Posology : מינונים

4.2     Posology and method of administration

Docetaxel Venus Pharma 20 mg/ml is for intravenous use only.
The use of docetaxel should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy (see section 6.6).

Posology

For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see section 4.4).

For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.4).

Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.

Docetaxel is administered as a 1 hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive 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.

In the adjuvant treatment of patients with operable breast cancer whose tumours over-express HER2 the recommended docetaxel dose is as follows:
- AC-TH: AC (cycles 1-4): doxorubicin (A) 60 mg/m2 followed by cyclophosphamide (C) 600 mg/m2 administered every three weeks for 4 cycles.
TH (cycles 5-8): docetaxel (T) 100 mg/m2 administered every three weeks for 4 cycles, and trastuzumab (H) administered weekly according the following schedule: - Cycle 5 (starting three weeks after the last cycle of AC):
Day 1: trastuzumab 4 mg/kg (loading dose)
Day 2: docetaxel 100 mg/m2
Days 8 and 15: trastuzumab 2 mg/kg
- Cycles 6-8:
Day 1: docetaxel 100 mg/m2 and trastuzumab 2 mg/kg
Days 8 and 15: trastuzumab 2 mg/kg
Three weeks after day 1 of cycle 8: trastuzumab 6 mg/kg is given every three weeks.
Trastuzumab is administered for a total duration of 1 year.
- TCH: TCH (cycles 1-6): docetaxel (T) 75 mg/m2 and carboplatin (C) at AUC of 6 mg/mL/min administered every three weeks and trastuzumab (H) administered weekly according the following schedule:
- Cycle 1:
Day 1: trastuzumab 4 mg/kg (loading dose)
Day 2: docetaxel 75 mg/m2 and carboplatin at AUC of 6 mg/mL/min
Days 8 and 15: trastuzumab 2 mg/kg
- Cycles 2-6:
Day 1: docetaxel 75 mg/m2 followed by carboplatin at AUC of 6 mg/mL/min and trastuzumab 2 mg/kg
Days 8 and 15: trastuzumab 2 mg/kg
Three weeks after day 1 of cycle 6: trastuzumab 6 mg/kg is given every three weeks.
Trastuzumab is administered for a total duration of 1 year.

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.

Ovarian Cancer
The recommended dose of Docetaxel is 100 mg/m2 administered as a one-hour infusion every 3 weeks.
When used in combination, Docetaxel is administered at the recommended dose of 75 mg/m2.

Prostate cancer


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

Gastric adenocarcinoma
The recommended dose of docetaxel is 75 mg/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).

Esophageal cancer
The usual adult dose is 70 mg/m2 (body surface area) as docetaxel, intravenously drip infused over 1 hour once a day at the intervals of 3- 4 weeks. The dose may be reduced depending on the patient's symptoms.

Head and neck cancer
• Docetaxel as monotherapy in the treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck after failure of a previous chemotherapy regimen.
In patients treated for recurrent and/or metastatic squamous cell carcinoma of the head and neck after failure of a previous chemotherapy regimen the recommended dosage of docetaxel is 100 mg/m2 administered as a one-hour infusion every three weeks as a single agent.
• Docetaxel plus Cisplatin plus 5-FU as neoadjuvant in patients with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN).
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 ≥ 1500 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 mg/m2 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

In a pivotal trial in patients who received adjuvant therapy for breast cancer and who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia or infection), it was recommended to use G-CSF to provide prophylactic coverage (e.g., day 4 to 11) in all subsequent cycles. Patients who continued to experience this reaction should remain on G-CSF and have their docetaxel dose reduced to 60 mg/m2.
However, in clinical practice neutropenia could occur earlier. Thus, the use of G-CSF should be considered a function of the neutropenic risk of the patient and current recommendations. 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 < 25000 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 a 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 a Grade 2 toxicity, or the first appearance of a Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1, 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 >1500 cells/mm3 and platelets recover to a level > 100000 cells/mm3. Discontinue treatment if these toxicities persist (see section 4.4).

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

Toxicity                        Dose adjustment


Diarrhoea grade 3        First episode: reduce 5-FU dose by 20%.

Second episode: then reduce docetaxel dose by 20%.
Diarrhoea grade 4        First episode: reduce docetaxel and 5-FU doses by 20%.
Second episode: discontinue treatment.
Stomatitis/mucositis     First episode: reduce 5-FU dose by 20%.
grade 3                  Second episode: stop 5-FU only, at all subsequent cycles.

Third episode: reduce docetaxel dose by 20%.
Stomatitis/mucositis     First episode: stop 5-FU only, at all subsequent cycles.
grade 4
Second episode: reduce docetaxel dose by 20%.
For cisplatin and 5-fluorouracil dosage adjustments, see the corresponding summary of product characteristics.

Patients Treated with Docetaxel in AC-TH or TCH

Patients who received AC-TH or TCH adjuvant therapy for operable breast cancer whose tumours over-express HER2 and who experience an episode of febrile neutropenia or infection should receive prophylactic G-CSF in all subsequent cycles. For a second episode of febrile neutropenia or infection, patients should continue prophylactic G-CSF, and docetaxel will be reduced from 100 mg/m2 to 75 mg/m2 (in the AC-TH regimen); docetaxel will be reduced from 75 mg/m2 to 60 mg/m2 (in the TCH regimen).
However, in clinical practice neutropenia could occur in cycle 1. Thus, G-CSF should be used in consideration of the neutropenic risk of the patient and current recommendations. Depending on the treatment regimen, patients who experience Grade 3 or 4 stomatitis should have their dose decreased from100 mg/m2 to 75 mg/m2 (in the AC-TH regimen) or from 75 mg/m2 to 60 mg/m2 (in the TCH regimen).

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 (e.g., day 6-15) in all subsequent cycles.

Special populations

Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m2 as single agent, patients who have both elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m2 (see sections 4.4 and 5.2). For those patients with serum bilirubin > ULN and/or ALT and AST > 3.5 times the ULN associated with alkaline phosphatase > 6 times the ULN, no dose- reduction can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical trial excluded patients with ALT and/or AST >1.5 times ULN associated with alkaline phosphatase >2.5 times ULN, and bilirubin > 1 times 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 docetaxel in nasopharyngeal carcinoma in children aged 1 month to less than 18 years have not yet been established.


There is no relevant use of docetaxel in the paediatric population in the indications breast cancer, non- small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and III less differentiated nasopharyngeal carcinoma.

Older people

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

Method of administration

For instructions on preparation and administration of the product, see section 6.6.