Docetaxel Sandoz

Breast cancer

Docetaxel Sandoz Accord 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.

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

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

Gastric adenocarcinoma

Docetaxel Sandoz Accord 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 Sandoz Accord 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 Sandoz 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.

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 twice daily) for 3 days starting 1 day prior to Docetaxel Sandoz administration, unless contraindicated, can be used. 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 Sandoz infusion.

Docetaxel Sandoz 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 Sandoz is 75 mg/m² administered 1-hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks for 6 cycles (TAC regimen) (see also Dose adjustments during treatment). For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose of Docetaxel Sandoz is 100 mg/m² in monotherapy. In first-line treatment, Docetaxel Sandoz 75 mg/m² is given in combination therapy with doxorubicin (50 mg/m²).

In combination with trastuzumab the recommended dose of Docetaxel Sandoz is 100 mg/m² every three weeks, with trastuzumab administered weekly. In the pivotal study the initial Docetaxel Sandoz infusion was started the day following the first dose of trastuzumab. The subsequent Docetaxel Sandoz 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 Sandoz is 75 mg/m² every three weeks, combined with capecitabine at 1250 mg/m² twice 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 Sandoz 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 Sandoz is 75 mg/m². Prednisone or prednisolone 5 mg orally twice daily is administered continuously.

Gastric adenocarcinoma

The recommended dose of Docetaxel Sandoz is 75 mg/m² as 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/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 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 Sandoz-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 Sandoz is 75 mg/m² as a 1 hour infusion followed by cisplatin 75 mg/m² over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750 mg/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 Sandoz is 75 mg/m² as 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 Sandoz should be administered when the neutrophil count is > 1,500 cells/mm³. In patients who experienced either febrile neutropenia, neutrophil count < 500 cells/mm³ for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during Docetaxel Sandoz therapy, the dose of Docetaxel Sandoz should be reduced from 100 mg/m² to 75 mg/m² and/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-CSF prophylaxis should be considered in patients who receive Docetaxel Sandoz, doxorubicin and cyclophosphamide (TAC) adjuvant therapy for breast cancer. Patients who experience febrile neutropenia and/or neutropenic infection should have their Docetaxel Sandoz dose reduced to 60 mg/m² in all subsequent cycles. Patients who experience Grade 3 or 4 stomatitis should have their dose decreased to 60 mg/m².

In combination with cisplatin

For patients who are dosed initially at Docetaxel Sandoz 75 mg/m² in combination with cisplatin and whose nadir of platelet count during the previous course of therapy is < 25,000 cells/mm³, or in patients who experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the Docetaxel Sandoz 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 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 Sandoz/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 Sandoz 55 mg/m².

- For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the Docetaxel Sandoz 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 Sandoz dose should be reduced from 75 to 60 mg/m². If subsequent episodes of complicated neutropenia occur the Docetaxel Sandoz dose should be reduced from 60 to 45 mg/m². In case of Grade 4 thrombocytopenia the Docetaxel Sandoz dose should be reduced from 75 to 60 mg/m². Patients should not be retreated with subsequent cycles of Docetaxel Sandoz until neutrophils recover to a level > 1,500 cells/mm³ and platelets recover to a level > 100,000 cells/mm³. Discontinue treatment if these toxicities persist.

Recommended dose modifications for toxicities in patients treated with Docetaxel Sandoz 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 Sandoz 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 Sandoz is 75 mg/m². 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 Sandoz 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 Sandoz should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by Docetaxel Sandoz in combination in the other indications.

Paediatric population

The safety and efficacy of Docetaxel Sandoz 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 Sandoz 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).

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

Patients with severe liver impairment.

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

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 twice daily) for 3 days starting 1 day prior to Docetaxel Sandoz 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 Sandoz infusion.

Haematology

Neutropenia is the most frequent adverse reaction of Docetaxel Sandoz. 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 Sandoz. Patients should be retreated with Docetaxel Sandoz when neutrophils recover to a level > 1,500 cells/mm³.

In the case of severe neutropenia (< 500 cells/mm³ for seven days or more) during a course of Docetaxel Sandoz therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are recommended.

In patients treated with Docetaxel Sandoz 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.

In patients treated with Docetaxel Sandoz in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received primary G-CSF prophylaxis. 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.

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 Sandoz, 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 Sandoz and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with Docetaxel Sandoz. Patients who have previously experienced a hypersensitivity reaction to paclitaxel may be at risk to develop hypersensitivity reaction to Docetaxel Sandoz, including more severe hypersensitivity reaction. These patients should be closely monitored during initiation of Docetaxel Sandoz therapy.

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 Sandoz treatment were reported.

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 Sandoz therapy is recommended until diagnosis is available. Early use of supportive care measures may help improve the condition. The benefit of resuming Docetaxel Sandoz treatment must be carefully evaluated.

Patients with liver impairment

In patients treated with Docetaxel Sandoz at 100 mg/m² as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase 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 Sandoz in those patients with elevated liver function test (LFTs) is 75 mg/m² and LFTs should be measured at baseline and before each cycle.

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 Sandoz 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 Sandoz should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by Docetaxel Sandoz 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 Sandoz.

Nervous system

The development of severe peripheral neurotoxicity requires a reduction of dose.

Cardiac toxicity

Heart failure has been observed in patients receiving Docetaxel Sandoz in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin) -containing chemotherapy. This may be moderate to severe and has been associated with death.

When patients are candidates for treatment with Docetaxel Sandoz 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.

Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with Docetaxel Sandoz in combination regimens including doxorubicin, 5-fluorouracil and/ or cyclophosphamide.

Baseline cardiac assessment is recommended.

Eye disorders

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

Others

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

The concomitant use of Docetaxel Sandoz with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided.

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.

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.

Leukaemia

In the Docetaxel Sandoz, 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.

Elderly

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

Of the 333 patients treated with Docetaxel Sandoz 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 Sandoz 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 Sandoz 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 elderly 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 treated with TCF should be closely monitored.

Excipients

This medicinal product contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 395 mg ethanol anhydrous per vial, equivalent to 10 ml of beer or 4 ml wine.

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.

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

No studies on the effects on the ability to drive and use machines have been performed. The amount of alcohol in this medicinal products may impair the ability to drive or use machines.

Summary of the safety profile for all indications

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

- 1,312 and 121 patients who received 100 mg/m² and 75 mg/m² of Docetaxel Sandoz as a single agent respectively.

- 258 patients who received Docetaxel Sandoz in combination with doxorubicin.

- 406 patients who received Docetaxel Sandoz in combination with cisplatin.

- 92 patients treated with Docetaxel Sandoz in combination with trastuzumab.

- 255 patients who received Docetaxel Sandoz in combination with capecitabine.

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

- 1,276 patients (744 and 532 in TAX 316 and GEICAM 9,805 respectively) who received Docetaxel Sandoz 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 Sandoz 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 Sandoz 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 (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); 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 Sandoz 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, diarrhoea and asthenia. The severity of adverse events of Docetaxel Sandoz may be increased when Docetaxel Sandoz 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 Sandoz 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 Sandoz:

Immune system disorders

Hypersensitivity reactions have generally occurred within a few minutes following the start of the infusion of Docetaxel Sandoz 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.

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose. 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 Sandoz infusion. Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of Docetaxel Sandoz treatment were reported. 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.

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

Description of selected adverse reactions in breast cancer for Docetaxel Sandoz 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 Sandoz 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 lung cancer for Docetaxel Sandoz 75 mg/m² single agent

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

Tabulated list of adverse reactions in non-small cell lung cancer for Docetaxel Sandoz 75 mg/m² in combination with cisplatin

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

Description of selected adverse reactions in breast cancer for Docetaxel Sandoz 100 mg/m² in combination with trastuzumab

Blood and lymphatic system disorders

Very common: Haematological toxicity was increased in patients receiving trastuzumab and Docetaxel Sandoz, compared with Docetaxel Sandoz alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria). Note that this is likely to be an underestimate since Docetaxel Sandoz alone at a dose of 100 mg/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 Sandoz (23% versus 17% for patients treated with Docetaxel Sandoz alone).

Cardiac disorders

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

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

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

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

MedDRA System Organ classes	Very common adverse reactions	Common adverse reactions	Uncommon adverse reactions
Infections and Overdose There were a few reports of overdose. There is no known antidote for Docetaxel Sandoz 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. Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, Taxanes, ATC Code: L01CD02 Mechanism of action Docetaxel Sandoz 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 Sandoz to microtubules does not alter the number of protofilaments. Docetaxel Sandoz has been shown in vitro to disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions. Pharmacodynamic effects Docetaxel Sandoz 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 Sandoz achieves high intracellular concentrations with a long cell residence time. In addition, Docetaxel Sandoz 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 Sandoz 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 Sandoz 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 Sandoz 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 Sandoz 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens were administered once every 3 weeks for 6 cycles. Docetaxel Sandoz 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 enrollment 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: Disease free survival Overall survival Patient subset Number of patients Hazard ratio* 95% CI p = Hazard ratio* 95% CI p = No of positive nodes Overall 1-3 4+   745 467 278   0.80 0.72 0.87   0.68-0.93 0.58-0.91 0.70-1.09   0.0043 0.0047 0.2290   0.74 0.62 0.87   0.61-0.90 0.46-0.82 0.67-1.12   0.0020 0.0008 0.2746 *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-negative breast cancer eligible to receive chemotherapy (GEICAM 9805) Data from a multicenter open label randomized trial support the use of Docetaxel Sandoz for the adjuvant treatment of patients with operable node-negative breast cancer eligible to receive chemotherapy. 1060 patients were randomized to receive either Docetaxel Sandoz 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (539 patients in TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/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 Sandoz was administered as a 1-hour infusion, all other medicinal products were given intravenously 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. In both arms, after the last cycle of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant 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. One primary analysis and one updated analysis were performed. The primary analysis was done when all patients had a follow-up of greater than 5 years (median follow-up time of 77 months). The updated analysis was performed when all patients had reached their 10-year (median follow up time of 10 years and 5 months) follow-up visit (unless they had a DFS event or were lost to follow-up previously). Disease-free survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the secondary efficacy endpoint. At the median follow-up time of 77 months significantly longer disease-free survival for the 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). At the median follow up time of 10 years and 5 months, TAC-treated patients had a 16.5% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.84, 95% CI (0.64-1.08), p=0.1646). DFS data were not statistically significant but were still associated with a positive trend in favour of TAC. At the median follow-up time of 77 months, overall survival (OS) was longer in the TAC arm with TAC-treated patients having a 24% reduction in the risk of death compared to FAC (hazard ratio = 0.76, 95% CI (0.46-1.26, p = 0.29). However, the distribution of OS was not significantly different between the 2 groups. At the median follow up time of 10 years and 5 months, TAC-treated patients had a 9% reduction in the risk of death compared to FAC-treated patients (hazard ratio = 0.91, 95% CI (0.63-1.32)). The survival rate was 93.7% in the TAC arm and 91.4 % in the FAC arm, at the 8-year follow-up timepoint, and 91.3 % in the TAC arm and 89 % in the FAC arm, at the 10-year follow-up timepoint. The positive benefit risk ratio for TAC compared to FAC remained unchanged. TAC-treated patient subsets according to prospectively defined major prognostic factors were analysed in the primary analysis (at the median follow-up time of 77 months) (see table below): Subset analyses-adjuvant therapy in patients with node-negative breast cancer study (Intent-to-treat analysis) Patient subset Number of patients in TAC group Disease free survival Hazard ratio* 95% CI Overall 539 0.68 0.49-0.93 Age category 1 <50 years >50 years   260 279   0.67 0.67   0.43-1.05 0.43-1.05 Age category 2 <35 years >35 years   42 497   0.31 0.73   0.11-0.89 0.52-1.01 Hormonal receptor status Negative Positive   195 344   0.7 0.62   0.45-1.1 0.4-0.97 Tumour size ≤ 2 cm >2 cm   285 254   0.69 0.68   0.43-1.1 0.45-1.04 Histological grade Grade1 (includes grade not assessed) Grade 2 Grade 3   64 216 259   0.79 0.77 0.59   0.24-2.6 0.46-1.3 0.39-0.9 Menopausal status Pre-Menopausal Post-Menopausal   285 254   0.64 0.72   0.40-1 0.47-1.12 *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: Subgroups TAC (n=539) FAC (n=521) Hazard ratio (TAC/FAC) (95% CI) p-value Meeting relative indication for chemotherapy a No 18/214 (8.4%) 26/227 (11.5%) 0.796 (0.434 - 1.459) 0.4593 Yes 48/325 (14.8%) 69/294 (23.5%) 0.606 (0.42 - 0.877) 0.0072 TAC = Docetaxel Sandoz, doxorubicin and cyclophosphamide FAC = 5-fluorouracil, doxorubicin and cyclophospamide CI = confidence interval; ER = estrogen receptor PR = progesterone receptor a ER/PR-negative or Grade 3 or tumor size >5 cm The estimated hazard ratio was using Cox proportional hazard model with treatment group as the factor. Docetaxel Sandoz 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 Sandoz at the recommended dose and regimen of 100 mg/m2 every 3 weeks. In alkylating-failure patients, Docetaxel Sandoz was compared to doxorubicin (75 mg/m2 every 3 weeks). Without affecting overall survival time (Docetaxel Sandoz 15 months vs. doxorubicin 14 months, p = 0.38) or time to progression (Docetaxel Sandoz 27 weeks vs. doxorubicin 23 weeks, p = 0.54), Docetaxel Sandoz increased response rate (52% vs. 37%, p = 0.01) and shortened time to response (12 weeks vs. 23 weeks, p = 0.007). Three Docetaxel Sandoz 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 Sandoz was compared to the combination of mitomycin C and vinblastine (12 mg/m2 every 6 weeks and 6 mg/m2 every 3 weeks). Docetaxel Sandoz 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 Sandoz was consistent with the safety profile observed in phase II studies. An open-label, multicenter, randomized phase III study was conducted to compare Docetaxel Sandoz 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 Sandoz monotherapy 100 mg/m2 as a 1 hour infusion or paclitaxel 175 mg/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 Sandoz 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 Sandoz monotherapy (55.4%) compared to paclitaxel (23.0%). Docetaxel Sandoz in combination with doxorubicin One large randomized phase III study, involving 429 previously untreated patients with metastatic disease, has been performed with doxorubicin (50 mg/m2) in combination with Docetaxel Sandoz (75 mg/m2) (AT arm) versus doxorubicin (60 mg/m2) in combination with cyclophosphamide (600 mg/m2) (AC arm). Both regimens were administered on day 1 every 3 weeks. - Time to progression (TTP) was significantly longer in the AT arm versus AC arm, p = 0.0138. 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 anaemia (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 Sandoz in combination with trastuzumab Docetaxel Sandoz in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2, and who previously had not received chemotherapy for metastatic disease. One hundred eighty six patients were randomized to receive Docetaxel Sandoz (100 mg/m2) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant chemotherapy. Docetaxel Sandoz 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 study 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: Parameter Docetaxel Sandoz plus trastuzumab1 n = 92 Docetaxel Sandoz1 n = 94 Response rate (95% CI) 61% (50-71) 34% (25-45) Median duration of response (months) (95% CI)   11.4 (9.2-15.0)   5.1 (4.4-6.2) Median TTP (months) (95% CI) 10.6 (7.6-12.9) 5.7 (5.0-6.5) Median survival (months) (95% CI) 30.52 (26.8-ne) 22.12 (17.6-28.9) TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached. 1Full analysis set (intent-to-treat) 2Estimated median survival Docetaxel Sandoz in combination with capecitabine Data from one multicenter, randomised, controlled phase III clinical study support the use of Docetaxel Sandoz 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 Sandoz (75 mg/m2 as a 1 hour intravenous infusion every 3 weeks) and capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). 256 patients were randomised to treatment with Docetaxel Sandoz alone (100 mg/m2 as a 1 hour intravenous infusion every 3 weeks). Survival was superior in the Docetaxel Sandoz + capecitabine combination arm (p = 0.0126). Median survival was 442 days (Docetaxel Sandoz + capecitabine) vs. 352 days (Docetaxel Sandoz alone). The overall objective response rates in the all-randomised population (investigator assessment) were 41.6% (Docetaxel Sandoz + capecitabine) vs. 29.7% (Docetaxel Sandoz alone); p = 0.0058. Time to progressive disease was superior in the Docetaxel Sandoz + capecitabine combination arm (p < 0.0001). The median time to progression was 186 days (Docetaxel Sandoz + capecitabine) vs. 128 days (Docetaxel Sandoz 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 Sandoz at 75 mg/m2 compared to Best Supportive Care. The 1-year survival rate was also significantly longer in Docetaxel Sandoz (40%) versus BSC (16%). There was less use of morphinic analgesic (p < 0.01), non-morphinic analgesics (p < 0.01), other disease-related medicinal products (p = 0.06) and radiotherapy (p < 0.01) in patients treated with Docetaxel Sandoz at 75 mg/m2 compared to those with BSC. The overall response rate was 6.8% in the evaluable patients, and the median duration of response was 26.1 weeks. Docetaxel Sandoz 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 Sandoz (T) 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m2 over 30-60 minutes every 3 weeks (TCis), Docetaxel Sandoz 75 mg/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 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks (VCis). Survival data, median time to progression and response rates for two arms of the study are illustrated in the following table: TCis n = 408 VCis n = 404 Statistical analysis Overall survival (Primary end-point): Median survival (months)   1-year Survival (%)   2-year Survival (%)     11.3   46   21     10.1   41   14     Hazard Ratio: 1.122 [97.2% CI: 0.937; 1.342]* Treatment difference: 5.4% [95% CI: -1.1; 12.0] Treatment difference: 6.2% [95% CI: 0.2; 12.3] Median time to progression (weeks): 22.0 23.0 Hazard Ratio: 1.032 [95% CI: 0.876; 1.216] Overall response rate (%): 31.6 24.5 Treatment difference: 7.1% [95% CI: 0.7; 13.5] *: Corrected for multiple comparisons and adjusted for stratification factors (stage of disease 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 Sandoz/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 Sandoz 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 Sandoz 75 mg/m2 every 3 weeks for 10 cycles. - Docetaxel Sandoz 30 mg/m2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles. - Mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles. All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily, continuously. Patients who received Docetaxel Sandoz every three weeks demonstrated significantly longer overall survival compared to those treated with mitoxantrone. The increase in survival seen in the Docetaxel Sandoz weekly arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for the Docetaxel Sandoz arms versus the control arm are summarized in the following table: Endpoint Docetaxel Sandoz every 3 weeks Docetaxel Sandoz every week Mitoxantrone every 3 weeks Number of patients Median survival (months) 95% CI Hazard ratio 95% CI p-value†* 335 18.9 (17.0-21.2) 0.761 (0.619-0.936) 0.0094 334 17.4 (15.7-19.0) 0.912 (0.747-1.113) 0.3624 337 16.5 (14.4-18.6) -- -- -- Number of patients PSA** response rate (%) 95% CI p-value* 291 45.4 (39.5-51.3) 0.0005 282 47.9 (41.9-53.9) <0.0001 300 31.7 (26.4-37.3) -- Number of patients Pain response rate (%) 95% CI p-value* 153 34.6 (27.1-42.7) 0.0107 154 31.2 (24.0-39.1) 0.0798 157 21.7 (15.5-28.9) -- Number of patients Tumour response rate (%) 95% CI p-value* 141 12.1 (7.2-18.6) 0.1112 134 8.2 (4.2-14.2) 0.5853 137 6.6 (3.0-12.1) -- †Stratified log rank test *Threshold for statistical significance = 0.0175 **PSA: Prostate-Specific Antigen Given the fact that Docetaxel Sandoz every week presented a slightly better safety profile than Docetaxel Sandoz every 3 weeks, it is possible that certain patients may benefit from Docetaxel Sandoz 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 Sandoz 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 Sandoz (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and 5-fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 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 Sandoz in the treatment of patients with gastric adenocarcinoma Pharmacokinetic properties Absorption The pharmacokinetics of Docetaxel Sandoz have been evaluated in cancer patients after administration of 20-115 mg/m2 in phase I studies. The kinetic profile of Docetaxel Sandoz 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 Sandoz from the peripheral compartment. Distribution 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 Sandoz is more than 95% bound to plasma proteins. Elimination A study of 14C-Docetaxel Sandoz has been conducted in three cancer patients. Docetaxel Sandoz 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. Special populations Age and gender A population pharmacokinetic analysis has been performed with Docetaxel Sandoz in 577 patients. Pharmacokinetic parameters estimated by the model were very close to those estimated from phase I studies. The pharmacokinetics of Docetaxel Sandoz were not altered by the age or sex of the patient. Hepatic impairment 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. Fluid retention Docetaxel Sandoz clearance was not modified in patients with mild to moderate fluid retention and there are no data available in patients with severe fluid retention. Combination therapy Doxorubicin When used in combination, Docetaxel Sandoz does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of Docetaxel Sandoz, doxorubicin and cyclophosphamide were not influenced by their co-administration. Capecitabine Phase I study evaluating the effect of capecitabine on the pharmacokinetics of Docetaxel Sandoz and vice versa showed no effect by capecitabine on the pharmacokinetics of Docetaxel Sandoz (Cmax and AUC) and no effect by Docetaxel Sandoz on the pharmacokinetics of a relevant capecitabine metabolite 5'-DFUR. Cisplatin Clearance of Docetaxel Sandoz in combination therapy with cisplatin was similar to that observed following monotherapy. The pharmacokinetic profile of cisplatin administered shortly after Docetaxel Sandoz infusion is similar to that observed with cisplatin alone. Cisplatin and 5-fluorouracil The combined administration of Docetaxel Sandoz, cisplatin and 5-fluorouracil in 12 patients with solid tumours had no influence on the pharmacokinetics of each individual medicinal product. Prednisone and dexamethasone The effect of prednisone on the pharmacokinetics of Docetaxel Sandoz administered with standard dexamethasone premedication has been studied in 42 patients. Prednisone No effect of prednisone on the pharmacokinetics of Docetaxel Sandoz was observed. Pharmacotherapeutic group Antineoplastic agents, plant alkaloids and other natural products, Taxanes, ATC Code: L01CD02 Preclinical safety data The carcinogenic potential of Docetaxel Sandoz has not been studied. Docetaxel Sandoz 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 Sandoz. Undesirable effects on the testis observed in rodent toxicity studies suggest that Docetaxel Sandoz may impair male fertility. Incompatibilities Tapentadol Special precautions for disposal and other handling Docetaxel Sandoz is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing Docetaxel Sandoz Accord solutions. The use of gloves is recommended. If Docetaxel Sandoz Accord concentrate or infusion solution should come into contact with skin, wash immediately and thoroughly with soap and water. If Docetaxel Sandoz Accord concentrate or infusion solution should come into contact with mucous membranes, wash immediately and thoroughly with water. Preparation for the intravenous administration Preparation of the infusion solution DO NOT use other Docetaxel Sandoz medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product which contains only 1 vial of concentrate. Docetaxel Sandoz Accord 20 mg/1 ml concentrate for solution for infusion requires NO prior dilution with a solvent and is ready to add to the infusion solution. Each vial is of single use and should be used immediately. If the vials are stored under refrigeration, allow the required number of boxes of Docetaxel Sandoz Accord concentrate for solution for infusion to stand below 25°C for 5 minutes before use. More than one vial of Docetaxel Sandoz Accord concentrate for solution for infusion may be necessary to obtain the required dose for the patient. Aseptically withdraw the required amount of Docetaxel Sandoz Accord concentrate for solution for infusion using a calibrated syringe fitted with a 21G needle. In Docetaxel Sandoz Accord 20 mg/1 ml vial the concentration of Docetaxel Sandoz is 20 mg/ml. The required volume of Docetaxel Sandoz Accord concentrate for solution for infusion must be injected via a single injection (one shot) into a 250 ml infusion bag containing either 5% glucose solution or sodium chloride 9 mg/ml (0.9%) solution for infusion. If a dose greater than 190 mg of Docetaxel Sandoz is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml Docetaxel Sandoz is not exceeded. Mix the infusion bag manually using a rocking motion. The infusion bag solution should be used within 6 hours below 25°C including the one hour infusion to the patient. As with all parenteral products, Docetaxel Sandoz Accord infusion solution should be visually inspected prior to use, solutions containing a precipitate should be discarded. Docetaxel Sandoz infusion solution is supersaturated and may therefore crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. ATC - Anatomical and therapeutic chemical classification R52.1 – Chronic intractable pain R52.2 – Other chronic pain R52.9 – Unspecified pain Available in countries Belgium Ecuador Italy Japan Lithuania Netherlands New Zealand Portugal Russia Serbia Slovakia Switzerland Venezuela A-Z index: ABCDEFGHIJKLMNOPQRSTUVYZ Endpoint TCF n = 221 CF n = 224 Median TTP (months) (95% CI) Hazard ratio (95% CI) *p-value 5.6 (4.86-5.91) 3.7 (3.45-4.47) 1.473 (1.189-1.825) 0.0004