALT, AST 1.5 times the ULN associated with alkaline phosphatase 2.5 times the ULN), total clearance was lowered by 27% on average (see section 4.2). Docetaxel clearance was not modified in patients with mild to moderate fluid retention and there are no data available in patients with severe fluid retention.

When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their coadministration.

Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (C_max and AUC) and no effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5'-DFUR.

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

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

The effect of prednisone on the pharmacokinetics of docetaxel administered with standard dexamethasone premedication has been studied in 42 patients. 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 mutagenic in the in vitro micronucleus and 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 impair male fertility.

Citric acid anhydrous

Povidone

Polysorbate 80

Ethanol absolute

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

Vials as packed for sale:

24 months.

Vials after opening:

The solution should be used immediately after opening of the vial. However, the physical, chemical and microbiological stability of the drug product after first vial opening has been demonstrated for 28 days at 2-8°C and at 25°C and normal lighting conditions.

After dilution:

The diluted solution should be used immediately after preparation. However, the physical and chemical stability of the diluted solution (0.74 mg/ ml) in the recommended solutions for infusion (50 mg/ml (5%) glucose solution for infusion and 9 mg/ml (0.9%) sodium chloride solution for infusion) has been demonstrated for 8 hours at about 25°C and normal lighting conditions and for 3 days at 2-8°C protected from light.

Store below 25°C.

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

For storage conditions after opening of the vials and of the diluted medicinal product, see section 6.3.

Colourless glass vial (type I) closed with a bromobutyl rubber stopper (type I) sealed with aluminium cap with polypropylene disc. Vial will be packed with or without a protective plastic overwrap.

Pack sizes:

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1 x 4 ml single dose vial

1 x 7 ml single dose vial

Not all pack sizes may be marketed.

Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion solutions. Cytotoxic agents should be prepared for administration only by personnel who have been trained in the safe handling of such preparations. Refer to local cytotoxic guidelines before commencing. The use of gloves is recommended. If Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion concentrate or infusion solution should come into contact with skin, wash immediately and thoroughly with soap and water. If Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion concentrate or infusion solution should come into contact with mucous membranes, wash immediately and thoroughly with water.

Preparation of the solution for infusion

More than one vial of Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion may be necessary to obtain the required dose for individual patients. Based on the required dose for the patient expressed in mg, aseptically withdraw the corresponding volume of 20 mg/ml docetaxel from the appropriate number of vials using graduated syringes fitted with a needle. For example, a dose of 140 mg docetaxel would require 7 ml of Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion.

For doses below 192 mg of docetaxel, inject the required volume of Docetaxel Actavis 20mg/ml Concentrate for Solution for Infusion into a 250 ml infusion bag or bottle containing either 250 ml of 50 mg/ml (5%) glucose solution for infusion or 9 mg/ml (0.9%) sodium chloride solution for infusion. For doses exceeding 192 mg of docetaxel more than 250 ml of the infusion solution is required, as the maximum concentration of docetaxel is 0.74 mg per ml of infusion solution.

Mix the infusion bag or bottle manually using a rocking motion. The diluted solution should be used within 8 hours and should be aseptically administered as a 1-hour infusion at room temperature and normal lighting conditions.

Administration

For instructions on administration see Section 4.2.

As with all parenteral products, this medicinal product should be visually inspected prior to use and solutions containing a precipitate should be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

Actavis Group PTC ehf.

Reykjavíkurvegur 76-78,

220 Hafnarfjörður

Iceland

PL 30306/0261

13.08.2010

25.03.11

IF APPLICABLE

IF APPLICABLE