Doxekal

Overdose

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

There is no known antidote for Doxekal overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic granulocyte – colony stimulating factor (G-CSF) as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

In two reports of overdose, one patient received 150 mg/m² and the other received 200 mg/m² as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.

In mice, lethality was observed following single intravenous doses that were ≥ 154 mg/kg (about 4.5 times the human dose of 100 mg/m² on a mg/m² basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m² basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m² on a mg/m² basis) and was associated with abnormal mitosis and necrosis of multiple organs.

Contraindications

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.

• Doxekal is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred.
• Doxekal should not be used in patients with neutrophil counts of < 1,500 cells/mm³.

Undesirable effects

Summary of the safety profile for all indications

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

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

- 258 patients who received docetaxel in combination with doxorubicin.

- 406 patients who received docetaxel in combination with cisplatin.

- 92 patients treated with docetaxel in combination with trastuzumab.

- 255 patients who received docetaxel in combination with capecitabine.

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

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

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

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

These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA terms. Frequencies are defined as: very common (> 1/10), common (> 1/100 to < 1/10); uncommon (> 1/1,000 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 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 may be increased when docetaxel is given in combination with other chemotherapeutic agents.

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

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

The following adverse reactions are frequently observed with docetaxel:

Immune system disorders

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

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 infusion. Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel 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 Doxekal 100 mg/m2 single agent

Description of selected adverse reactions in breast cancer for Doxekal 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 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 Doxekal 75 mg/m2 single agent

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

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

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

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

Blood and lymphatic system disorders

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

Cardiac disorders

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

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

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

Tabulated list of adverse reactions in breast cancer for adjuvant therapy with Doxekal 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

Preclinical safety data

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.

Therapeutic indications

Breast cancer

Doxekal 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.

Doxekal 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.

Doxekal 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.

Doxekal 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.

Doxekal 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

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

Doxekal 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

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

Gastric adenocarcinoma

Doxekal 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

Doxekal 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.

Doxekal is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.

Doxekal as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.

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

Doxekal in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Taxanes, ATC Code: L01CD02

Mechanism of action

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

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

Pharmacodynamic effects

Docetaxel was found to be cytotoxic in 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 efficacy and safety

Breast cancer

Doxekal 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 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 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:

*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 Doxekal for the adjuvant treatment of patients with operable node-negative breast cancer eligible to receive chemotherapy. 1060 patients were randomized to receive either Doxekal 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. Doxekal was administered as a 1-hour infusion, all other medicinal products 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. 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 (0.65-1.08), 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 analyzed 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)

*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

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.

Doxekal 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 100 mg/m2 every 3 weeks.

In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m2 every 3 weeks). Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p = 0.38) 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 6 mg/m2 every 3 weeks). Docetaxel increased response rate (33% vs. 12%, p < 0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p = 0.0004) 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.

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 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 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%).

Doxekal 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 (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.

Doxekal in combination with trastuzumab

Docetaxel 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 (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 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:

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

Doxekal 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 (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 alone (100 mg/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 75 mg/m2 compared to Best Supportive Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).

There was less use of morphinic analgesic (p < 0.01), non-morphinic analgesics (p < 0.01), other disease-related medicinal products (p = 0.06) and radiotherapy (p < 0.01) in patients treated with docetaxel 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.

Doxekal 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) 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 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:

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

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

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

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

Patients who received docetaxel every three weeks demonstrated significantly longer overall 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:

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

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

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 > 1,500 cells/mm3.

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

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.

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 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, thus facilities for the treatment of hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel.

Cutaneous reactions

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

Fluid retention

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

Respiratory disorders

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

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

Patients with liver impairment

In patients treated with docetaxel at 100 mg/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 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 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.

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.

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

Eye disorders

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

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 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, 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.

Older people

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

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

Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part) patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse events was higher in older people 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.

Older people treated with TCF should be closely monitored.

Excipients

This medicinal product contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 1.58 g ethanol anhydrous per vial, equivalent to 40 ml of beer or 17 ml wine per vial.

Harmful for those suffering from alcoholism.

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

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

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

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

Included as part of the PRECAUTIONS section.

Doxekal administered at 100 mg/m² was associated with deaths considered possibly or probably related to treatment in 2.0 % (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT > 1.5 times ULN together with AP > 2.5 times ULN). Among patients dosed at 60 mg/m², mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.

Doxekal administered at a dose of 100 mg/m² in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m² dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m² dose level, 3 of 5 patients had an ECOG PS of 2 at study entry.

Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Doxekal.

Perform frequent peripheral blood cell counts on all patients receiving Doxekal. Patients should not be retreated with subsequent cycles of Doxekal until neutrophils recover to a level > 1,500 cells/mm³ and platelets recover to a level > 100,000 cells/mm³.

A 25% reduction in the dose of Doxekal is recommended during subsequent cycles following severe neutropenia ( < 500 cells/mm³ ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Doxekal cycle.

Neutropenia ( < 2000 neutrophils/mm³ ) occurs in virtually all patients given 60 mg/m² to 100 mg/m² of docetaxel and grade 4 neutropenia ( < 500 cells/mm³ ) occurs in 85% of patients given 100 mg/m² and 75% of patients given 60 mg/m². Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Doxekal should not be administered to patients with neutrophils < 1,500 cells/mm³.

Febrile neutropenia occurred in about 12% of patients given 100 mg/m² but was very uncommon in patients given 60 mg/m². Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related.

Three breast cancer patients with severe liver impairment (bilirubin > 1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia..

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Doxekal infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Doxekal.

Hypersensitivity reactions may occur within a few minutes following initiation of a Doxekal infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Doxekal.

Severe fluid retention has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each Doxekal administration to reduce the incidence and severity of fluid retention Â. Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.

When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.

Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m². Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1,021 mg/m².

Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).

Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. The risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up.

Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity.

Severe neurosensory symptoms (e.g.paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).

Cystoid macular edema (CME) has been reported in patients treated with Doxekal. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, Doxekal treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.

Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of Docetaxel Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Docetaxel Injection on the ability to drive or use machines immediately after the infusion.

Each administration of Docetaxel Injection at 100 mg/m² delivers 1.425 g/m² of ethanol. For a patient with a BSA of 2.0 m², this would deliver 2.85 grams of ethanol. Other docetaxel products may have a different amount of alcohol.

Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

Doxekal can cause fetal harm when administered to a pregnant woman. Docetaxel caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis.

There are no adequate and well-controlled studies in pregnant women using Doxekal. If Doxekal is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Doxekal.

See FDA-Approved Patient Labeling

• Explain to patients the possible effects of the alcohol content in Docetaxel Injection, including possible effects on the central nervous system. Patients in whom alcohol should be avoided or minimized should consider the alcohol content of Docetaxel Injection. Alcohol could impair their ability to drive or use machines immediately after infusion.
• Doxekal may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives if receiving Doxekal.
• Obtain detailed allergy and concomitant drug information from the patient prior to Doxekal administration.
• Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen.
• Instruct patients to immediately report signs of a hypersensitivity reaction.
• Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea.
• Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.
• Instruct patients to report myalgia, cutaneous, or neurologic reactions.
• Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and hair loss are associated with docetaxel administration.

Carcinogenicity studies with docetaxel have not been performed.

Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m² basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.

Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on a mg/m² basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on a mg/m² basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

Based on its mechanism of action and findings in animals, Doxekal can cause fetal harm when administered to a pregnant woman. If Doxekal is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Doxekal. Doxekal can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥ 0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m² basis), administered during the period of organogenesis, have shown that docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity.

It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Doxekal, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of docetaxel in pediatric patients receiving monotherapy was consistent with the known safety profile in adults.

Docetaxel has been studied in a total of 239 pediatric patients in 2 trials with monotherapy.

Docetaxel monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1-22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m² as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia.

The recommended dose for docetaxel monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1-26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.

Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m² to 235 mg/m² in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m².

In summary, the body surface area adjusted clearance of docetaxel monotherapy in children was comparable to those in adults.

The alcohol content of Docetaxel Injection should be taken into account when given to pediatric patients.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.

Non-Small Cell Lung Cancer

In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).

When docetaxel was combined with carboplatin for the treatment of chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.

Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 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 following treatment emergent adverse reactions occurred at rates ≥ 10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively.

Patients with bilirubin > ULN should not receive docetaxel. Also, patients with AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN should not receive docetaxel..

The alcohol content of Docetaxel Injection should be taken into account when given to patients with hepatic impairment.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. The amount of ethanol in Doxekal may impair the ability to drive or use machines.

Dosage (Posology) and method of administration

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

Recommended dose

For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used. Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.

For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion.

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 (TAC regimen) (see also Dose adjustments during treatment).

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

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

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

Non-small cell lung cancer

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

Prostate cancer

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

Gastric adenocarcinoma

The recommended dose of docetaxel 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-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 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 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 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 therapy, the dose of docetaxel 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, doxorubicin and cyclophosphamide (TAC) adjuvant therapy for breast cancer. Patients who experience febrile neutropenia and/or neutropenic infection should have their docetaxel 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 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 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/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at 100% of the original dose.

- For patients developing the second appearance of Grade 2 toxicity, or the first appearance of Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1 and then resume treatment with docetaxel 55 mg/m2.

- For 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 60 mg/m2. If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m2. In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m2. Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level > 1,500 cells/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 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 100 mg/m2 as single agent, patients who have both elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m2. 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 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.

Paediatric population

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

There is no relevant use of Doxekal 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.

Older people

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

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).

For all indications, toxicities may warrant dosage adjustments. Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).

• For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of Doxekal is 60 mg/m² to 100 mg/m² administered intravenously over 1 hour every 3 weeks.

• For treatment after failure of prior platinum-based chemotherapy, docetaxel was evaluated as monotherapy, and the recommended dose is 75 mg/m² administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m² in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized, controlled trials.
• For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin. The recommended dose of Doxekal is 75 mg/m² administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m² over 30 to 60 minutes every 3 weeks.

• For hormone-refractory metastatic prostate cancer, the recommended dose of Doxekal is 75 mg/m² every 3 weeks as a 1 hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously.

All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Doxekal administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.

For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the Doxekal infusion.

Patients who are dosed initially at 100 mg/m² and who experience either febrile neutropenia, neutrophils < 500 cells/mm³for more than 1 week, or severe or cumulative cutaneous reactions during Doxekal therapy should have the dosage adjusted from 100 mg/m² to 75 mg/m². If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m² to 55 mg/m² or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m² and who do not experience febrile neutropenia, neutrophils < 500 cells/mm³for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Doxekal therapy may tolerate higher doses. Patients who develop ≥ grade 3 peripheral neuropathy should have Doxekal treatment discontinued entirely.

Monotherapy With Doxekal For NSCLC Treatment After Failure Of Prior Platinum-Based Chemotherapy

Patients who are dosed initially at 75 mg/m² and who experience either febrile neutropenia, neutrophils < 500 cells/mm³for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 nonhematological toxicities during Doxekal treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m². Patients who develop ≥ grade 3 peripheral neuropathy should have Doxekal treatment discontinued entirely.

Combination Therapy With Doxekal For Chemotherapy-Naïve NSCLC

For patients who are dosed initially at Doxekal 75 mg/m² in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is < 25,000 cells/mm³ , in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Doxekal dosage in subsequent cycles should be reduced to 65 mg/m². In patients who require a further dose reduction, a dose of 50 mg/m² is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.

Combination therapy With Doxekal For Hormone-Refractory Metastatic Prostate Cancer

Doxekal should be administered when the neutrophil count is ≥ 1,500 cells/mm³. Patients who experience either febrile neutropenia, neutrophils < 500 cells/mm³for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Doxekal therapy should have the dosage of Doxekal reduced from 75 mg/m² to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.

Combination Therapy with Strong CYP3A4 inhibitors: Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor..

Doxekal is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Doxekal solutions. The use of gloves is recommended. Please refer to.

If Doxekal lyophilized powder, reconstituted solution, or infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If Doxekal lyophilized powder, reconstituted solution or infusion solution should come into contact with mucosa, immediately and thoroughly wash with water.

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

Doxekal for Injection requires reconstitution with Diluent and one further dilution with infusion solution prior to administration. Please follow the preparation instructions provided below.

The table below provides the fill range of the Diluent, the volume of Diluent to be added for the reconstitution and the concentration of the reconstituted solution for Doxekal 20 mg and Doxekal 80 mg (See Table 1).

Table 1 : Reconstitution of Doxekal (docetaxel) for Injection

Preparation of the Reconstituted Solution

1. 1. Doxekal vials should be stored between 2°C and 8°C (36°F and 46°F). Allow the appropriate number of vials of Doxekal (docetaxel) for Injection and diluent (35.4% ethanol in polysorbate 80) vials to stand at room temperature for approximately 5 minutes.
2. 1. For Doxekal 20: Use 1 mL syringe with needle of 18-to 21-gauge, 1½-inch for withdrawing diluent for Doxekal 20.
   2. For Doxekal 80: Use 4 mL syringe with needle of 18-to 21-gauge, 1½-inch for withdrawing diluent for Doxekal 80.
3. 1. For Doxekal 20: Aseptically withdraw 1 mL from the diluent vial into a syringe by partially inverting the vial, and transfer it to product vial of Doxekal (docetaxel) for Injection.
   2. For Doxekal 80: Aseptically withdraw 4 mL from the diluent vial into a syringe by partially inverting the vial, and transfer it to product vial of Doxekal (docetaxel) for Injection.
4. Shake the reconstituted vial well in order to completely dissolve the docetaxel powder present in the vial. For the 20 mg vial, the resultant concentration is 20 mg/0.8 mL. For the 80 mg vial, the resultant concentration is 24 mg/mL.

The reconstituted Doxekal solution should be clear; however, there may be some air bubbles in the solution due to the polysorbate 80. Allow the solution to stand for a few minutes to allow any air bubbles to dissipate.

The reconstituted solution may be used immediately or stored either in the refrigerator or at room temperature for a maximum of 8 hours.

Preparation of the Infusion Solution

1. Aseptically withdraw the required amount of reconstituted Doxekal solution with a calibrated syringe and inject into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL. If a dose greater than 200 mg of Doxekal is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded.
2. Thoroughly mix the infusion by manual rotation.
3. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the Doxekal reconstituted solution or infusion solution is not clear or appears to have precipitation, these should be discarded.
4. Doxekal reconstituted solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

The final Doxekal infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25o C) and lighting conditions.

Doxekal infusion solution, if stored between 2°C and 25°C (36°F and 77°F) is stable for 6 hours. Doxekal infusion solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 6 hours (including the 1 hour intravenous administration).

In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36°F and 46°F).

Special precautions for disposal and other handling

Doxekal is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing Doxekal solutions. The use of gloves is recommended.

If Doxekal concentrate or infusion solution should come into contact with skin, wash immediately and thoroughly with soap and water. If Doxekal 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 medicinal products consisting of 2 vials (concentrate and solvent) with this medicinal product (Doxekal 80 mg/4 ml concentrate for solution for infusion, which contains only 1 vial).

Doxekal 80 mg/4 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 Doxekal concentrate for solution for infusion to stand below 25°C for 5 minutes before use.

More than one vial of Doxekal concentrate for solution for infusion may be necessary to obtain the required dose for the patient. Aseptically withdraw the required amount of Doxekal concentrate for solution for infusion using a calibrated syringe fitted with a 21G needle.

In Doxekal 80 mg /4 ml vial the concentration of docetaxel is 20 mg/ml.

The required volume of Doxekal concentrate for solution for infusion must be injected via a single injection (one shot) into a 250 ml infusion bag or bottle 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 is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.

Mix the infusion bag or bottle 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, Doxekal infusion solution should be visually inspected prior to use, solutions containing a precipitate should be discarded.

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