docetaxel: prescribing information – dosing, contraindications, interactions, side effects

Breast cancer
TAXOTERE in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with:
- operable node-positive breast cancer
- operable node-negative breast cancer
For patients with operable node-negative breast cancer, adjuvant treatment should be restricted to patients eligible to receive chemotherapy according to internationally established criteria for primary therapy of early breast cancer (see section 5.1).
TAXOTERE 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.
TAXOTERE 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.
TAXOTERE 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.
TAXOTERE 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
TAXOTERE is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.
TAXOTERE 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
TAXOTERE in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.
TAXOTERE in combination with androgen-deprivation therapy (ADT), with or without prednisone or prednisolone, is indicated for the treatment of patients with metastatic hormone-sensitive prostate cancer.
Gastric adenocarcinoma
TAXOTERE 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
TAXOTERE 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.

Breast cancer

TAXOTERE in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with:
- operable node-positive breast cancer
- operable node-negative breast cancer.

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

TAXOTERE 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.

TAXOTERE 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.

TAXOTERE 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.

TAXOTERE 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

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

TAXOTERE 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

TAXOTERE in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

TAXOTERE in combination with androgen-deprivation therapy (ADT), with or without prednisone or prednisolone, is indicated for the treatment of patients with metastatic hormone-sensitive prostate cancer.

Gastric adenocarcinoma

TAXOTERE 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

TAXOTERE 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.

Breast cancer

TAXOTERE in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with:
- operable node- positive breast cancer
- operable node-negative breast cancer

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

TAXOTERE 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.

TAXOTERE 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.

TAXOTERE 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.

TAXOTERE 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

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

TAXOTERE 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

TAXOTERE in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

TAXOTERE in combination with androgen-deprivation therapy (ADT), with or without prednisone or prednisolone, is indicated for the treatment of patients with metastatic hormone-sensitive prostate cancer.

Gastric adenocarcinoma

TAXOTERE 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

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

The use of docetaxel should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy (see section 6.6).
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 metastatic castration-resistant 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).
For metastatic hormone-sensitive prostate cancer, irrespective of the concurrent use of prednisone or prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg 12 hours, 3 hours, and 1 hour before docetaxel infusion (see section 4.4).
Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.
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 1 250 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
Metastatic castration-resistant 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).
Metastatic hormone-sensitive prostate cancer
The recommended dose of docetaxel is 75 mg/m2 every 3 weeks for 6 cycles. Prednisone or prednisolone 5 mg orally twice daily may be 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 1 000 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 (see sections 4.4 and 4.8). 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 see section 4.4).
Recommended dose modifications for 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 grade 3
First episode: reduce 5-FU dose by 20%.
Second episode: stop 5-FU only, at all subsequent cycles.
Third episode: reduce docetaxel dose by 20%.
Stomatitis/mucositis grade 4
First episode: stop 5-FU only, at all subsequent cycles.
Second episode: reduce docetaxel dose by 20%.
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 (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 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 TAXOTERE in nasopharyngeal carcinoma in children aged 1 month to less than 18 years have not yet been established.
There is no relevant use of TAXOTERE 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).
Method of administration
For instructions on preparation and administration of the product, see section 6.6.

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 metastatic castration-resistant 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).

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

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

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 1 250 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
Metastatic castration-resistant 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).

Metastatic hormone-sensitive prostate cancer
The recommended dose of docetaxel is 75 mg/m2 every 3 weeks for 6 cycles. Prednisone or prednisolone 5 mg orally twice daily may be 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 1 000 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 (see sections 4.4 and 4.8). 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 see section 4.4).

Recommended dose modifications for 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 grade 3
First episode: reduce 5-FU dose by 20%.
Second episode: stop 5-FU only, at all subsequent cycles.
Third episode: reduce docetaxel dose by 20%.
Stomatitis/mucositis grade 4
First episode: stop 5-FU only, at all subsequent cycles.
Second episode: reduce docetaxel dose by 20%.

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 (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 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 TAXOTERE in nasopharyngeal carcinoma in children aged 1 month to less than 18 years have not yet been established.

There is no relevant use of TAXOTERE 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.

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 metastatic castration-resistant 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).

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

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

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 1 250 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
Metastatic castration-resistant 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).

Metastatic hormone-sensitive prostate cancer
The recommended dose of docetaxel is 75 mg/m2 every 3 weeks for 6 cycles. Prednisone or prednisolone 5 mg orally twice daily may be 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 1 000 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 (see sections 4.4 and 4.8). 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 (see section 4.4).

Recommended dose modifications for 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 grade 3
First episode: reduce 5-FU dose by 20%.
Second episode: stop 5-FU only, at all subsequent cycles.
Third episode: reduce docetaxel dose by 20%.
Stomatitis/mucositis grade 4
First episode: stop 5-FU only, at all subsequent cycles.
Second episode: reduce docetaxel dose by 20%.

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 (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 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 TAXOTERE in nasopharyngeal carcinoma in children aged 1 month to less than 18 years have not yet been established.

There is no relevant use of TAXOTERE 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).

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Docetaxel must not be used in patients with baseline neutrophil count of < 1 500 cells/mm3.
Docetaxel must not be used in patients with severe liver impairment since there is no data available (see sections 4.2 and 4.4).
Contraindications for other medicinal products also apply, when combined with docetaxel.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Patients with severe liver impairment (see sections 4.2 and 4.4).

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

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:
- 1 312 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 (TAX327) 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).
- 545 patients (STAMPEDE study) who received docetaxel in combination with prednisone or prednisolone and ADT.
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).
For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse events occurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in the docetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE grading scale.
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 (see section 4.4).
Nervous system disorders
The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders
Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.
Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.
General disorders and administration site conditions
Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).
Tabulated list of adverse reactions in breast cancer for TAXOTERE 100 mg/m² single agent MedDRA system organ classes Very common adverse reactions Common adverse reactions Uncommon adverse reactions Infections and infestations Infections (G3/4: 5.7%;
including sepsis and pneumonia, fatal in
1.7%)
Infection associated with G4 neutropenia
(G3/4: 4.6%)
Blood and lymphatic system disorders
Neutropenia (G4:
76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia (G4:
0.2%)
Immune system disorders
Hypersensitivity (G3/4:
5.3%)
Metabolism and nutrition disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy (G3: 4.1%);
Peripheral motor neuropathy (G3/4: 4%);
Dysgeusia (severe:
0.07%)
Cardiac disorders
Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders
Hypotension;
Hypertension;
Haemorrhage
Respiratory, thoracic and mediastinal disorders
Dyspnoea (severe:
2.7%)
Gastrointestinal disorders
Stomatitis (G3/4:
5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe:
0.2%);
Abdominal pain
(severe: 1%);
Gastrointestinal haemorrhage (severe:
Oesophagitis (severe:
0.4%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
0.3%)
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4:
5.9%);
Nail disorders (severe:
2.6%)
Musculoskeletal and connective tissue disorders
Myalgia (severe: 1.4%) Arthralgia
General disorders and administration site conditions
Fluid retention (severe:
6.5%);
Asthenia (severe:
11.2%);
Pain
Infusion site reaction;
Non-cardiac chest pain
(severe: 0.4%)
Investigations
G3/4 Blood bilirubin increased (< 5%);
G3/4 Blood alkaline phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)
Description of selected adverse reactions in breast cancer for TAXOTERE 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 TAXOTERE 75 mg/m² single agent MedDRA system organ classes Very common adverse reactions Common adverse reactions Infections and infestations Infections (G3/4: 5%) Blood and lymphatic system disorders Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Febrile neutropenia

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Immune system disorders
Hypersensitivity (no severe)
Metabolism and nutrition disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders
Arrhythmia (no severe)
Vascular disorders
Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe: 0.8%)
Musculoskeletal and connective tissue disorders
Myalgia
General disorders and administration site conditions
Asthenia (severe: 12.4%);
Fluid retention (severe: 0.8%);
Pain
Investigations
G3/4 Blood bilirubin increased
(< 2%)
Tabulated list of adverse reactions in breast cancer for TAXOTERE 75 mg/m² in combination with doxorubicin MedDRA system organ classes Very common adverse reactions Common adverse reactions Uncommon adverse reactions Infections and infestations Infection (G3/4: 7.8%) Blood and lymphatic system disorders Neutropenia (G4: 91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia (G4: 0.8%)
Immune system disorders
Hypersensitivity
(G3/4: 1.2%)
Metabolism and nutrition disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3: 0.4%)
Peripheral motor neuropathy (G3/4:
0.4%)
Cardiac disorders
Cardiac failure;
Arrhythmia (no severe)
Vascular disorders
Hypotension
Gastrointestinal disorders
Nausea (G3/4: 5%); Stomatitis
(G3/4: 7.8%);
Diarrhoea (G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation
Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe: 0.4%);
Skin reaction (no severe)
Musculoskeletal and
Myalgia

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions connective tissue disorders
General disorders and administration site conditions
Asthenia (severe: 8.1%);
Fluid retention (severe: 1.2%);
Pain
Infusion site reaction
Investigations
G3/4 Blood bilirubin increased (< 2.5%);
G3/4 Blood alkaline phosphatase increased
(< 2.5%)
G3/4 AST increased (< 1%);
G3/4 ALT increased (< 1%)
Tabulated list of adverse reactions in non-small cell lung cancer for TAXOTERE 75 mg/m² in combination with cisplatin MedDRA system organ classes Very common adverse reactions Common adverse reactions Uncommon adverse reactions Infections and infestations Infection (G3/4: 5.7%) Blood and lymphatic system disorders Neutropenia (G4: 51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia (G4: 0.5%)
Febrile neutropenia
Immune system disorders
Hypersensitivity (G3/4: 2.5%)
Metabolism and nutrition disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3: 3.7%); Peripheral motor neuropathy (G3/4: 2%)
Cardiac disorders
Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders
Hypotension
(G3/4: 0.7%)
Gastrointestinal disorders
Nausea (G3/4: 9.6%); Vomiting
(G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%)
Constipation
Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe: 0.7%);
Skin reaction (G3/4: 0.2%)
Musculoskeletal and connective tissue disorders
Myalgia (severe: 0.5%)
General disorders and administration site conditions
Asthenia (severe: 9.9%);
Fluid retention (severe: 0.7%);
Fever (G3/4: 1.2%)
Infusion site reaction; Pain
Investigations
G3/4 Blood bilirubin increased
(2.1%);
G3/4 ALT increased (1.3%)
G3/4 AST increased
(0.5%);
G3/4 Blood alkaline phosphatase increased (0.3%)

Tabulated list of adverse reactions in breast cancer for TAXOTERE 100 mg/m² in combination with trastuzumab MedDRA system organ classes Very common adverse reactions Common adverse reactions Blood and lymphatic system disorders Neutropenia (G3/4: 32%);
Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis Metabolism and nutrition disorders Anorexia Psychiatric disorders Insomnia Nervous system disorders Paraesthesia; Headache;
Dysgeusia; Hypoaesthesia
Eye disorders
Lacrimation increased;
Conjunctivitis
Cardiac disorders
Cardiac failure
Vascular disorders
Lymphoedema
Respiratory, thoracic and mediastinal disorders
Epistaxis; Pharyngolaryngeal pain; Nasopharyngitis;
Dyspnoea;
Cough; Rhinorrhoea
Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain
Skin and subcutaneous tissue disorders
Alopecia; Erythema; Rash; Nail disorders
Musculoskeletal and connective tissue disorders
Myalgia; Arthralgia; Pain in extremity; Bone pain; Back pain
General disorders and administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills Lethargy Investigations Weight increased Description of selected adverse reactions in breast cancer for TAXOTERE 100 mg/m² in combination with trastuzumab Cardiac disorders Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus trastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm, 64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm alone.
Blood and 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).

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Infections and infestations

Oral candidiasis (G3/4: < 1%)
Blood and lymphatic system disorders
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Nervous system disorders
Dysgeusia (G3/4: < 1%);
Paraesthesia (G3/4: < 1%)
Dizziness;
Headache (G3/4: < 1%);
Neuropathy peripheral
Eye disorders
Lacrimation increased

Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain (G3/4:
2%)
Dyspnoea (G3/4: 1%);
Cough (G3/4: < 1%);
Epistaxis (G3/4: < 1%)
Gastrointestinal disorders
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue disorders
Hand-foot syndrome (G3/4:
24%);
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4:
< 1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: < 1%);
Back pain (G3/4: 1%)
General disorders and administration site conditions
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%)
Lethargy;
Pain
Investigations

Weight decreased;
G3/4 Blood bilirubin increased
(9%)

Tabulated list of adverse reactions in metastatic castration-resistant prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions

Infections and infestations
Infection (G3/4: 3.3%)

Blood and lymphatic system disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia (G3/4:
0.6%);
Febrile neutropenia
Immune system disorders

Hypersensitivity (G3/4: 0.6%)
Metabolism and nutrition disorders
Anorexia (G3/4: 0.6%)

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Peripheral motor neuropathy
(G3/4: 0%)
Eye disorders

Lacrimation increased (G3/4:
0.6%)

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions

Cardiac disorders

Cardiac left ventricular function decrease (G3/4: 0.3%)
Respiratory, thoracic and mediastinal disorders

Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Gastrointestinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4:
0.9%);
Vomiting (G3/4: 1.2%)

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective bone disorders

Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe: 0.6%)

Tabulated list of adverse reactions in high-risk locally advanced or metastatic hormone-sensitive prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone and ADT (STAMPEDE study)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Blood and lymphatic system disorders
Neutropenia (G3-4: 12 %)
Anaemia
Febrile neutropenia (G3-4: 15%)

Immune system disorders

Hypersensitivity (G3-4: 1%)
Endocrine disorders

Diabetes (G3-4: 1%)
Metabolism and nutrition disorders

Anorexia
Psychiatric disorders
Insomnia (G3: 1%)

Nervous system disorders
Peripheral sensory neuropathy
(≥G3: 2%)a
Headache
Dizziness
Eye disorders

Blurred vision
Cardiac disorders

Hypotension (G3: 0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea (G3: 1%)
Coughing (G3: 0%)
Upper respiratory tract infection
(G3: 1%)
Pharyngitis (G3: 0%)

Gastrointestinal disorders
Diarrhoea (G3: 3%)
Stomatitis (G3: 0%)
Constipation (G3: 0%)
Nausea (G3: 1%)
Dyspepsia
Abdominal pain (G3: 0%)
Flatulence
Vomiting (G3: 1%)

Skin and subcutaneous tissue disorders
Alopecia (G3: 3%)a
Nail changes (G3: 1%)
Rash
Musculoskeletal and connective tissue disorders
Myalgia

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
General disorders and administration site conditions
Lethargy (G3-4: 2%)
Flu-like symptoms (G3: 0%)
Asthenia (G3: 0%)
Fluid retention
Fever (G3: 1%)
Oral candidiasis
Hypocalcaemia (G3: 0%)
Hypophosphataemia (G3-4: 1%)
Hypokalaemia (G3: 0%)

a From the GETUG AFU15 study

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

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 2.4%);
Neutropenic infection
(G3/4: 2.6%)

Blood and lymphatic system disorders
Anaemia (G3/4: 3%);
Neutropenia (G3/4: 59.2%);
Thrombocytopenia (G3/4:
1.6%);
Febrile neutropenia (G3/4:
NA)

Immune system disorders

Hypersensitivity (G3/4:
0.6%)

Metabolism and nutrition disorders
Anorexia (G3/4: 1.5%)

Nervous system disorders
Dysgeusia (G3/4: 0.6%);
Peripheral sensory neuropathy (G3/4: <0.1%)
Peripheral motor neuropathy (G3/4: 0%)
Syncope (G3/4: 0%);
Neurotoxicity (G3/4:
0%);
Somnolence (G3/4:
0%)
Eye disorders
Conjunctivitis (G3/4:
<0.1%)
Lacrimation increased
(G3/4: <0.1%)

Cardiac disorders

Arrhythmia (G3/4:
0.2%)

Vascular disorders
Hot flush (G3/4: 0.5%)
Hypotension (G3/4:
0%);
Phlebitis (G3/4: 0%)
Lymphoedema
(G3/4: 0%)

Respiratory, thoracic and mediastinal disorders

Cough (G3/4: 0%)

Gastrointestinal disorders
Nausea (G3/4: 5.0%);
Stomatitis (G3/4: 6.0%);
Vomiting (G3/4: 4.2%);
Diarrhoea (G3/4: 3.4%);
Constipation (G3/4: 0.5%)
Abdominal pain (G3/4:
0.4%)

Skin and subcutaneous tissue disorders
Alopecia (persisting: <3%);
Skin disorder (G3/4: 0.6%);
Nail disorders (G3/4: 0.4%)

Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4: 0.2%)

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Reproductive system and breast disorders
Amenorrhoea (G3/4: NA)

General disorders and administration site conditions
Asthenia (G3/4: 10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral (G3/4:
0.2%)

Investigations

Weight increased
(G3/4: 0%);
Weight decreased
(G3/4: 0.2%)

Description of selected adverse reactions for adjuvant therapy with TAXOTERE 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer

Nervous system disorders
In study TAX316 peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2 %) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.
In GEICAM 9805 study peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Cardiac disorders
In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC arm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed congestive heart failure during the follow-up period. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

Skin and subcutaneous tissue disorders
In study TAX316 alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%).
At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study alopecia that started during the treatment period and persisted into the follow- up period was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in FAC arm. Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Reproductive system and breast disorders
In TAX316 amenorrhoea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736

FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).
In GEICAM 9805 study amenorrhoea that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in FAC arm.

General disorders and administration site conditions
In study TAX316 peripheral oedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral oedema was ongoing in19 TAC patients (2.6%) and 4 FAC patients (0.5%).
In study TAX316 lymphoedema that started during the treatment period and persisted into the follow- up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).
In study TAX316 asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805 peripheral oedema that started during the treatment period persisted into the follow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC arm had peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm.
Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients (0.9%) in TAC arm and 2 patients (0.4 %) in FAC arm. At the end of the follow-up period, lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.

Acute leukaemia / Myelodysplastic syndrome.
After 10 years of follow up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients (0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).

After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%) patients in TAC arm. No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

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

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

Without primary
G-CSF prophylaxis
(n = 111) n (%)
With primary
G-CSF prophylaxis
(n = 421) n (%)
Neutropenia (Grade 4)
104 (93.7)
135 (32.1)
Febrile neutropenia
28 (25.2)
23 (5.5)
Neutropenic infection
14 (12.6)
21 (5.0)
Neutropenic infection (Grade 3-4)
2 (1.8)
5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Infections and infestations
Neutropenic infection;
Infection (G3/4: 11.7%)

Blood and lymphatic system disorders
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4:
8.8%);
Febrile neutropenia

Immune system disorders
Hypersensitivity (G3/4: 1.7%)

Metabolism and nutrition disorders
Anorexia (G3/4: 11.7%)

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%)
Eye disorders

Lacrimation increased (G3/4:
0%)
Ear and labyrinth disorders

Hearing impaired (G3/4: 0%)
Cardiac disorders

Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%)
Constipation (G3/4: 1.0%);
Gastrointestinal pain (G3/4:
1.0%);
Oesophagitis/dysphagia/odynop hagia (G3/4: 0.7%)
Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%)
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%)
General disorders and administration site conditions
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention
(severe/life-threatening: 1%)

Description of selected adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m2 in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of

patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 6.3%);
Neutropenic infection

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

Cancer pain (G3/4:
0.6%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Febrile neutropenia

Immune system disorders

Hypersensitivity (no severe)

Metabolism and nutrition disorders
Anorexia (G3/4: 0.6%)

Nervous system disorders
Dysgeusia/Parosmia;
Peripheral sensory neuropathy (G3/4:
0.6%)
Dizziness

Eye disorders

Lacrimation increased;
Conjunctivitis

Ear and labyrinth disorders

Hearing impaired

Cardiac disorders

Myocardial ischemia
(G3/4:1.7%)
Arrhythmia (G3/4:
0.6%)
Vascular disorders

Venous disorder (G3/4:
0.6%)

Gastrointestinal disorders
Nausea (G3/4: 0.6%);
Stomatitis (G3/4:
4.0%);
Diarrhoea (G3/4: 2.9%);
Vomiting (G3/4: 0.6%)
Constipation;
Esophagitis/dysphagia/ odynophagia (G3/4:
0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal haemorrhage (G3/4:
0.6%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 10.9%) Rash pruritic;
Dry skin;
Skin exfoliative (G3/4:
0.6%)

Musculoskeletal and connective tissue disorders

Myalgia (G3/4: 0.6%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
General disorders and administration site conditions
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema

Investigations

Weight increased

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 3.6%)

Neutropenic infection

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

Cancer pain (G3/4:
1.2%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
83.5%);
Anaemia (G3/4:
12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia

Immune system disorders

Hypersensitivity
Metabolism and nutrition disorders
Anorexia (G3/4:
12.0%)

Nervous system disorders
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory neuropathy (G3/4:
1.2%)
Dizziness (G3/4:
2.0%);
Peripheral motor neuropathy (G3/4:
0.4%)

Eye disorders

Lacrimation increased
Conjunctivitis
Ear and labyrinth disorders
Hearing impaired
(G3/4: 1.2%)

Cardiac disorders

Arrhythmia (G3/4:
2.0%)
Ischemia myocardial
Vascular disorders

Venous disorder
Gastrointestinal disorders
Nausea (G3/4: 13.9%);
Stomatitis (G3/4:
20.7%);
Vomiting (G3/4:
8.4%);
Diarrhoea (G3/4:
6.8%);
Esophagitis/dysphagia/ odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Dyspepsia (G3/4:
0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal haemorrhage (G3/4:
0.4%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritic
Dry skin ;
Desquamation

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Musculoskeletal, connective tissue bone disorders

Myalgia (G3/4: 0.4%)

General disorders and administration site conditions
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)

Investigations
Weight decreased

Weight increased

Post-marketing experience

Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukaemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen.

Blood and lymphatic system disorders
Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure, has been reported.

Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the medicinal product.

Eye disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been rarely reported. Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel.

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

Cardiac disorders
Rare cases of myocardial infarction have been reported.
Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5- fluorouracil and/ or cyclophosphamide.

Vascular disorders
Venous thromboembolic events have rarely been reported.

Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome and cases of interstitial pneumonia/ pneumonitis, interstitial lung

disease, pulmonary fibrosis and respiratory failure sometimes fatal have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders
Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).
Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinal perforation.
Rare cases of ileus and intestinal obstruction have been reported.

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

Skin and subcutaneous tissue disorders
Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel.
Scleroderma-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia and cases of psoriasis, including cases of recurrence or aggravation of pre-existing psoriasis (frequency not known) have been reported.

Renal and urinary disorders
Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro- intestinal disorders.

General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).
Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration and pulmonary oedema have rarely been reported.

Metabolism and nutrition disorders
Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea. Tumour lysis syndrome, potentially fatal, has been reported (frequency not known).

Musculoskeletal disorder
Myositis has been reported with docetaxel (frequency not known).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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:
- 1 312 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 (TAX327) 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).
• 545 patients (STAMPEDE study) who received docetaxel in combination with prednisone or prednisolone and ADT.

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).

For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse events occurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in the docetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE grading scale.

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 (see section 4.4).

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.
Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions

Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infections (G3/4: 5.7%;
including sepsis and pneumonia, fatal in
1.7%)
Infection associated with G4 neutropenia
(G3/4: 4.6%)

Blood and lymphatic system disorders
Neutropenia (G4:
76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia (G4:
0.2%)

Immune system disorders
Hypersensitivity (G3/4:
5.3%)

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 4.1%);
Peripheral motor neuropathy (G3/4: 4%);
Dysgeusia (severe:
0.07%)

Cardiac disorders

Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders

Hypotension;
Hypertension;
Haemorrhage

Respiratory, thoracic and mediastinal disorders
Dyspnoea (severe:
2.7%)

Gastrointestinal disorders
Stomatitis (G3/4:
5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe:
0.2%);
Abdominal pain
(severe: 1%);
Gastrointestinal haemorrhage (severe:
0.3%)

Oesophagitis (severe:
0.4%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4:
5.9%);
Nail disorders (severe:
2.6%)

Musculoskeletal and connective tissue disorders
Myalgia (severe: 1.4%) Arthralgia

General disorders and administration site conditions
Fluid retention (severe:
6.5%);
Asthenia (severe:
11.2%);
Pain
Infusion site reaction;
Non-cardiac chest pain
(severe: 0.4%)

Investigations

G3/4 Blood bilirubin increased (< 5%);
G3/4 Blood alkaline phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Infections and infestations
Infections (G3/4: 5%)

Blood and lymphatic system disorders
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Febrile neutropenia
Immune system disorders

Hypersensitivity (no severe)
Metabolism and nutrition
Anorexia

MedDRA system organ classes Very common adverse reactions
Common adverse reactions disorders
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders

Arrhythmia (no severe)
Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe: 0.8%)
Musculoskeletal and connective tissue disorders

Myalgia
General disorders and administration site conditions
Asthenia (severe: 12.4%);
Fluid retention (severe: 0.8%);
Pain

Investigations

G3/4 Blood bilirubin increased
(< 2%)

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 7.8%)

Blood and lymphatic system disorders
Neutropenia (G4:
91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia (G4:
0.8%)

Immune system disorders

Hypersensitivity (G3/4:
1.2%)

Metabolism and nutrition disorders

Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 0.4%)
Peripheral motor neuropathy (G3/4:
0.4%)

Cardiac disorders

Cardiac failure;
Arrhythmia (no severe)

Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 5%);
Stomatitis (G3/4:
7.8%);
Diarrhoea (G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe:
0.4%);
Skin reaction (no severe)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions
Asthenia (severe:
8.1%);
Fluid retention (severe:
1.2%);
Pain
Infusion site reaction

Investigations

G3/4 Blood bilirubin increased (< 2.5%);
G3/4 Blood alkaline phosphatase increased
(< 2.5%)
G3/4 AST increased
(< 1%);
G3/4 ALT increased
(< 1%)

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

MedDRA system organ classes
Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations
Infection (G3/4: 5.7%)

Blood and lymphatic system disorders
Neutropenia (G4:
51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia (G4:
0.5%)
Febrile neutropenia

Immune system disorders
Hypersensitivity (G3/4:
2.5%)

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 3.7%);
Peripheral motor neuropathy (G3/4: 2%)

Cardiac disorders

Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders

Hypotension (G3/4:
0.7%)

Gastrointestinal disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%)
Constipation

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe:
0.7%);
Skin reaction (G3/4:
0.2%)

Musculoskeletal and connective tissue disorders
Myalgia (severe: 0.5%)

General disorders and administration site conditions
Asthenia (severe:
9.9%);
Fluid retention (severe:
Infusion site reaction;
Pain

MedDRA system organ classes
Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

0.7%);
Fever (G3/4: 1.2%)
Investigations

G3/4 Blood bilirubin increased (2.1%);
G3/4 ALT increased
(1.3%)

G3/4 AST increased
(0.5%);
G3/4 Blood alkaline phosphatase increased
(0.3%)

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Blood and lymphatic system disorders
Neutropenia (G3/4: 32%);
Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis

Metabolism and nutrition disorders
Anorexia

Psychiatric disorders
Insomnia

Nervous system disorders
Paraesthesia; Headache;
Dysgeusia; Hypoesthesia

Eye disorders
Lacrimation increased;
Conjunctivitis

Cardiac disorders

Cardiac failure
Vascular disorders
Lymphoedema

Respiratory, thoracic and mediastinal disorders
Epistaxis; Pharyngolaryngeal pain; Nasopharyngitis;
Dyspnoea;
Cough; Rhinorrhoea

Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain

Skin and subcutaneous tissue disorders
Alopecia; Erythema; Rash; Nail disorders

Musculoskeletal and connective tissue disorders
Myalgia; Arthralgia; Pain in extremity; Bone pain; Back pain

General disorders and administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills Lethargy Investigations Weight increased

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

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

Blood and 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).

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Infections and infestations

Oral candidiasis (G3/4: < 1%)
Blood and lymphatic system disorders
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Nervous system disorders
Dysgeusia (G3/4: < 1%);
paraesthesia (G3/4: < 1%)
Dizziness;
Headache (G3/4: < 1%);
Neuropathy peripheral
Eye disorders
Lacrimation increased

Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain (G3/4:
2%)
Dyspnoea (G3/4: 1%);
Cough (G3/4: < 1%);
Epistaxis (G3/4: < 1%)
Gastrointestinal disorders
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue disorders
Hand-foot syndrome (G3/4:
24%);
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4:
< 1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: < 1%);
Back pain (G3/4: 1%)
General disorders and administration site conditions
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%)
Lethargy;
Pain
Investigations

Weight decreased;
G3/4 Blood bilirubin increased
(9%)

Tabulated list of adverse reactions in metastatic castration-resistant prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions

Infections and infestations
Infection (G3/4: 3.3%)

Blood and lymphatic system disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia (G3/4:
0.6%);
Febrile neutropenia

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions

Immune system disorders

Hypersensitivity (G3/4: 0.6%)
Metabolism and nutrition disorders
Anorexia (G3/4: 0.6%)

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Peripheral motor neuropathy
(G3/4: 0%)
Eye disorders

Lacrimation increased (G3/4:
0.6%)
Cardiac disorders

Cardiac left ventricular function decrease (G3/4: 0.3%)
Respiratory, thoracic and mediastinal disorders

Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Gastrointestinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4:
0.9%);
Vomiting (G3/4: 1.2%)

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective bone disorders

Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe: 0.6%)

Tabulated list of adverse reactions in high-risk locally advanced or metastatic hormone-sensitive prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone and ADT (STAMPEDE sutdy)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Blood and lymphatic system disorders
Neutropenia (G3-4: 12 %)
Anaemia
Febrile neutropenia (G3-4: 15%)

Immune system disorders

Hypersensitivity (G3-4: 1%)
Endocrine disorders

Diabetes (G3-4: 1%)
Metabolism and nutrition disorders

Anorexia
Psychiatric disorders
Insomnia (G3: 1%)

Nervous system disorders
Peripheral sensory neuropathy
(≥G3: 2%)a
Headache
Dizziness
Eye disorders

Blurred vision
Cardiac disorders

Hypotension (G3: 0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea (G3: 1%)
Coughing (G3: 0%)
Upper respiratory tract infection
(G3: 1%)
Pharyngitis (G3: 0%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Gastrointestinal disorders
Diarrhoea (G3: 3%)
Stomatitis (G3: 0%)
Constipation (G3: 0%)
Nausea (G3: 1%)
Dyspepsia
Abdominal pain (G3: 0%)
Flatulence
Vomiting (G3: 1%)

Skin and subcutaneous tissue disorders
Alopecia (G3: 3%)a
Nail changes (G3: 1%)
Rash
Musculoskeletal and connective tissue disorders
Myalgia

General disorders and administration site conditions
Lethargy (G3-4: 2%)
Flu-like symptoms (G3: 0%)
Asthenia (G3: 0%)
Fluid retention
Fever (G3: 1%)
Oral candidiasis
Hypocalcaemia (G3: 0%)
Hypophosphataemia (G3-4: 1%)
Hypokalaemia (G3: 0%) a From the GETUG AFU15 study

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

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 2.4%);
Neutropenic infection
(G3/4: 2.6%)

Blood and lymphatic system disorders
Anaemia (G3/4: 3%);
Neutropenia (G3/4:
59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4: NA)

Immune system disorders

Hypersensitivity (G3/4:
0.6%)

Metabolism and nutrition disorders
Anorexia (G3/4: 1.5%)

Nervous system disorders
Dysgeusia (G3/4:
0.6%);
Peripheral sensory neuropathy (G3/4:
<0.1%)
Peripheral motor neuropathy (G3/4: 0%)
Syncope (G3/4: 0%);
Neurotoxicity (G3/4:
0%);
Somnolence (G3/4: 0%)
Eye disorders
Conjunctivitis (G3/4:
<0.1%)
Lacrimation increased
(G3/4: <0.1%)

Cardiac disorders

Arrhythmia (G3/4:
0.2%)

Vascular disorders
Hot flush (G3/4: 0.5%)
Hypotension (G3/4:
0%);
Phlebitis (G3/4: 0%)
Lymphoedema (G3/4:
0%)

Respiratory, thoracic and mediastinal disorders

Cough (G3/4: 0%)

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Gastrointestinal disorders
Nausea (G3/4: 5.0%);
Stomatitis (G3/4:
6.0%);
Vomiting (G3/4: 4.2%);
Diarrhoea (G3/4: 3.4%);
Constipation (G3/4:
0.5%)
Abdominal pain (G3/4:
0.4%)

Skin and subcutaneous tissue disorders
Alopecia (persisting:
<3%);
Skin disorder (G3/4:
0.6%);
Nail disorders (G3/4:
0.4%)

Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4: 0.2%)

Reproductive system and breast disorders
Amenorrhoea (G3/4:
NA)

General disorders and administration site conditions
Asthenia (G3/4:
10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral
(G3/4: 0.2%)

Investigations

Weight increased (G3/4:
0%);
Weight decreased
(G3/4: 0.2%)

Description of selected adverse reactions for adjuvant therapy with Taxotere 75 mg/m2 in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer

Nervous system disorders
In study TAX316 peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2 %) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.
In GEICAM 9805 study peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Cardiac disorders
In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC arm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed congestive heart failure during the follow-up period. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

Skin and subcutaneous tissue disorders
In study TAX316 alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%).
At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study alopecia that started during the treatment period and persisted into the follow- up period was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in FAC arm. Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Reproductive system and breast disorders
In TAX316 amenorrhoea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

In GEICAM 9805 study amenorrhoea that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in FAC arm.

General disorders and administration site conditions
In study TAX316 peripheral oedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral oedema was ongoing in19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316 lymphoedema that started during the treatment period and persisted into the follow- up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).
In study TAX316 asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805 peripheral oedema that started during the treatment period persisted into the follow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC arm had peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm.
Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients (0.9%) in TAC arm and 2 patients (0.4 %) in FAC arm. At the end of the follow-up period, lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in FAC arm.
Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.

Acute leukaemia / Myelodysplastic syndrome.
After 10 years of follow up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients (0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic

syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).
After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%) patients in TAC arm. No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

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

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

Without primary
G-CSF prophylaxis
(n = 111) n (%)
With primary
G-CSF prophylaxis
(n = 421) n (%)
Neutropenia (Grade 4)
104 (93.7)
135 (32.1
Febrile neutropenia
28 (25.2)
23 (5.5)
Neutropenic infection
14 (12.6)
21 (5.0)
Neutropenic infection
(Grade 3-4)
2 (1.8)
5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Infections and infestations
Neutropenic infection;
Infection (G3/4: 11.7%)

Blood and lymphatic system disorders
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4:
8.8%);
Febrile neutropenia

Immune system disorders
Hypersensitivity (G3/4: 1.7%)

Metabolism and nutrition disorders
Anorexia (G3/4: 11.7%)

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%)
Eye disorders

Lacrimation increased (G3/4:
0%)
Ear and labyrinth disorders

Hearing impaired (G3/4: 0%)
Cardiac disorders

Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%)
Constipation (G3/4: 1.0%);
Gastrointestinal pain (G3/4:
1.0%);
Oesophagitis/dysphagia/odynop hagia (G3/4: 0.7%)
Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%)
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%)

General disorders and administration site conditions
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention
(severe/life-threatening: 1%)

Description of selected adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m2 in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 6.3%);
Neutropenic infection

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

Cancer pain (G3/4:
0.6%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Febrile neutropenia

Immune system disorders

Hypersensitivity (no severe)

Metabolism and nutrition disorders
Anorexia (G3/4: 0.6%)

Nervous system disorders
Dysgeusia/Parosmia;
Peripheral sensory neuropathy (G3/4:
0.6%)
Dizziness

Eye disorders

Lacrimation increased;
Conjunctivitis

Ear and labyrinth disorders

Hearing impaired

Cardiac disorders

Myocardial ischemia
(G3/4:1.7%)
Arrhythmia (G3/4:
0.6%)
Vascular disorders

Venous disorder (G3/4:
0.6%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Gastrointestinal disorders
Nausea (G3/4: 0.6%);
Stomatitis (G3/4:
4.0%);
Diarrhoea (G3/4: 2.9%);
Vomiting (G3/4: 0.6%)
Constipation;
Esophagitis/dysphagia/ odynophagia (G3/4:
0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal haemorrhage (G3/4:
0.6%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 10.9%) Rash pruritic;
Dry skin;
Skin exfoliative (G3/4:
0.6%)

Musculoskeletal and connective tissue disorders

Myalgia (G3/4: 0.6%)

General disorders and administration site conditions
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema

Investigations

Weight increased

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system organ classes
Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations
Infection (G3/4: 3.6%)

Neutropenic infection

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

Cancer pain (G3/4:
1.2%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
83.5%);
Anaemia (G3/4:
12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia

Immune system disorders

Hypersensitivity
Metabolism and nutrition disorders
Anorexia (G3/4:
12.0%)

Nervous system disorders
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory neuropathy (G3/4:
1.2%)
Dizziness (G3/4:
2.0%);
Peripheral motor neuropathy (G3/4:
0.4%)

Eye disorders

Lacrimation increased
Conjunctivitis
Ear and labyrinth disorders
Hearing impaired
(G3/4: 1.2%)

Cardiac disorders

Arrhythmia (G3/4:
2.0%)
Ischemia myocardial

MedDRA system organ classes
Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Vascular disorders

Venous disorder
Gastrointestinal disorders
Nausea (G3/4: 13.9%);
Stomatitis (G3/4:
20.7%);
Vomiting (G3/4:
8.4%);
Diarrhoea (G3/4:
6.8%);
Esophagitis/dysphagia/ odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Dyspepsia (G3/4:
0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal haemorrhage (G3/4:
0.4%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritic
Dry skin ;
Desquamation

Musculoskeletal, connective tissue bone disorders

Myalgia (G3/4: 0.4%)

General disorders and administration site conditions
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)

Investigations
Weight decreased

Weight increased

Post-marketing experience

Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukaemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen.

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

Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the medicinal product.

Eye disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been

rarely reported. Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel.

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

Cardiac disorders
Rare cases of myocardial infarction have been reported.
Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5- fluorouracil and/ or cyclophosphamide.

Vascular disorders
Venous thromboembolic events have rarely been reported.

Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome and cases of interstitial pneumonia/ pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure sometimes fatal have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders
Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).

Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinal perforation.
Rare cases of ileus and intestinal obstruction have been reported.

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

Skin and subcutaneous tissue disorders
Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel.
Scleroderma-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia and cases of psoriasis, including cases of recurrence or aggravation of pre-existing psoriasis (frequency not known) have been reported.

Renal and urinary disorders
Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro- intestinal disorders.

General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).

Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration and pulmonary oedema have rarely been reported.

Metabolism and nutrition disorders
Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, and

hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea. Tumour lysis syndrome, potentially fatal, has been reported (frequency not known).

Musculoskeletal disorder
Myositis has been reported with docetaxel (frequency not known).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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:
- 1 312 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 (TAX327) who received docetaxel in combination with prednisone or prednisolone (clinically important treatment related adverse events are presented).
- 1 276 patients (744 and 532 in TAX 316 and GEICAM 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).
• 545 patients (STAMPEDE study) who received docetaxel in combination with prednisone or prednisolone and ADT.

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).

For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse events occurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in the docetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE grading scale.

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 (see section 4.4).

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.

Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions

Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infections (G3/4: 5.7%;
including sepsis and pneumonia, fatal in
1.7%)
Infection associated with G4 neutropenia
(G3/4: 4.6%)

Blood and lymphatic system disorders
Neutropenia (G4:
76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia (G4:
0.2%)

Immune system disorders
Hypersensitivity (G3/4:
5.3%)

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 4.1%);
Peripheral motor neuropathy (G3/4: 4%);
Dysgeusia (severe:
0.07%)

Cardiac disorders

Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders

Hypotension;
Hypertension;
Haemorrhage

Respiratory, thoracic and mediastinal disorders
Dyspnoea (severe:
2.7%)

Gastrointestinal disorders
Stomatitis (G3/4:
5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe:
0.2%);
Abdominal pain
(severe: 1%);
Gastrointestinal haemorrhage (severe:
0.3%)
Oesophagitis (severe:
0.4%)
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4:
5.9%);
Nail disorders (severe:
2.6%)

Musculoskeletal and
Myalgia (severe: 1.4%) Arthralgia

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions connective tissue disorders

General disorders and administration site conditions
Fluid retention (severe:
6.5%);
Asthenia (severe:
11.2%);
Pain
Infusion site reaction;
Non-cardiac chest pain
(severe: 0.4%)

Investigations

G3/4 Blood bilirubin increased (< 5%);
G3/4 Blood alkaline phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Infections and infestations
Infections (G3/4: 5%)

Blood and lymphatic system disorders
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Febrile neutropenia
Immune system disorders

Hypersensitivity (no severe)
Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders

Arrhythmia (no severe)

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe: 0.8%)
Musculoskeletal and connective tissue disorders

Myalgia
General disorders and administration site conditions
Asthenia (severe: 12.4%);
Fluid retention (severe: 0.8%);
Pain

Investigations

G3/4 Blood bilirubin increased
(< 2%)

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 7.8%)

Blood and lymphatic system disorders
Neutropenia (G4:
91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia (G4:
0.8%)

Immune system disorders

Hypersensitivity (G3/4:
1.2%)

Metabolism and nutrition disorders

Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 0.4%)
Peripheral motor neuropathy (G3/4:
0.4%)

Cardiac disorders

Cardiac failure;
Arrhythmia (no severe)

Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 5%);
Stomatitis (G3/4:
7.8%);
Diarrhoea (G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe:
0.4%);
Skin reaction (no severe)

Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site
Asthenia (severe:
8.1%);
Infusion site reaction

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions conditions
Fluid retention (severe:
1.2%);
Pain
Investigations

G3/4 Blood bilirubin increased (< 2.5%);
G3/4 Blood alkaline phosphatase increased
(< 2.5%)
G3/4 AST increased
(< 1%);
G3/4 ALT increased
(< 1%)

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 5.7%)

Blood and lymphatic system disorders
Neutropenia (G4:
51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia (G4:
0.5%)
Febrile neutropenia

Immune system disorders
Hypersensitivity (G3/4:
2.5%)

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 3.7%);
Peripheral motor neuropathy (G3/4: 2%)

Cardiac disorders

Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders

Hypotension (G3/4:
0.7%)

Gastrointestinal disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%)
Constipation

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe:
0.7%);
Skin reaction (G3/4:
0.2%)

Musculoskeletal and connective tissue disorders
Myalgia (severe: 0.5%)

General disorders and administration site conditions
Asthenia (severe:
9.9%);
Fluid retention (severe:
0.7%);
Fever (G3/4: 1.2%)
Infusion site reaction;
Pain

Investigations

G3/4 Blood bilirubin increased (2.1%);
G3/4 ALT increased
(1.3%)
G3/4 AST increased
(0.5%);
G3/4 Blood alkaline phosphatase increased

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions

(0.3%)

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Blood and lymphatic system disorders
Neutropenia (G3/4: 32%);
Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis

Metabolism and nutrition disorders
Anorexia

Psychiatric disorders
Insomnia

Nervous system disorders
Paraesthesia; Headache;
Dysgeusia; Hypoesthesia

Eye disorders
Lacrimation increased;
Conjunctivitis

Cardiac disorders

Cardiac failure
Vascular disorders
Lymphoedema

Respiratory, thoracic and mediastinal disorders
Epistaxis; Pharyngolaryngeal pain; Nasopharyngitis;
Dyspnoea;
Cough; Rhinorrhoea

Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain

Skin and subcutaneous tissue disorders
Alopecia; Erythema; Rash; Nail disorders

Musculoskeletal and connective tissue disorders
Myalgia; Arthralgia; Pain in extremity; Bone pain; Back pain

General disorders and administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills Lethargy Investigations Weight increased

Description of selected adverse reactions in breast cancer for Taxotere 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 TAXOTERE 75 mg/m² in combination with capecitabine

MedDRA system organ classes Very common adverse reactions

Common adverse reactions

Infections and infestations

Oral candidiasis (G3/4: < 1%)
Blood and lymphatic system disorders
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Nervous system disorders
Dysgeusia (G3/4: < 1%);
paraesthesia (G3/4: < 1%)
Dizziness;
Headache (G3/4: < 1%);
Neuropathy peripheral
Eye disorders
Lacrimation increased

Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain (G3/4:
2%)
Dyspnoea (G3/4: 1%);
Cough (G3/4: < 1%);
Epistaxis (G3/4: < 1%)
Gastrointestinal disorders
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue disorders
Hand-foot syndrome (G3/4:
24%);
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4:
< 1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: < 1%);
Back pain (G3/4: 1%)
General disorders and administration site conditions
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%)
Lethargy;
Pain
Investigations

Weight decreased;
G3/4 Blood bilirubin increased
(9%)

Tabulated list of adverse reactions in metastatic castration-resistant prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions
Infections and infestations
Infection (G3/4: 3.3%)

Blood and lymphatic system disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia (G3/4:
0.6%);
Febrile neutropenia
Immune system disorders

Hypersensitivity (G3/4: 0.6%)
Metabolism and nutrition disorders
Anorexia (G3/4: 0.6%)

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Peripheral motor neuropathy
(G3/4: 0%)

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions
Eye disorders

Lacrimation increased (G3/4:
0.6%)
Cardiac disorders

Cardiac left ventricular function decrease (G3/4: 0.3%)
Respiratory, thoracic and mediastinal disorders

Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Gastrointestinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4:
0.9%);
Vomiting (G3/4: 1.2%)

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective bone disorders

Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe: 0.6%)

Tabulated list of adverse reactions in high-risk locally advanced or metastatic hormone-sensitive prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone and ADT (STAMPEDE study)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Blood and lymphatic system disorders
Neutropenia (G3-4: 12 %)
Anaemia
Febrile neutropenia (G3-4: 15%)

Immune system disorders

Hypersensitivity (G3-4: 1%)
Endocrine disorders

Diabetes (G3-4: 1%)
Metabolism and nutrition disorders

Anorexia
Psychiatric disorders
Insomnia (G3: 1%)

Nervous system disorders
Peripheral sensory neuropathy
(≥G3: 2%)a
Headache
Dizziness
Eye disorders

Blurred vision
Cardiac disorders

Hypotension (G3: 0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea (G3: 1%)
Coughing (G3: 0%)
Upper respiratory tract infection
(G3: 1%)
Pharyngitis (G3: 0%)

Gastrointestinal disorders
Diarrhoea (G3: 3%)
Stomatitis (G3: 0%)
Constipation (G3: 0%)
Nausea (G3: 1%)
Dyspepsia
Abdominal pain (G3: 0%)
Flatulence
Vomiting (G3: 1%)

Skin and subcutaneous tissue disorders
Alopecia (G3: 3%)a
Nail changes (G3: 1%)
Rash

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Musculoskeletal and connective tissue disorders
Myalgia

General disorders and administration site conditions
Lethargy (G3-4: 2%)
Flu-like symptoms (G3: 0%)
Asthenia (G3: 0%)
Fluid retention
Fever (G3: 1%)
Oral candidiasis
Hypocalcaemia (G3: 0%)
Hypophosphataemia (G3-4: 1%)
Hypokalaemia (G3: 0%) a From the GETUG AFU15 study

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

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 2.4%);
Neutropenic infection
(G3/4: 2.6%)

Blood and lymphatic system disorders
Anaemia (G3/4: 3%);
Neutropenia (G3/4:
59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4: NA)

Immune system disorders

Hypersensitivity (G3/4:
0.6%)

Metabolism and nutrition disorders
Anorexia (G3/4: 1.5%)

Nervous system disorders
Dysgeusia (G3/4:
0.6%);
Peripheral sensory neuropathy (G3/4:
<0.1%)
Peripheral motor neuropathy (G3/4: 0%)
Syncope (G3/4: 0%);
Neurotoxicity (G3/4:
0%);
Somnolence (G3/4: 0%)
Eye disorders
Conjunctivitis (G3/4:
<0.1%)
Lacrimation increased
(G3/4: <0.1%)

Cardiac disorders

Arrhythmia (G3/4:
0.2%)

Vascular disorders
Hot flush (G3/4: 0.5%)
Hypotension (G3/4:
0%);
Phlebitis (G3/4: 0%)
Lymphoedema (G3/4:
0%)

Respiratory, thoracic and mediastinal disorders

Cough (G3/4: 0%)

Gastrointestinal disorders
Nausea (G3/4: 5.0%);
Stomatitis (G3/4:
6.0%);
Vomiting (G3/4: 4.2%);
Diarrhoea (G3/4: 3.4%);
Constipation (G3/4:
0.5%)
Abdominal pain (G3/4:
0.4%)

Skin and subcutaneous
Alopecia (persisting:

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions tissue disorders
<3%);
Skin disorder (G3/4:
0.6%);
Nail disorders (G3/4:
0.4%)
Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4: 0.2%)

Reproductive system and breast disorders
Amenorrhoea (G3/4:
NA)

General disorders and administration site conditions
Asthenia (G3/4:
10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral
(G3/4: 0.2%)

Investigations

Weight increased (G3/4:
0%);
Weight decreased
(G3/4: 0.2%)

Description of selected adverse reactions for adjuvant therapy with TAXOTERE 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer

Nervous system disorders
In study TAX316 peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2 %) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.
In GEICAM 9805 study peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Cardiac disorders
In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC arm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed congestive heart failure during the follow-up period. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

Skin and subcutaneous tissue disorders
In study TAX316 alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%).
At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study alopecia that started during the treatment period and persisted into the follow- up period was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in

FAC arm. Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Reproductive system and breast disorders
In TAX316 amenorrhoea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

In GEICAM 9805 study amenorrhoea that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in FAC arm.

General disorders and administration site conditions
In study TAX316 peripheral oedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral oedema was ongoing in19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316 lymphoedema that started during the treatment period and persisted into the follow- up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).
In study TAX316 asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805 peripheral oedema that started during the treatment period persisted into the follow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC arm had peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm.
Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients (0.9%) in TAC arm and 2 patients (0.4 %) in FAC arm. At the end of the follow-up period, lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in FAC arm.
Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.

Acute leukaemia / Myelodysplastic syndrome.
After 10 years of follow up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients (0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).
After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%) patients in TAC arm. No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

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

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

Without primary
G-CSF prophylaxis
(n = 111) n (%)
With primary
G-CSF prophylaxis
(n = 421) n (%)
Neutropenia (Grade 4)
104 (93.7)
135 (32.1
Febrile neutropenia
28 (25.2)
23 (5.5)
Neutropenic infection
14 (12.6)
21 (5.0)
Neutropenic infection
(Grade 3-4)
2 (1.8)
5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Infections and infestations
Neutropenic infection;
Infection (G3/4: 11.7%)

Blood and lymphatic system disorders
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4:
8.8%);
Febrile neutropenia

Immune system disorders
Hypersensitivity (G3/4: 1.7%)

Metabolism and nutrition disorders
Anorexia (G3/4: 11.7%)

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%)
Eye disorders

Lacrimation increased (G3/4:
0%)
Ear and labyrinth disorders

Hearing impaired (G3/4: 0%)
Cardiac disorders

Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%)
Constipation (G3/4: 1.0%);
Gastrointestinal pain (G3/4:
1.0%);
Oesophagitis/dysphagia/odynop hagia (G3/4: 0.7%)
Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%)
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%)
General disorders and administration site conditions
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention (severe/life- threatening: 1%)

Description of selected adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m2 in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 6.3%);
Neutropenic infection

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

Cancer pain (G3/4:
0.6%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Febrile neutropenia

Immune system disorders

Hypersensitivity (no severe)

Metabolism and nutrition disorders
Anorexia (G3/4: 0.6%)

Nervous system disorders
Dysgeusia/Parosmia;
Peripheral sensory neuropathy (G3/4:
0.6%)
Dizziness

Eye disorders

Lacrimation increased;
Conjunctivitis

Ear and labyrinth disorders

Hearing impaired

Cardiac disorders

Myocardial ischemia
(G3/4:1.7%)
Arrhythmia (G3/4:
0.6%)
Vascular disorders

Venous disorder (G3/4:
0.6%)

Gastrointestinal disorders
Nausea (G3/4: 0.6%);
Stomatitis (G3/4:
4.0%);
Diarrhoea (G3/4: 2.9%);
Vomiting (G3/4: 0.6%)
Constipation;
Esophagitis/dysphagia/ odynophagia (G3/4:
0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal haemorrhage (G3/4:
0.6%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Skin and subcutaneous tissue disorders
Alopecia (G3/4: 10.9%) Rash pruritic;
Dry skin;
Skin exfoliative (G3/4:
0.6%)

Musculoskeletal and connective tissue disorders

Myalgia (G3/4: 0.6%)

General disorders and administration site conditions
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema

Investigations

Weight increased

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system organ classes
Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Infections and infestations
Infection (G3/4: 3.6%)

Neutropenic infection

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

Cancer pain (G3/4:
1.2%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
83.5%);
Anaemia (G3/4:
12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia

Immune system disorders

Hypersensitivity
Metabolism and nutrition disorders
Anorexia (G3/4:
12.0%)

Nervous system disorders
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory neuropathy (G3/4:
1.2%)
Dizziness (G3/4:
2.0%);
Peripheral motor neuropathy (G3/4:
0.4%)

Eye disorders

Lacrimation increased
Conjunctivitis
Ear and labyrinth disorders
Hearing impaired
(G3/4: 1.2%)

Cardiac disorders

Arrhythmia (G3/4:
2.0%)
Ischemia myocardial
Vascular disorders

Venous disorder

MedDRA system organ classes
Very common adverse reactions

Common adverse reactions

Uncommon adverse reactions

Gastrointestinal disorders
Nausea (G3/4: 13.9%);
Stomatitis (G3/4:
20.7%);
Vomiting (G3/4:
8.4%);
Diarrhoea (G3/4:
6.8%);
Esophagitis/dysphagia/ odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Dyspepsia (G3/4:
0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal haemorrhage (G3/4:
0.4%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritic
Dry skin ;
Desquamation

Musculoskeletal, connective tissue bone disorders

Myalgia (G3/4: 0.4%)

General disorders and administration site conditions
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)

Investigations
Weight decreased

Weight increased

Post-marketing experience

Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukaemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen.

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

Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the medicinal product.

Eye disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been rarely reported. Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel.

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

Cardiac disorders
Rare cases of myocardial infarction have been reported.
Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5- fluorouracil and/ or cyclophosphamide.

Vascular disorders
Venous thromboembolic events have rarely been reported.

Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome and cases of interstitial pneumonia/ pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure sometimes fatal have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders
Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).
Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinal perforation.
Rare cases of ileus and intestinal obstruction have been reported.

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

Skin and subcutaneous tissue disorders
Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel.
Scleroderma-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia and cases of psoriasis, including cases of recurrence or aggravation of pre-existing psoriasis (frequency not known) have been reported.

Renal and urinary disorders
Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro- intestinal disorders.

General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).

Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration and pulmonary oedema have rarely been reported.

Metabolism and nutrition disorders
Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea. Tumour lysis syndrome, potentially fatal, has been reported (frequency not known).

Musculoskeletal disorder
Myositis has been reported with docetaxel (frequency not known).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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:

• 1 312 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 (TAX327) who received docetaxel in combination with prednisone or prednisolone (clinically important treatment related adverse events are presented).
• 1 276 patients (744 and 532 in TAX 316 and GEICAM 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).
• 545 patients (STAMPEDE study) who received docetaxel in combination with prednisone or prednisolone and ADT.

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).

For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse events occurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in the docetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE grading scale.

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 (see section 4.4).

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.
Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions

Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

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

MedDRA system organ class
Very common adverse reaction
Common adverse reaction
Uncommon adverse reaction
Infections and infestations
Infections (G3/4: 5.7%;
including sepsis and pneumonia, fatal in
1.7%)
Infection associated with G4 neutropenia
(G3/4: 4.6%)

Blood and lymphatic system disorders
Neutropenia (G4:
76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia (G4:
0.2%)

Immune system disorders
Hypersensitivity (G3/4:
5.3%)

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 4.1%);
Peripheral motor neuropathy (G3/4: 4%);
Dysgeusia (severe:
0.07%)

Cardiac disorders

Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders

Hypotension;
Hypertension;
Haemorrhage

Respiratory, thoracic and mediastinal disorders
Dyspnoea (severe:
2.7%)

Gastrointestinal disorders
Stomatitis (G3/4:
5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe:
0.2%);
Abdominal pain
(severe: 1%);
Gastrointestinal haemorrhage (severe:
0.3%)

Oesophagitis (severe:
0.4%)

MedDRA system organ class
Very common adverse reaction
Common adverse reaction
Uncommon adverse reaction
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4:
5.9%);
Nail disorders (severe:
2.6%)

Musculoskeletal and connective tissue disorders
Myalgia (severe: 1.4%) Arthralgia

General disorders and administration site conditions
Fluid retention (severe:
6.5%);
Asthenia (severe:
11.2%);
Pain
Infusion site reaction;
Non-cardiac chest pain
(severe: 0.4%)

Investigations

G3/4 Blood bilirubin increased (< 5%);
G3/4 Blood alkaline phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Infections and infestations
Infections (G3/4: 5%)

Blood and lymphatic system disorders
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Febrile neutropenia
Immune system disorders

Hypersensitivity (no severe)

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders

Arrhythmia (no severe)
Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe: 0.8%)
Musculoskeletal and connective tissue disorders

Myalgia
General disorders and administration site conditions
Asthenia (severe: 12.4%);
Fluid retention (severe: 0.8%);
Pain

Investigations

G3/4 Blood bilirubin increased
(< 2%)

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 7.8%)

Blood and lymphatic system disorders
Neutropenia (G4:
91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia (G4:
0.8%)

Immune system disorders

Hypersensitivity (G3/4:
1.2%)

Metabolism and nutrition disorders

Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 0.4%)
Peripheral motor neuropathy (G3/4:
0.4%)

Cardiac disorders

Cardiac failure;
Arrhythmia (no severe)

Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 5%);
Stomatitis (G3/4:
7.8%);
Diarrhoea (G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe:
0.4%);
Skin reaction (no severe)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions
Asthenia (severe:
8.1%);
Fluid retention (severe:
1.2%);
Pain
Infusion site reaction

Investigations

G3/4 Blood bilirubin increased (< 2.5%);
G3/4 Blood alkaline phosphatase increased
(< 2.5%)
G3/4 AST increased
(< 1%);
G3/4 ALT increased
(< 1%)

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 5.7%)

Blood and lymphatic system disorders
Neutropenia (G4:
51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia (G4:
0.5%)
Febrile neutropenia

Immune system disorders
Hypersensitivity (G3/4:
2.5%)

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 3.7%);
Peripheral motor neuropathy (G3/4: 2%)

Cardiac disorders

Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders

Hypotension (G3/4:
0.7%)

Gastrointestinal disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%)
Constipation

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe:
0.7%);
Skin reaction (G3/4:
0.2%)

Musculoskeletal and connective tissue disorders
Myalgia (severe: 0.5%)

General disorders and administration site conditions
Asthenia (severe:
9.9%);
Fluid retention (severe:
0.7%);
Infusion site reaction;
Pain

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Fever (G3/4: 1.2%)
Investigations

G3/4 Blood bilirubin increased (2.1%);
G3/4 ALT increased
(1.3%)

G3/4 AST increased
(0.5%);
G3/4 Blood alkaline phosphatase increased
(0.3%)

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions

Blood and lymphatic system disorders
Neutropenia (G3/4: 32%);
Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis

Metabolism and nutrition disorders
Anorexia

Psychiatric disorders
Insomnia

Nervous system disorders
Paraesthesia; Headache;
Dysgeusia; Hypoesthesia

Eye disorders
Lacrimation increased;
Conjunctivitis

Cardiac disorders

Cardiac failure
Vascular disorders
Lymphoedema

Respiratory, thoracic and mediastinal disorders
Epistaxis; Pharyngolaryngeal pain; Nasopharyngitis;
Dyspnoea;
Cough; Rhinorrhoea

Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain

Skin and subcutaneous tissue disorders
Alopecia; Erythema; Rash; Nail disorders

Musculoskeletal and connective tissue disorders
Myalgia; Arthralgia; Pain in extremity; Bone pain; Back pain

General disorders and administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills Lethargy Investigations Weight increased

Description of selected adverse reactions in breast cancer for TAXOTERE 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 TAXOTERE 75 mg/m² in combination with capecitabine

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Infections and infestations

Oral candidiasis (G3/4: < 1%)
Blood and lymphatic system disorders
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Nervous system disorders
Dysgeusia (G3/4: < 1%);
paraesthesia (G3/4: < 1%)
Dizziness;
Headache (G3/4: < 1%);
Neuropathy peripheral
Eye disorders
Lacrimation increased

Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain (G3/4:
2%)
Dyspnoea (G3/4: 1%);
Cough (G3/4: < 1%);
Epistaxis (G3/4: < 1%)
Gastrointestinal disorders
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue disorders
Hand-foot syndrome (G3/4:
24%);
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4:
< 1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: < 1%);
Back pain (G3/4: 1%)
General disorders and administration site conditions
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%)
Lethargy;
Pain
Investigations

Weight decreased;
G3/4 Blood bilirubin increased
(9%)

Tabulated list of adverse reactions in metastatic castration-resistant prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions
Infections and infestations
Infection (G3/4: 3.3%)

Blood and lymphatic system disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia (G3/4:
0.6%);
Febrile neutropenia
Immune system disorders

Hypersensitivity (G3/4: 0.6%)
Metabolism and nutrition
Anorexia (G3/4: 0.6%)

MedDRA system organ classes

Very common adverse reactions
Common adverse reactions disorders
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Peripheral motor neuropathy
(G3/4: 0%)
Eye disorders

Lacrimation increased (G3/4:
0.6%)
Cardiac disorders

Cardiac left ventricular function decrease (G3/4: 0.3%)
Respiratory, thoracic and mediastinal disorders

Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Gastrointestinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4:
0.9%);
Vomiting (G3/4: 1.2%)

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective bone disorders

Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe: 0.6%)

Tabulated list of adverse reactions in high-risk locally advanced or metastatic hormone-sensitive prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone and ADT (STAMPEDE study)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Blood and lymphatic system disorders
Neutropenia (G3-4: 12 %)
Anaemia
Febrile neutropenia (G3-4: 15%)

Immune system disorders

Hypersensitivity (G3-4: 1%)
Endocrine disorders

Diabetes (G3-4: 1%)
Metabolism and nutrition disorders

Anorexia
Psychiatric disorders
Insomnia (G3: 1%)

Nervous system disorders
Peripheral sensory neuropathy
(≥G3: 2%)a
Headache
Dizziness
Eye disorders

Blurred vision
Cardiac disorders

Hypotension (G3: 0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea (G3: 1%)
Coughing (G3: 0%)
Upper respiratory tract infection
(G3: 1%)
Pharyngitis (G3: 0%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Gastrointestinal disorders
Diarrhoea (G3: 3%)
Stomatitis (G3: 0%)
Constipation (G3: 0%)
Nausea (G3: 1%)
Dyspepsia
Abdominal pain (G3: 0%)
Flatulence
Vomiting (G3: 1%)

Skin and subcutaneous tissue disorders
Alopecia (G3: 3%)a
Nail changes (G3: 1%)
Rash
Musculoskeletal and connective tissue disorders
Myalgia

General disorders and administration site conditions
Lethargy (G3-4: 2%)
Flu-like symptoms (G3: 0%)
Asthenia (G3: 0%)
Fluid retention
Fever (G3: 1%)
Oral candidiasis
Hypocalcaemia (G3: 0%)
Hypophosphataemia (G3-4: 1%)
Hypokalaemia (G3: 0%) a From the GETUG AFU15 study

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

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 2.4%);
Neutropenic infection
(G3/4: 2.6%)

Blood and lymphatic system disorders
Anaemia (G3/4: 3%);
Neutropenia (G3/4:
59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4: NA)

Immune system disorders

Hypersensitivity (G3/4:
0.6%)

Metabolism and nutrition disorders
Anorexia (G3/4: 1.5%)

Nervous system disorders
Dysgeusia (G3/4:
0.6%);
Peripheral sensory neuropathy (G3/4:
<0.1%)
Peripheral motor neuropathy (G3/4: 0%)
Syncope (G3/4: 0%);
Neurotoxicity (G3/4:
0%);
Somnolence (G3/4: 0%)
Eye disorders
Conjunctivitis (G3/4:
<0.1%)
Lacrimation increased
(G3/4: <0.1%)

Cardiac disorders

Arrhythmia (G3/4:
0.2%)

Vascular disorders
Hot flush (G3/4: 0.5%)
Hypotension (G3/4:
0%);
Phlebitis (G3/4: 0%)
Lymphoedema (G3/4:
0%)

Respiratory, thoracic and mediastinal disorders

Cough (G3/4: 0%)

MedDRA System
Organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Gastrointestinal disorders
Nausea (G3/4: 5.0%);
Stomatitis (G3/4:
6.0%);
Vomiting (G3/4: 4.2%);
Diarrhoea (G3/4: 3.4%);
Constipation (G3/4:
0.5%)
Abdominal pain (G3/4:
0.4%)

Skin and subcutaneous tissue disorders
Alopecia (persisting:
<3%);
Skin disorder (G3/4:
0.6%);
Nail disorders (G3/4:
0.4%)

Musculoskeletal and connective tissue disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4: 0.2%)

Reproductive system and breast disorders
Amenorrhoea (G3/4:
NA)

General disorders and administration site conditions
Asthenia (G3/4:
10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral
(G3/4: 0.2%)

Investigations

Weight increased (G3/4:
0%);
Weight decreased
(G3/4: 0.2%)

Description of selected adverse reactions for adjuvant therapy with TAXOTERE 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer

Nervous system disorders
In study TAX316 peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2 %) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

In GEICAM 9805 study peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Cardiac disorders
In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC arm died because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed congestive heart failure during the follow-up period. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.

Skin and subcutaneous tissue disorders
In study TAX316 alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%).
At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study alopecia that started during the treatment period and persisted into the follow- up period was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in FAC arm. Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Reproductive system and breast disorders
In TAX316 amenorrhoea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

In GEICAM 9805 study amenorrhoea that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in FAC arm.

General disorders and administration site conditions
In study TAX316 peripheral oedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of 8 years), peripheral oedema was ongoing in19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX316 lymphoedema that started during the treatment period and persisted into the follow- up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX316 asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805 peripheral oedema that started during the treatment period persisted into the follow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC arm had peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm.
Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients (0.9%) in TAC arm and 2 patients (0.4 %) in FAC arm. At the end of the follow-up period, lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in FAC arm.
Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.

Acute leukaemia / Myelodysplastic syndrome.
After 10 years of follow up in study TAX316, acute leukaemia was reported in 3 of 744 TAC patients

(0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).
After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%) patients in TAC arm. No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

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

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

Without primary
G-CSF prophylaxis
(n = 111) n (%)
With primary
G-CSF prophylaxis
(n = 421) n (%)
Neutropenia (Grade 4)
104 (93.7)
135 (32.1)
Febrile neutropenia
28 (25.2)
23 (5.5)
Neutropenic infection
14 (12.6)
21 (5.0)
Neutropenic infection
(Grade 3-4)
2 (1.8)
5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma center for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Infections and infestations
Neutropenic infection;
Infection (G3/4: 11.7%)

Blood and lymphatic system disorders
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4:
8.8%);
Febrile neutropenia

Immune system disorders
Hypersensitivity (G3/4: 1.7%)

Metabolism and nutrition disorders
Anorexia (G3/4: 11.7%)

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%)
Eye disorders

Lacrimation increased (G3/4:
0%)
Ear and labyrinth disorders

Hearing impaired (G3/4: 0%)
Cardiac disorders

Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%)
Constipation (G3/4: 1.0%);
Gastrointestinal pain (G3/4:
1.0%);
Oesophagitis/dysphagia/odynop hagia (G3/4: 0.7%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%)
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Skin exfoliation (G3/4: 0%)
General disorders and administration site conditions
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention
(severe/life-threatening: 1%)

Description of selected adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m2 in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively, regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF (see section 4.2).

Tabulated list of adverse reactions in head and neck cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 6.3%);
Neutropenic infection

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

Cancer pain (G3/4:
0.6%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Febrile neutropenia

Immune system disorders

Hypersensitivity (no severe)

Metabolism and nutrition disorders
Anorexia (G3/4: 0.6%)

Nervous system disorders
Dysgeusia/Parosmia;
Peripheral sensory neuropathy (G3/4:
0.6%)
Dizziness

Eye disorders

Lacrimation increased;
Conjunctivitis

Ear and labyrinth disorders

Hearing impaired

Cardiac disorders

Myocardial ischemia
(G3/4:1.7%)
Arrhythmia (G3/4:
0.6%)
Vascular disorders

Venous disorder (G3/4:
0.6%)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Gastrointestinal disorders
Nausea (G3/4: 0.6%);
Stomatitis (G3/4:
4.0%);
Diarrhoea (G3/4: 2.9%);
Vomiting (G3/4: 0.6%)
Constipation;
Esophagitis/dysphagia/ odynophagia (G3/4:
0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal haemorrhage (G3/4:
0.6%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 10.9%) Rash pruritic;
Dry skin;
Skin exfoliative (G3/4:
0.6%)

Musculoskeletal and connective tissue disorders

Myalgia (G3/4: 0.6%)

General disorders and administration site conditions
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema

Investigations

Weight increased

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 3.6%)

Neutropenic infection

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

Cancer pain (G3/4:
1.2%)

Blood and lymphatic system disorders
Neutropenia (G3/4:
83.5%);
Anaemia (G3/4:
12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia

Immune system disorders

Hypersensitivity
Metabolism and nutrition disorders
Anorexia (G3/4:
12.0%)

Nervous system disorders
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory neuropathy (G3/4:
1.2%)
Dizziness (G3/4:
2.0%);
Peripheral motor neuropathy (G3/4:
0.4%)

Eye disorders

Lacrimation increased
Conjunctivitis
Ear and labyrinth disorders
Hearing impaired
(G3/4: 1.2%)

Cardiac disorders

Arrhythmia (G3/4:
2.0%)
Ischemia myocardial
Vascular disorders

Venous disorder

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Gastrointestinal disorders
Nausea (G3/4: 13.9%);
Stomatitis (G3/4:
20.7%);
Vomiting (G3/4:
8.4%);
Diarrhoea (G3/4:
6.8%);
Esophagitis/dysphagia/ odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Dyspepsia (G3/4:
0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal haemorrhage (G3/4:
0.4%)

Skin and subcutaneous tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritic
Dry skin ;
Desquamation

Musculoskeletal, connective tissue bone disorders

Myalgia (G3/4: 0.4%)

General disorders and administration site conditions
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)

Investigations
Weight decreased

Weight increased

Post-marketing experience

Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukaemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen.

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

Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the medicinal product.

Eye disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been rarely reported. Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel.

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

Cardiac disorders
Rare cases of myocardial infarction have been reported.
Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5- fluorouracil and/ or cyclophosphamide.

Vascular disorders
Venous thromboembolic events have rarely been reported.

Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome and cases of interstitial pneumonia/ pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure sometimes fatal have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders
Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).
Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events including enterocolitis and gastrointestinal perforation.
Rare cases of ileus and intestinal obstruction have been reported.

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

Skin and subcutaneous tissue disorders
Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel.
Scleroderma-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia and cases of psoriasis, including cases of recurrence or aggravation of pre-existing psoriasis (frequency not known) have been reported.

Renal and urinary disorders
Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro- intestinal disorders.

General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).

Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration and pulmonary oedema have rarely been reported.

Metabolism and nutrition disorders
Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea. Tumour lysis syndrome, potentially fatal, has been reported (frequency not known).

Musculoskeletal disorder
Myositis has been reported with docetaxel (frequency not known).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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:

• 1 312 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 (TAX327) who received docetaxel in combination with prednisone or prednisolone (clinically important treatment related adverse events are presented).
• 1 276 patients (744 and 532 in TAX 316 and GEICAM 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).
• 545 patients (STAMPEDE study) who received docetaxel in combination with prednisone or prednisolone ADT.

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).

For combination with ADT and with prednisone or prednisolone (STAMPEDE study), adverse events occurring over the 6 cycles of treatment with docetaxel and having at least 2% higher incidence in the docetaxel treatment arm by comparison to the control arm, are presented, using the CTCAE grading scale.

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 (see section 4.4).

Nervous system disorders

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paraesthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders

Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.
Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions

Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infections (G3/4: 5.7%;
including sepsis and pneumonia, fatal in
1.7%)
Infection associated with G4 neutropenia
(G3/4: 4.6%)

Blood and lymphatic system disorders
Neutropenia (G4:
76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia (G4:
0.2%)

Immune system disorders
Hypersensitivity (G3/4:
5.3%)

Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 4.1%);
Peripheral motor neuropathy (G3/4: 4%);
Dysgeusia (severe:
0.07%)

Cardiac disorders

Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders

Hypotension;
Hypertension;
Haemorrhage

Respiratory, thoracic and mediastinal disorders
Dyspnoea (severe:
2.7%)

Gastrointestinal disorders
Stomatitis (G3/4:
5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe:
0.2%);
Abdominal pain
(severe: 1%);
Gastrointestinal haemorrhage (severe:
0.3%)
Oesophagitis (severe:
0.4%)
Skin and subcutaneous
Alopecia;

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions tissue disorders
Skin reaction (G3/4:
5.9%);
Nail disorders (severe:
2.6%)
Musculoskeletal and connective tissue disorders

Myalgia (severe: 1.4%) Arthralgia

General disorders and administration site conditions
Fluid retention (severe:
6.5%);
Asthenia (severe:
11.2%);
Pain
Infusion site reaction;
Non-cardiac chest pain
(severe: 0.4%)

Investigations

G3/4 Blood bilirubin increased (< 5%);
G3/4 Blood alkaline phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)

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

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Infections and infestations
Infections (G3/4: 5%)

Blood and lymphatic system disorders
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Febrile neutropenia
Immune system disorders

Hypersensitivity (no severe)

MedDRA system organ classes Very common adverse reactions
Common adverse reactions
Metabolism and nutrition disorders
Anorexia

Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders

Arrhythmia (no severe)
Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe: 0.8%)
Musculoskeletal and connective tissue disorders

Myalgia
General disorders and administration site conditions
Asthenia (severe: 12.4%);
Fluid retention (severe: 0.8%);
Pain

Investigations

G3/4 Blood bilirubin increased
(< 2%)

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

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Infections and infestations
Infection (G3/4: 7.8%)

Blood and lymphatic system disorders
Neutropenia (G4:
91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia (G4:
0.8%)

Immune system disorders

Hypersensitivity (G3/4:
1.2%)

Metabolism and nutrition disorders

Anorexia

Nervous system disorders
Peripheral sensory neuropathy (G3: 0.4%)
Peripheral motor neuropathy (G3/4:
0.4%)

Cardiac disorders

Cardiac failure;
Arrhythmia (no severe)

Vascular disorders

Hypotension
Gastrointestinal disorders
Nausea (G3/4: 5%);
Stomatitis (G3/4:
7.8%);
Diarrhoea (G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation

Skin and subcutaneous tissue disorders
Alopecia;
Nail disorders (severe:
0.4%);
Skin reaction (no severe)

MedDRA system organ classes
Very common adverse reactions
Common adverse reactions
Uncommon adverse reactions
Musculoskeletal and connective tissue disorders