4.1       Therapeutic indications

Breast Cancer

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

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

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

Gastric adenocarcinoma

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

4.2       Posology and method of administration

Docetaxel Hospira is for intravenous use only.

The use of docetaxel should be confined to units specialised in the administration of cytotoxic chemotherapy and it should 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 haematological 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 75 mg/m² administered 1-hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks for 6 cycles (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 75 mg/m² is given in combination therapy with doxorubicin (50 mg/m²). 

5        PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Pharmaco-therapeutic group: Taxanes, 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 multicentre open label randomized trial 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 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 was administered as a 1-hour infusion, all other drugs were given as IV 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 oestrogen 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.

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 multi-centre open label randomised trial 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 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 was administered as a 1-hour infusion, all other drugs 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 (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant 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-to-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, doxorubicin and cyclophospamide

CI = confidence interval; ER = estrogen receptor

PR = progesterone receptor

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

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

6.3       Shelf life

Unopened vial:  2 years 36 months

After dilution: 

After dilution in 0.9% sodium chloride or 5% glucose chemical and physical in-use stability has been demonstrated for 4 hours when stored below 25°C.  From a microbiological point of view, the infusion preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place in controlled and validated aseptic conditions.

6.6       Special precautions for disposal

Docetaxel Hospira is an antineoplastic agent and, as with other potentially toxic agents, caution should be exercised during handling and preparing solutions of Docetaxel Hospira. 

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

Guidelines for the safe handling and disposal of antineoplastic agents

Preparation

Local guidelines on safe preparation and handling should be consulted.

Cytotoxic agents should only be prepared and handled by personnel trained in the safe handling of such preparations. Pregnant personnel should not handle cytotoxic agents.

All personnel involved with handling cytotoxic agents should be adequately protected with appropriate personal protective equipment, including protective disposable gloves, eye shield, mask and long-sleeved gown. Preparation and manipulation of solutions should be performed in a designated handling area.

Contamination

In the event of skin contact, thoroughly wash the affected area with soap and water, taking care not to abrade the skin. A bland cream may be used to treat transient stinging of the skin. In the event of contact with the eyes, irrigate with copious amounts of water or sodium chloride 0.9%. Seek medical evaluation.

In the event of spillage, trained personnel wearing appropriate personal protective equipment should remove the maximum amount of material by use of a cytotoxic drug spill kit or designated absorbent materials. The area should be rinsed with copious amounts of water. All contaminated cleaning materials should be disposed of as described below.

Disposal

All contaminated waste materials (including sharps, containers, absorbent materials, unused solutions, etc) should be placed in a designated sealed and labelled impervious waste disposal bag or rigid waste container, and incinerated in accordance with local procedures for destruction of hazardous waste.

Instructions for preparation

Refer to section 6.3; Shelf Life.

Inspect visually prior to use. Only clear solutions without visible particles should be used.  Must be diluted before use. 

Contact of Docetaxel Hospira with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, Docetaxel Hospira should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Inject the required volume into a 250 ml infusion bag or bottle containing either:

• Sodium Chloride 9 mg/ml (0.9%)
• Glucose 50 mg/ml (5%)

If a dose greater than 185 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.

Compatibility: It is not recommended to mix docetaxel with other drugs.

Administration: For instructions on administration see Section 4.2.