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Docetaxel Winthrop

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Summary for the public


What is Docetaxel Winthrop?

Docetaxel Winthrop is a medicine that contains the active substance docetaxel. It is available in two forms:

  • as two vials (one containing a concentrated solution and the other containing a solvent), whose contents are mixed together before being made up into a solution for infusion (drip into a vein);
  • a single vial containing a concentrate that is ready to make up into a solution for infusion.

What is Docetaxel Winthrop used for?

Docetaxel Winthrop is used to treat the following types of cancer:

  • breast cancer. Docetaxel Winthrop can be used on its own after other treatments have failed. It can also be used with other anticancer medicines (doxorubicin, cyclophosphamide, trastuzumab or capecitabine) in patients who have not yet received any treatment for their cancer or after other treatments have failed, depending on the type and stage of the breast cancer being treated;
  • non-small-cell lung cancer. Docetaxel Winthrop can be used on its own after other treatments have failed. It can also be used with cisplatin (another anticancer medicine) in patients who have not yet received any treatment for their cancer;
  • prostate cancer, when the cancer does not respond to hormonal treatment. Docetaxel Winthrop is used with prednisone or prednisolone (anti-inflammatory medicines);
  • gastric adenocarcinoma (a type of stomach cancer) in patients who have not yet received any treatment for their cancer. Docetaxel Winthrop is used with cisplatin and 5-fluorouracil (other anticancer medicines);
  • head and neck cancer in patients whose cancer is advanced (has started to spread). Docetaxel Winthrop is used with cisplatin and 5-fluorouracil.

For full details, see the Summary of Product Characteristics (also part of the EPAR).

The medicine can only be obtained with a prescription.


How is Docetaxel Winthrop used?

Docetaxel Winthrop should be used in wards specialising in chemotherapy (using medicines to treat cancer) under the supervision of a doctor who is qualified in the use of chemotherapy.

Docetaxel Winthrop is given as a one-hour infusion every three weeks. The dose, duration of treatment and the medicines it is used with depend on the type of cancer being treated. Docetaxel Winthrop is only used when the neutrophil count (the level of a type of white blood cell in the blood) is normal (at least 1,500 cells/mm3). Dexamethasone (an anti-inflammatory medicine) should also be given to the patient, starting on the day before the Docetaxel Winthrop infusion. For more information, see the summary of product characteristics.


How does Docetaxel Winthrop work?

The active substance in Docetaxel Winthrop, docetaxel, belongs to the group of anticancer medicines known as the taxanes. Docetaxel blocks the ability of cells to destroy the internal ‘skeleton’ that allows them to divide and multiply. With the skeleton still in place, the cells cannot divide and they eventually die. Docetaxel also affects non cancer cells such as blood cells, which can cause side effects.


How has Docetaxel Winthrop been studied?

Docetaxel Winthrop has been studied in over 4,000 breast-cancer patients, around 2,000 small-celllung- cancer patients, 1,006 prostate-cancer patients, 457 gastric-adenocarcinoma patients and 897 head- and neck-cancer patients. In most of these studies, Docetaxel Winthrop was combined with other anticancer treatments and compared either with combinations of different treatments or with the same treatments but without Docetaxel Winthrop. The main measures of effectiveness were the number of patients whose cancer responded to treatment, how long the patients lived without their disease getting worse and how long the patients survived.


What benefit has Docetaxel Winthrop shown during the studies?

Adding Docetaxel Winthrop to other anticancer treatments produced increases in the number of patients whose cancer responded to treatment, how long the patients lived without their disease getting worse and how long the patients survived, in all five types of cancer. When used on its own, Docetaxel Winthrop was at least as effective as and sometimes more effective than the comparator medicines in breast cancer, and more effective than best supportive care (any medicines or techniques to help patients, but not other anticancer medicines) in lung cancer.


What is the risk associated with Docetaxel Winthrop?

The most common side effects with Docetaxel Winthrop (seen in more than 1 patient in 10) are neutropenia (low levels of neutrophils), anaemia (low red blood cell counts), thrombocytopenia (low blood platelet counts), febrile neutropenia (neutropenia with fever), peripheral sensory neuropathy (nerve damage in the hands and feet), peripheral motor neuropathy (damage to the nerves causing difficulty co-ordinating movements), dysgeusia (taste disturbances), dyspnoea (difficulty breathing), stomatitis (inflammation of the lining of the mouth), diarrhoea, nausea (feeling sick), vomiting, alopecia (hair loss), skin reactions, nail disorders, myalgia (muscle pain), loss of appetite, infections, fluid retention, asthenia (weakness), pain and hypersensitivity (allergic reactions). These side effects may be more severe when Docetaxel Winthrop is used with other anticancer medicines. For the full list of all side effects reported with Docetaxel Winthrop, see the package leaflet.

Docetaxel Winthrop should not be used in people who may be hypersensitive (allergic) to docetaxel or any of the other ingredients. Docetaxel Winthrop must not be used in patients who have a neutrophil count of less than 1,500 cells/mm3 or who have severe problems with their liver.


Why has Docetaxel Winthrop been approved?

The CHMP decided that Docetaxel Winthrop’s benefits are greater than its risks and recommended that it be given marketing authorisation.


Other information about Docetaxel Winthrop

The European Commission granted a marketing authorisation valid throughout the European Union for Docetaxel Winthrop to Aventis Pharma S.A. on 20 April 2007. This authorisation was based on the authorisation granted to Taxotere in 1995 (‘informed consent’). The marketing authorisation is valid for five years, after which it can be renewed.

Authorisation details
Name: Docetaxel Winthrop
EMEA Product number: EMEA/H/C/000808
Active substance: docetaxel
INN or common name: docetaxel
Therapeutic area: Carcinoma, Non-Small-Cell LungProstatic NeoplasmsHead and Neck NeoplasmsStomach NeoplasmsAdenocarcinomaBreast Neoplasms
ATC Code: L01CD02
Marketing Authorisation Holder: Sanofi-Aventis Pharma S.A.
Revision: 7
Date of issue of Market Authorisation valid throughout the European Union: 20/04/2007
Contact address:
Sanofi-Aventis Pharma S.A.
20 avenue Raymond Aron
92165 Antony Cedex
France



Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


1.
NAME OF THE MEDICINAL PRODUCT
Docetaxel Winthrop 20 mg/0.5 ml concentrate and solvent for solution for infusion
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each single-dose vial of Docetaxel Winthrop 20 mg/0.5 ml concentrate contains docetaxel which is a
trihydrate corresponding to 20 mg of docetaxel (anhydrous). The viscous solution contains 40 mg/ml
docetaxel (anhydrous).
Excipient: Each single-dose vial of solvent contains 13% (w/w) ethanol 95% in water for injection.
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Concentrate and solvent for solution for infusion.
The concentrate is a clear viscous, yellow to brown-yellow solution.
The solvent is a colourless solution.
4.
CLINICAL PARTICULARS
4.1 Therapeutic indications
Breast cancer
Docetaxel Winthrop in combination with doxorubicin and cyclophosphamide is indicated for the
adjuvant treatment of patients with:
operable node-positive breast cancer
Operable node-negative breast cancer
For patients with operable node-negative breast cancer, adjuvant treatment should be restricted to
patients eligible to receive chemotherapy according to internationally established criteria for primary
therapy of early breast cancer (see section 5.1).
Docetaxel Winthrop in combination with doxorubicin is indicated for the treatment of patients with
locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for
this condition.
Docetaxel Winthrop monotherapy is indicated for the treatment of patients with locally advanced or
metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have
included an anthracycline or an alkylating agent.
Docetaxel Winthrop in combination with trastuzumab is indicated for the treatment of patients with
metastatic breast cancer whose tumours over express HER2 and who previously have not received
chemotherapy for metastatic disease.
Docetaxel Winthrop in combination with capecitabine is indicated for the treatment of patients with
locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy
should have included an anthracycline.
Non-small cell lung cancer
Docetaxel Winthrop is indicated for the treatment of patients with locally advanced or metastatic non-
small cell lung cancer after failure of prior chemotherapy.
2
Docetaxel Winthrop in combination with cisplatin is indicated for the treatment of patients with
unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not
previously received chemotherapy for this condition.
Prostate cancer
Docetaxel Winthrop in combination with prednisone or prednisolone is indicated for the treatment of
patients with hormone refractory metastatic prostate cancer.
Gastric adenocarcinoma
Docetaxel Winthrop in combination with cisplatin and 5-fluorouracil is indicated for the treatment of
patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal
junction, who have not received prior chemotherapy for metastatic disease.
Head and neck cancer
Docetaxel Winthrop 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.
4.2 Posology and method of administration
The use of docetaxel should be confined to units specialised in the administration of cytotoxic
chemotherapy and it should only be administered under the supervision of a physician qualified in the
use of anticancer chemotherapy (see section 6.6).
Recommended dose
For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral
corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to
docetaxel administration, unless contraindicated, can be used (see section 4.4). Prophylactic G-CSF
may be used to mitigate the risk of haematological toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended
premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel
infusion (see section 4.4).
Docetaxel is administered as a one-hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive and node-negative breast cancer, the recommended
dose of docetaxel is 75 mg/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide
500 mg/m 2 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/m 2 in monotherapy. In first-line treatment, docetaxel 75 mg/m 2 is given in
combination therapy with doxorubicin (50 mg/m 2 ).
In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m 2 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/m 2 every three weeks,
combined with capecitabine at 1250 mg/m 2 twice daily (within 30 minutes after a meal) for 2 weeks
3
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/m 2 immediately followed by cisplatin 75 mg/m 2 over 30-60 minutes. For treatment
after failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m² as a single
agent.
Prostate cancer
The recommended dose of docetaxel is 75 mg/m 2 . Prednisone or prednisolone 5 mg orally twice daily
is administered continuously (see section 5.1).
Gastric adenocarcinoma
The recommended dose of docetaxel is 75 mg/m 2 as a 1-hour infusion, followed by cisplatin
75 mg/m 2 , as a 1- to 3-hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m 2 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/m 2 as a 1 hour infusion
followed by cisplatin 75 mg/m 2 over 1 hour, on day one, followed by 5-fluorouracil as a
continuous infusion at 750 mg/m 2 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/m 2 as a 1 hour intravenous
infusion on day 1, followed by cisplatin 100 mg/m 2 administered as a 30-minute to 3-hour
infusion, followed by 5-fluorouracil 1000 mg/m 2 /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/mm 3 .
In patients who experienced either febrile neutropenia, neutrophil count < 500 cells/mm 3 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/m 2 to 75 mg/m 2 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.
4
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/m 2 in combination with cisplatin and whose
nadir of platelet count during the previous course of therapy is < 25,000 cells/mm 3 , 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/m 2 . 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/m 2 . If subsequent episodes of
complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m 2 . In case of
Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m 2 . Patients should
not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level
> 1,500 cells/mm 3 and platelets recover to a level > 100,000 cells/mm 3 . 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 (eg, day 6-15) in all subsequent cycles.
5
 
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/m 2 (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 Docetaxel Winthrop in nasopharyngeal carcinoma in children aged 1 month
to less than 18 years have not yet been established.
There is no relevant use of Docetaxel Winthrop in the paediatric population in the indications breast
cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not
including type II and III less differentiated nasopharyngeal carcinoma.
Elderly
Based on a population pharmacokinetic analysis, there are no special instructions for use in the elderly.
In combination with capecitabine, for patients 60 years of age or more, a starting dose reduction of
capecitabine to 75% is recommended (see capecitabine summary of product characteristics).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Docetaxel must not be used in patients with baseline neutrophil count of < 1,500 cells/mm 3 .
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.
4.4 Special warnings and precautions for use
For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as
dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel
administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well
as the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral
dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).
Haematology
Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median
of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of
complete blood counts should be conducted on all patients receiving docetaxel. Patients should be
retreated with docetaxel when neutrophils recover to a level ≥ 1,500 cells/mm 3 (see section 4.2).
In the case of severe neutropenia (< 500 cells/mm 3 for seven days or more) during a course of
docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate
symptomatic measures are recommended (see section 4.2).
6
In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile
neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic
G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of
complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection).
Patients receiving TCF should be closely monitored (see sections 4.2 and 4.8).
In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC),
febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received
primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive
adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile
neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be
closely monitored (see sections 4.2 and 4.8).
Hypersensitivity reactions
Patients should be observed closely for hypersensitivity reactions especially during the first and
second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation
of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should
be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised
cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe
hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of
docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions
should not be re-challenged with docetaxel.
Cutaneous reactions
Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema
followed by desquamation has been observed. Severe symptoms such as eruptions followed by
desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see
section 4.2).
Fluid retention
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be
monitored closely.
Patients with liver impairment
In patients treated with docetaxel at 100 mg/m 2 as single agent who have serum transaminase levels
(ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels
greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as
toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia,
infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel
in those patients with elevated liver function test (LFTs) is 75 mg/m 2 and LFTs should be measured at
baseline and before each cycle (see section 4.2).
For patients with serum bilirubin levels > ULN and/or ALT and AST > 3.5 times the ULN concurrent
with serum alkaline phosphatase levels > 6 times the ULN, no dose-reduction can be recommended
and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric
adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN
associated with alkaline phosphatase > 2.5 × ULN, and bilirubin > 1 x ULN; for these patients, no
dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No
data are available in patients with hepatic impairment treated by docetaxel in combination in the other
indications.
7
Patients with renal impairment
There are no data available in patients with severely impaired renal function treated with docetaxel.
Nervous system
The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).
Cardiac toxicity
Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab,
particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may
be moderate to severe and has been associated with death (see section 4.8).
When patients are candidates for treatment with docetaxel in combination with trastuzumab, they
should undergo baseline cardiac assessment. Cardiac function should be further monitored during
treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For
more details see summary of product characteristics of trastuzumab.
Others
Contraceptive measures must be taken by both men and women during treatment and for men at least
6 months after cessation of therapy (see section 4.6).
Additional cautions for use in adjuvant treatment of breast cancer
Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or
infection), G-CSF and dose reduction should be considered (see section 4.2).
Gastrointestinal reactions
Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia,
may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated
promptly.
Congestive heart failure
Patients should be monitored for symptoms of congestive heart failure during therapy and during the
follow up period.
Leukaemia
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed
myelodysplasia or myeloid leukaemia requires haematological follow-up.
Patients with 4+ nodes
The benefit/risk ratio for TAC in patients with 4+ nodes was not defined fully at the interim analysis
(see section 5.1).
Elderly
There are limited data available in patients > 70 years of age on docetaxel use in combination with
doxorubicin and cyclophosphamide.
Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study, 209 patients
were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with
docetaxel every three weeks, the incidence of related nail changes occurred at a rate ≥ 10% higher in
patients who were 65 years of age or greater compared to younger patients. The incidence of related
fever, diarrhoea, anorexia, and peripheral oedema occurred at rates ≥ 10% higher in patients who were
75 years of age or greater versus less than 65 years.
Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part)
patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer
study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of
serious adverse events was higher in the elderly patients compared to younger patients. The incidence
8
of the following adverse events (all grades): lethargy, stomatitis, neutropenic infection occurred at
rates ≥ 10% higher in patients who were 65 years of age or older compared to younger patients.
Elderly patients treated with TCF should be closely monitored.
4.5 Interaction with other medicinal products and other forms of interaction
In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant
administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the
enzyme competitively) cytochrome P450-3A such as ciclosporine, terfenadine, ketoconazole,
erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with
these medicinal products as concomitant therapy since there is a potential for a significant interaction.
Docetaxel is highly protein bound (> 95%). Although the possible in vivo interaction of docetaxel with
concomitantly administered medicinal product has not been investigated formally, in vitro interactions
with tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone,
phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of
docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not
influence the binding of digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their
co-administration. Limited data from a single uncontrolled study were suggestive of an interaction
between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was
about 50% higher than values previously reported for carboplatin monotherapy.
Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic
prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4.
No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.
Docetaxel should be administered with caution in patients concomitantly receiving potent CYP3A4
inhibitors (e.g. protease inhibitors like ritonavir, azole antifungals like ketoconazole or itraconazole).
A drug interaction study performed in patients receiving ketoconazole and docetaxel showed that the
clearance of docetaxel was reduced by half by ketoconazole, probably because the metabolism of
docetaxel involves CYP3A4 as a major (single) metabolic pathway. Reduced tolerance of docetaxel
may occur, even at lower doses.
4.6 Pregnancy and lactation
There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be
both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other
cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant
women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.
Women of childbearing potential /contraception:
Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to
inform the treating physician immediately should this occur.
An effective method of contraception should be used during treatment.
In non clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3).
Therefore, men being treated with docetaxel are advised not to father a child during and up to
6 months after treatment and to seek advice on conservation of sperm prior to treatment.
Lactation:
Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk.
Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be
discontinued for the duration of docetaxel therapy.
9
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable effects
The adverse reactions considered to be possibly or probably related to the administration of docetaxel
have been obtained in:
1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent
respectively.
258 patients who received docetaxel in combination with doxorubicin.
406 patients who received docetaxel in combination with cisplatin.
92 patients treated with docetaxel in combination with trastuzumab.
255 patients who received docetaxel in combination with capecitabine.
332 patients who received docetaxel in combination with prednisone or prednisolone
(clinically important treatment related adverse events are presented).
1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received
docetaxel in combination with doxorubicin and cyclophosphamide (clinically important
treatment related adverse events are presented).
300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and
79 patients in the phase II part) who received docetaxel in combination with cisplatin and
5-fluorouracil (clinically important treatment related adverse events are presented).
174 and 251 head and neck cancer patients who received docetaxel in combination with
cisplatin and 5-fluorouracil (clinically important treatment related adverse events are
presented).
These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3;
grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA terms. Frequencies are defined as:
very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available
data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which was
reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe
neutropenia (< 500 cells/mm 3 ) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea
and asthenia. The severity of adverse events of docetaxel may be increased when docetaxel is given in
combination with other chemotherapeutic agents.
For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are displayed. There
was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the
trastuzumab combination arm compared to docetaxel monotherapy.
For combination with capecitabine, the most frequent treatment-related undesirable effects (≥ 5%)
reported in a phase III study in breast cancer patients failing anthracycline treatment are presented (see
capecitabine summary of product characteristics).
The following adverse reactions are frequently observed with docetaxel:
Immune system disorders
Hypersensitivity reactions have generally occurred within a few minutes following the start of the
infusion of docetaxel and were usually mild to moderate. The most frequently reported symptoms
were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and fever or chills.
Severe reactions were characterised by hypotension and/or bronchospasm or generalized
rash/erythema (see section 4.4).
10
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 paresthesia, dysesthesia or pain
including burning. Neuro-motor events are mainly characterised by weakness.
Skin and subcutaneous tissue disorders
Reversible cutaneous reactions have been observed and were generally considered as mild to
moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and
hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently
associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.
Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to
interruption or discontinuation of docetaxel treatment were reported (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).
Docetaxel Winthrop 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%)
11
 
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
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
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%)
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/m 2 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/m 2 ) in patients with premedication
compared with patients without premedication (median cumulative dose: 489.7 mg/m 2 ); however, it
has been reported in some patients during the early courses of therapy.
12
 
Docetaxel Winthrop 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)
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%)
13
 
Docetaxel Winthrop 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
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%)
14
 
Docetaxel Winthrop 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%)
15
 
Docetaxel Winthrop 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
Paresthesia; 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
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/m 2 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).
16
 
Docetaxel Winthrop 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%)
17
 
Docetaxel Winthrop 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%)
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%)
18
 
Adjuvant therapy with Docetaxel Winthrop 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: 2.7%)
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 (G3/4:
<0.1%);
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%)
19
 
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%)
Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in 12 patients out of the
83 patients with peripheral sensory neuropathy at the end of the chemotherapy.
Cardiac disorders
Congestive Heart Failure (CHF) has been reported in 18 of 1276 patiens during the follow-up period.
In the node positive study (TAX316) one patient in each treatment arm died because of cardiac failure.
Skin and subcutaneous tissue disorders
Alopecia was observed to be ongoing during follow-up in 25 patients out of the 736 patients with
alopecia at the end of the chemotherapy.
Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing during follow-up in 140 patients out of the 251 patients
with amenorrhoea at the end of the chemotherapy.
General disorders and administration site conditions
Peripheral oedema was observed to be ongoing during follow-up time in 18 patients out of the
112 patients with peripheral oedema at the end of the chemotherapy in study TAX 316, whereas
lymphoedema was observed to be ongoing in 4 of the 5 patients with lymphoedema at the end of the
chemotherapy in the study GEICAM 9805.
Acute leukaemia / Myelodysplastic syndrome.
At a median follow-up time of 77 months, acute leukaemia occurred in 1 of 532 (0.2%) patients who
received docetaxel, doxorubicin, and cyclophosphamide in the GEICAM 9805 study. No cases were
reported in patients who received fluorouracil, doxorubicin and cyclophosphamide. No patient was
diagnosed with myelodysplastic syndrome in either treatment groups.
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)
20
 
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)
Docetaxel Winthrop 75 mg/m² in combination with cisplatin and 5-fluorouracil for gastric
adenocarcinoma cancer
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%)
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).
21
 
Docetaxel Winthrop 75 mg/m² in combination with cisplatin and 5-fluorouracil for Head and Neck
cancer
Induction chemotherapy followed by radiotherapy (TAX 323)
MedDRA ystem 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%)
General disorders and
administration site
conditions
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema
Investigations
Weight increased
22
 
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
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%)
23
 
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Investigations
Weight decreased
Weight increased
Post-marketing experience
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Very rare cases of acute myeloid leukaemia and myelodysplastic syndrome have been reported in
association with docetaxel when used in combination with other chemotherapy agents and/or
radiotherapy.
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.
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.
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.
Vascular disorders
Venous thromboembolic events have rarely been reported.
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome, interstitial pneumonia and pulmonary fibrosis have rarely been
reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant
radiotherapy.
Gastrointestinal disorders
Rare occurrences of dehydration as a consequence of gastrointestinal events, gastrointestinal
perforation, colitis ischaemic, colitis and neutropenic enterocolitis have been reported. 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
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some
24
 
cases concomitant factors may have contributed to the development of these effects. Sclerodermal-like
changes usually preceded by peripheral lymphoedema have been reported with docetaxel.
General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration
and pulmonary oedema have rarely been reported.
4.9 Overdose
There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of
overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In
cases of overdose, exacerbation of adverse events may be expected. The primary anticipated
complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and
mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose.
Other appropriate symptomatic measures should be taken, as needed.
5.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Taxanes, ATC Code: L01CD 02
Preclinical data
Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable
microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The
binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential for
vital mitotic and interphase cellular functions.
Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines and
against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular
concentrations with a long cell residence time. In addition, docetaxel was found to be active on some
but not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistance
gene. In vivo , docetaxel is schedule independent and has a broad spectrum of experimental antitumour
activity against advanced murine and human grafted tumours.
Clinical data
Breast cancer
Docetaxel Winthrop in combination with doxorubicin and cyclophosphamide: adjuvant therapy
Patients with operable node-positive breast cancer (TAX 316)
Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant
treatment of patients with operable node-positive breast cancer and KPS ≥ 80%, between 18 and
70 years of age. After stratification according to the number of positive lymph nodes (1-3, 4+),
1491 patients were randomized to receive either docetaxel 75 mg/m 2 administered 1-hour after
doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (TAC arm), or doxorubicin 50 mg/m 2
followed by fluorouracil 500 mg/m 2 and cyclosphosphamide 500 mg/m 2 (FAC arm). Both regimens
were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion,
all other medicinal products were given as intravenous bolus on day one. G-CSF was administered as
secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia,
25
prolonged neutropenia, or infection). Patients on the TAC arm received antibiotic prophylaxis with
ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent. In
both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone
receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed
according to guidelines in place at participating institutions and was given to 69% of patients who
received TAC and 72% of patients who received FAC.
An interim analysis was performed with a median follow up of 55 months. Significantly longer
disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of
relapses at 5 years was reduced in patients receiving TAC compared to those who received FAC (25%
versus 32%, respectively) i.e. an absolute risk reduction by 7% (p = 0.001). Overall survival at 5 years
was also significantly increased with TAC compared to FAC (87% versus 81%, respectively) i.e. an
absolute reduction of the risk of death by 6% (p = 0.008). TAC-treated patient subsets according to
prospectively defined major prognostic factors were analyzed:
Disease free survival
Overall survival
Patient subset
Number
of
patients
Hazard
ratio*
95% CI
p =
Hazard
ratio*
95% CI
p =
No of positive
nodes
Overall 745 0.72 0.59-0.88 0.001 0.70 0.53-0.91 0.008
1-3 467 0.61 0.46-0.82 0.0009 0.45 0.29-0.70 0.0002
4+ 278 0.83 0.63-1.08 0.17 0.94 0.66-1.33 0.72
*a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival and
overall survival compared to FAC
The beneficial effect of TAC was not proven in patients with 4 and more positive nodes (37% of the
population) at the interim analysis stage. The effect appears to be less pronounced than in patients with
1-3 positive nodes. The benefit/risk ratio was not defined fully in patients with 4 and more positive
nodes at this analysis stage.
Patients with operable node - negative breast cancer eligible to receive chemotherapy (GEICAM 9805)
Data from a multicenter open label randomized trial support the use of Docetaxel Winthrop for the
adjuvant treatment of patients with operable node-negative breast cancer eligible to receive
chemotherapy. 1 060 patients were randomized to receive either Docetaxel Winthrop 75 mg/m 2
administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (539 patients in
TAC arm), or doxorubicin 50 mg/m 2 followed by fluorouracil 500 mg/m 2 and cyclosphosphamide
500 mg/m 2 (521 patients in FAC arm), as adjuvant treatment of operable node-negative breast cancer
patients with high risk of relapse according to 1998 St. Gallen criteria (tumour size >2 cm and/or
negative ER and PR and/or high histological/nuclear grade (grade 2 to 3) and /or age <35 years). Both
regimens were administered once every 3 weeks for 6 cycles. Docetaxel Winthrop was administered as
a 1-hour infusion, all other drugs were given intraveinously on day 1 every three weeks. Primary
prophylactic G-CSF was made mandatory in TAC arm after 230 patients were randomized. The
incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in
patients who received primary G-CSF prophylaxis (see section 4.8). In both arms, after the last cycle
of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen 20 mg once a day for
up to 5 years. Adjuvant radiation therapy was administered according to guidelines in place at
participating institutions and was given to 57.3% of patients who received TAC and 51.2% of patients
who received FAC.
Median duration of follow-up was 77 months. Significantly longer disease-free survival for the TAC
arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the
risk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93),
p = 0.01). Overall survival (OS) was also longer in the TAC arm with TAC-treated patients having a
24% reduction in the risk of death compared to FAC (hazard ratio = 0.76, 95% CI (0.46-1.26,
p = 0.29). However, the distribution of OS was not significantly different between the 2 groups.
26
 
TAC-treated patient subsets according to prospectively defined major prognostic factors were
analyzed (see table below):
Subset Analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study
(Intent-to-Treat Analysis)
Disease Free Survival
Patient subset
Number of patients
in TAC group
Hazard ratio*
95% CI
Overall
539
0.68
0.49-0.93
Age category 1
<50 years
260
0.67
0.43-1.05
≥50 years
279
0.67
0.43-1.05
Age category 2
<35 years
42
0.31
0.11-0.89
≥35 years
497
0.73
0.52-1.01
Hormonal receptor
status
Negative
195
0.7
0.45-1.1
Positive
344
0.62
0.4-0.97
Tumour size
≤2 cm
285
0.69
0.43-1.1
>2 cm
254
0.68
0.45-1.04
Histological grade
Grade1 (includes grade
not assessed)
64
0.79
0.24-2.6
Grade 2 216 0.77 0.46-1.3
Grade 3 259 0.59 0.39-0.9
Menopausal status
Pre-Menopausal 285 0.64 0.40-1
Post-Menopausal 254 0.72 0.47-1.12
*a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer disease free
survival compared to FAC.
Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallen
chemotherapy criteria – (ITT population) were performed and presented here below
TAC
FAC
Hazard ratio
(TAC/FAC)
Subgroups
(n=539)
(n=521)
(95% CI)
p-value
Meeting relative indication
for chemotherapy a
No
18/214
(8.4%)
26/227
(11.5%)
0.796 (0.434 - 1.459)
0.4593
Yes
48/325
(14.8%)
69/294
(23.5%)
0.606 (0.42 - 0.877)
0.0072
TAC = docetaxel, doxorubicin and cyclophosphamide
FAC = 5-fluorouracil, doxorubicin and cyclophospamide
CI = confidence interval; ER = estrogen receptor
PR = progesterone receptor
a ER/PR-negative or Grade 3 or tumor size >5 cm
27
 
The estimated hazard ratio was using Cox proportional hazard model with treatment group as the
factor.
Docetaxel Winthrop as single agent
Two randomised phase III comparative studies, involving a total of 326 alkylating or
392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the
recommended dose and regimen of 100 mg/m² every 3 weeks.
In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m² every 3 weeks).
Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p = 0.38) or
time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p = 0.54), docetaxel increased
response rate (52% vs. 37%, p = 0.01) and shortened time to response (12 weeks vs. 23 weeks,
p = 0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas
15 doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart
failure).
In anthracycline-failure patients, docetaxel was compared to the combination of mitomycin C and
vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel increased response rate
(33% vs. 12%, p < 0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p = 0.0004) and
prolonged overall survival (11 months vs. 9 months, p = 0.01).
During these two phase III studies, the safety profile of docetaxel was consistent with the safety profile
observed in phase II studies (see section 4.8).
An open-label, multicenter, randomized phase III study was conducted to compare docetaxel
monotherapy and paclitaxel in the treatment of advanced breast cancer in patients whose previous
therapy should have included an anthracycline. A total of 449 patients were randomized to receive
either docetaxel monotherapy 100 mg/m² as a 1 hour infusion or paclitaxel 175 mg/m² as a 3 hour
infusion. Both regimens were administered every 3 weeks.
Without affecting the primary endpoint, overall response rate (32% vs 25%, p = 0.10), docetaxel
prolonged median time to progression (24.6 weeks vs 15.6 weeks; p < 0.01) and median survival
(15.3 months vs 12.7 months; p = 0.03).
More grade 3/4 adverse events were observed for docetaxel monotherapy (55.4%) compared to
paclitaxel (23.0%).
Docetaxel Winthrop in combination with doxorubicin
One large randomized phase III study, involving 429 previously untreated patients with metastatic
disease, has been performed with doxorubicin (50 mg/m²) in combination with docetaxel (75 mg/m²)
(AT arm) versus doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²) (AC
arm). Both regimens were administered on day 1 every 3 weeks.
Time to progression (TTP) was significantly longer in the AT arm versus AC arm, p = 0.0138.
The median TTP was 37.3 weeks (95% CI: 33.4 - 42.1) in AT arm and 31.9 weeks (95% CI:
27.4 - 36.0) in AC arm.
Overall response rate (ORR) was significantly higher in the AT arm versus AC arm, p = 0.009.
The ORR was 59.3% (95% CI: 52.8 - 65.9) in AT arm versus 46.5% (95% CI: 39.8 - 53.2) in AC arm.
In this study, AT arm showed a higher incidence of severe neutropenia (90% versus 68.6%), febrile
neutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhoea (7.5% versus 1.4%), asthenia
(8.5% versus 2.4%), and pain (2.8% versus 0%) than AC arm. On the other hand, AC arm showed a
higher incidence of severe anemia (15.8% versus 8.5%) than AT arm, and, in addition, a higher
incidence of severe cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEF
decrease 20% (13.1% versus 6.1%), absolute LVEF decrease 30% (6.2% versus 1.1%). Toxic
deaths occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC arm (1
due to septic shock and 3 due to congestive heart failure).
28
In both arms, quality of life measured by the EORTC questionnaire was comparable and stable during
treatment and follow-up.
Docetaxel Winthrop in combination with trastuzumab
Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic
breast cancer whose tumours over express HER2, and who previously had not received chemotherapy
for metastatic disease. One hundred eighty six patients were randomized to receive docetaxel
(100 mg/m 2 ) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant
chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had
received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in
this pivotal study was immunohistochemistry (IHC). A minority of patients were tested using
fluorescence in-situ hybridization (FISH). In this study, 87% of patients had disease that was IHC 3+,
and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are
summarized in the following table:
Parameter
Docetaxel plus trastuzumab 1
n = 92
Docetaxel 1
n = 94
Response rate
(95% CI)
61%
(50-71)
34%
(25-45)
Median duration of response
(months)
(95% CI)
11.4
(9.2-15.0)
5.1
(4.4-6.2)
Median TTP (months)
(95% CI)
10.6
(7.6-12.9)
5.7
(5.0-6.5)
22.1 2
(17.6-28.9)
TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached.
1 Full analysis set (intent-to-treat)
2 Estimated median survival
30.5 2
(26.8-ne)
Docetaxel Winthrop in combination with capecitabine
Data from one multicenter, randomised, controlled phase III clinical study support the use of docetaxel
in combination with capecitabine for treatment of patients with locally advanced or metastatic breast
cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this study, 255 patients
were randomised to treatment with docetaxel (75 mg/m 2 as a 1 hour intravenous infusion every
3 weeks) and capecitabine (1250 mg/m 2 twice daily for 2 weeks followed by 1-week rest period).
256 patients were randomised to treatment with docetaxel alone (100 mg/m 2 as a 1 hour intravenous
infusion every 3 weeks). Survival was superior in the docetaxel + capecitabine combination arm
(p = 0.0126). Median survival was 442 days (docetaxel + capecitabine) vs. 352 days (docetaxel alone).
The overall objective response rates in the all-randomised population (investigator assessment) were
41.6% (docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive
disease was superior in the docetaxel + capecitabine combination arm (p < 0.0001). The median time
to progression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks)
and overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive
Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).
There was less use of morphinic analgesic (p < 0.01), non-morphinic analgesics (p < 0.01), other
disease-related medications (p = 0.06) and radiotherapy (p < 0.01) in patients treated with docetaxel at
75 mg/m² compared to those with BSC.
29
Median survival (months)
(95% CI)
 
The overall response rate was 6.8% in the evaluable patients, and the median duration of response was
26.1 weeks.
Docetaxel Winthrop in combination with platinum agents in chemotherapy-naïve patients
In a phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or
greater, and who did not receive previous chemotherapy for this condition, were randomised to either
docetaxel (T) 75 mg/m 2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m 2 over
30-60 minutes every 3 weeks (TCis), docetaxel 75 mg/m 2 as a 1 hour infusion in combination with
carboplatin (AUC 6 mg/ml.min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m 2
administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2 administered on
day 1 of cycles repeated every 4 weeks (VCis).
Survival data, median time to progression and response rates for two arms of the study are illustrated
in the following table:
TCis
n = 408
VCis
n = 404
Statistical analysis
Overall survival
(Primary end-point):
Median survival (months)
11.3
10.1
Hazard ratio: 1.122
[97.2% CI: 0.937; 1.342]*
1-year Survival (%)
46
41
Treatment difference: 5.4%
[95% CI: -1.1; 12.0]
2-year Survival (%)
21
14
Treatment difference: 6.2%
[95% CI: 0.2; 12.3]
Hazard ratio: 1.032
[95% CI: 0.876; 1.216]
Overall response rate (%): 31.6 24.5 Treatment difference: 7.1%
[95% CI: 0.7; 13.5]
*: Corrected for multiple comparisons and adjusted for stratification factors (stage of disease and
region of treatment), based on evaluable patient population.
22.0
23.0
Secondary end-points included change of pain, global rating of quality of life by EuroQoL-5D, Lung
Cancer Symptom Scale, and changes in Karnosfky performance status. Results on these end-points
were supportive of the primary end-points results.
For docetaxel/carboplatin combination, neither equivalent nor non-inferior efficacy could be proven
compared to the reference treatment combination VCis.
Prostate cancer
The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients with
hormone refractory metastatic prostate cancer were evaluated in a randomized multicenter phase III
study. A total of 1006 patients with KPS ≥ 60 were randomized to the following treatment groups:
Docetaxel 75 mg/m 2 every 3 weeks for 10 cycles.
Docetaxel 30 mg/m 2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.
Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily,
continuously.
Patients who received docetaxel every three weeks demonstrated significantly longer overall survival
compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly
arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for
the docetaxel arms versus the control arm are summarized in the following table:
30
Median time to progression
(weeks):
 
Endpoint
Docetaxel every
3 weeks
Docetaxel every
week
Mitoxantrone
every 3 weeks
Number of patients
Median survival (months)
95% CI
Hazard ratio
95% CI
p-value *
335
18.9
(17.0-21.2)
0.761
(0.619-0.936)
0.0094
334
17.4
(15.7-19.0)
0.912
(0.747-1.113)
0.3624
337
16.5
(14.4-18.6)
--
--
--
Number of patients
PSA** response rate (%)
95% CI
p-value*
291
45.4
(39.5-51.3)
0.0005
282
47.9
(41.9-53.9)
<0.0001
300
31.7
(26.4-37.3)
--
Number of patients
Pain response rate (%)
95% CI
p-value*
153
34.6
(27.1-42.7)
0.0107
154
31.2
(24.0-39.1)
0.0798
157
21.7
(15.5-28.9)
--
Number of patients
Tumour response rate (%)
95% CI
p-value*
141
12.1
(7.2-18.6)
0.1112
134
8.2
(4.2-14.2)
0.5853
137
6.6
(3.0-12.1)
--
Stratified log rank test
*Threshold for statistical significance = 0.0175
**PSA: Prostate-Specific Antigen
Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every
3 weeks, it is possible that certain patients may benefit from docetaxel every week.
No statistical differences were observed between treatment groups for Global Quality of Life.
Gastric adenocarcinoma
A multicenter, open-label, randomized study was conducted to evaluate the safety and efficacy of
docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including
adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for
metastatic disease. A total of 445 patients with KPS > 70 were treated with either docetaxel (T)
(75 mg/m 2 on day 1) in combination with cisplatin (C) (75 mg/m 2 on day 1) and 5-fluorouracil (F)
(750 mg/m 2 per day for 5 days) or cisplatin (100 mg/m 2 on day 1) and 5-fluorouracil (1000 mg/m 2 per
day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF
arm. The median number of cycles administered per patient was 6 (with a range of 1-16) for the TCF
arm compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary
endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer
TTP (p = 0.0004) in favor of the TCF arm. Overall survival was also significantly longer (p = 0.0201)
in favor of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized
in the following table:
31
 
Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma
Endpoint
TCF
n = 221
CF
n = 224
Median TTP (months)
5.6
3.7
(95% CI)
(4.86-5.91)
(3.45-4.47)
Hazard ratio
1.473
(95% CI)
(1.189-1.825)
*p-value
0.0004
Median survival (months)
9.2
8.6
(95% CI)
(8.38-10.58)
(7.16-9.46)
2-year estimate (%)
18.4
8.8
Hazard ratio
1.293
(95% CI)
(1.041-1.606)
*p-value
0.0201
Overall response rate (CR+PR) (%)
36.7
25.4
p-value
0.0106
Progressive disease as best overall
Response (%)
16.7
25.9
*Unstratified logrank test
Subgroup analyses across age, gender and race consistently favored the TCF arm compared to the CF
arm.
A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed
a statistically significant difference although always in favour of the TCF regimen and showed that the
benefit of TCF over CF is clearly observed between 18 and 30 months of follow up.
Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favor
of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global
health status on the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive worsening of
Karnofsky performance status (p = 0.0088) compared to patients treated with CF.
Head and neck cancer
Induction chemotherapy followed by radiotherapy (TAX323)
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell
carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label,
randomized study (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN,
and WHO perfomance status 0 or 1, were randomized to one of two treatment arms. Patients on the
docetaxel arm received docetaxel (T) 75 mg/m 2 followed by cisplatin (P) 75 mg/m 2 followed by
5-fluorouracil (F) 750 mg/m 2 per day as a continuous infusion for 5 days. This regimen was
administered every three weeks for 4 cycles in case at least a minor response (≥ 25% reduction in
bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with
a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not
progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (TPF/RT).
Patients on the comparator arm received cisplatin (P) 100 mg/m 2 followed by 5-fluorouracil (F)
1000 mg/m 2 per day for 5 days. This regimen was administered every three weeks for 4 cycles in case
at least a minor response (≥ 25% reduction in bidimensionally measured tumour size) was observed
after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval
of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to
institutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered either
with a conventional fraction (1.8 Gy - 2.0 Gy once a day, 5 days per week for a total dose of 66 to
70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a minimum
interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for accelerated
regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following
chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic prophylaxis
32
 
with ciprofloxacin 500 mg orally twice daily for 10 days starting on day 5 of each cycle, or equivalent.
The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the
TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 vs. 8.3 months respectively) with an
overall median follow up time of 33.7 months. Median overall survival was also significantly longer in
favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with a
28% risk reduction of mortality, p = 0.0128. Efficacy results are presented in the table below:
Efficacy of docetaxel in the induction treatment of patients
with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)
Endpoint
Docetaxel +
Cis + 5-FU
n = 177
Cis + 5-FU
n = 181
Median progression free survival (months)
(95% CI)
11.4
(10.1-14.0)
8.3
(7.4-9.1)
Adjusted hazard ratio
(95% CI)
*p-value
0.70
(0.55-0.89)
0.0042
Median survival (months)
(95% CI)
18.6
(15.7-24.0)
14.5
(11.6-18.7)
Hazard ratio
(95% CI)
**p-value
0.72
(0.56-0.93)
0.0128
Best overall response to chemotherapy (%)
(95% CI)
67.8
(60.4-74.6)
53.6
(46.0-61.0)
***p-value
0.006
Best overall response to study treatment
[chemotherapy +/- radiotherapy] (%)
(95% CI)
72.3
(65.1-78.8)
58.6
(51.0-65.8)
***p-value
0.006
Median duration of response to chemotherapy ±
radiotherapy (months)
(95% CI)
n = 128
15.7
(13.4-24.6)
n = 106
11.7
(10.2-17.4)
Hazard ratio
(95% CI)
**p-value
0.72
(0.52-0.99)
0.0457
A hazard ratio of less than 1 favors docetaxel + cisplatin + 5-FU
*Cox model (adjustment for Primary tumour site, T and N clinical stages and PSWHO)
**Logrank test
*** Chi-square test
Quality of life parameters
Patients treated with TPF experienced significantly less deterioration of their Global health score
compared to those treated with PF (p = 0.01, using the EORTC QLQ-C30 scale).
Clinical benefit parameters
The performance status scale, for head and neck (PSS-HN) subscales designed to measure
understandability of speech, ability to eat in public, and normalcy of diet, was significantly in favor of
TPF as compared to PF.
Median time to first deterioration of WHO performance status was significantly longer in the TPF arm
compared to PF. Pain intensity score improved during treatment in both groups indicating adequate
pain management.
33
Induction chemotherapy followed by chemoradiotherapy (TAX324)
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced
squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a randomized, multicenter
open-label, phase III study (TAX324). In this study, 501 patients, with locally advanced SCCHN, and
a WHO performance status of 0 or 1, were randomized to one of two arms. The study population
comprised patients with technically unresectable disease, patients with low probability of surgical cure
and patients aiming at organ preservation. The efficacy and safety evaluation solely addressed survival
endpoints and the success of organ preservation was not formally addressed. Patients on the docetaxel
arm received docetaxel (T) 75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P)
100 mg/m² administered as a 30-minute to three-hour intravenous infusion, followed by the continuous
intravenous infusion of 5-fluorouracil (F) 1000 mg/m²/day from day 1 to day 4. The cycles were
repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to receive
chemoradiotherapy (CRT) as per protocol (TPF/CRT). Patients on the comparator arm received
cisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous infusion on day 1 followed by the
continuous intravenous infusion of 5-fluorouracil (F) 1000 mg/m²/day from day 1 to day 5. The cycles
were repeated every 3 weeks for 3 cycles. All patients who did not have progressive disease were to
receive CRT as per protocol (PF/CRT).
Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy
with a minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to
day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour
intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment
using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of
70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime
following completion of CRT. All patients on the docetaxel-containing arm of the study received
prophylactic antibiotics. The primary efficacy endpoint in this study, overall survival (OS) was
significantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF
(median OS: 70.6 versus 30.1 months respectively), with a 30% risk reduction in mortality compared
to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90) with an overall median
follow up time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29% risk reduction of
progression or death and a 22 month improvement in median PFS (35.5 months for TPF and 13.1 for
PF). This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90; log-rank test
p = 0.004. Efficacy results are presented in the table below:
34
Efficacy of docetaxel in the induction treatment of patients
with locally advanced SCCHN (Intent-to-Treat Analysis)
Endpoint
Docetaxel + Cis + 5-FU
n = 255
Cis + 5-FU
n = 246
Median overall survival (months)
(95% CI)
70.6
(49.0-NA)
30.1
(20.9-51.5)
Hazard ratio:
(95% CI)
*p-value
0.70
(0.54-0.90)
0.0058
Median PFS (months)
(95% CI)
35.5
(19.3-NA)
13.1
(10.6 - 20.2)
Hazard ratio:
(95% CI)
**p-value
0.71
(0.56 - 0.90)
0.004
Best overall response (CR + PR) to
chemotherapy (%)
(95% CI)
71.8
(65.8-77.2)
64.2
(57.9-70.2)
***p-value
0.070
Best overall response (CR + PR) to
study treatment [chemotherapy +/-
chemoradiotherapy] (%)
(95%CI)
76.5
(70.8-81.5)
71.5
(65.5-77.1)
***p-value 0.209
A hazard ratio of less than 1 favors docetaxel + cisplatin + fluorouracil
*un-adjusted log-rank test
**un-adjusted log-rank test, not adjusted for multiple comparisons
***Chi square test, not adjusted for multiple comparisons
NA-not applicable
The European Medicines Agency has waived the obligation to submit the results of studies with
Docetaxel Winthrop in all subsets of the paediatric population in breast cancer, non-small cell lung
cancer, prostated cancer, gastric carcinoma and head and neck cancer, not including type II and III less
differentiated nasopharyngeal carcinoma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of
20-115 mg/m 2 in phase I studies. The kinetic profile of docetaxel is dose independent and consistent
with a three-compartment pharmacokinetic model with half lives for the α, β and γ phases of 4 min,
36 min and 11.1 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel
from the peripheral compartment. Following the administration of a 100 mg/m 2 dose given as a
one-hour infusion a mean peak plasma level of 3.7 µg/ml was obtained with a corresponding AUC of
4.6 h.µg/ml. Mean values for total body clearance and steady-state volume of distribution were
21 l/h/m 2 and 113 l, respectively. Inter individual variation in total body clearance was approximately
50%. Docetaxel is more than 95% bound to plasma proteins.
A study of 14 C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in
both the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl
ester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% of
the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is
excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites
and very low amounts of unchanged medicinal product.
35
 
A population pharmacokinetic analysis has been performed with docetaxel in 577 patients.
Pharmacokinetic parameters estimated by the model were very close to those estimated from phase I
studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient. In a small
number of patients (n = 23) with clinical chemistry data suggestive of mild to moderate liver function
impairment (ALT, AST ≥ 1.5 times the ULN associated with alkaline phosphatase ≥ 2.5 times the
ULN), total clearance was lowered by 27% on average (see section 4.2). Docetaxel clearance was not
modified in patients with mild to moderate fluid retention and there are no data available in patients
with severe fluid retention.
When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma
levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin
and cyclophosphamide were not influenced by their coadministration.
Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa
showed no effect by capecitabine on the pharmacokinetics of docetaxel (C max and AUC) and no effect
by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5’-DFUR.
Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following
monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is
similar to that observed with cisplatin alone.
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid
tumours had no influence on the pharmacokinetics of each individual medicinal product.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard
dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the
pharmacokinetics of docetaxel was observed.
5.3 Preclinical safety data
The carcinogenic potential of docetaxel has not been studied.
Docetaxel has been shown to be mutagenic in the in vitro micronucleus and chromosome aberration
test in CHO-K1 cells and in the in vivo micronucleus test in the mouse. However, it did not induce
mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent
with the pharmacological activity of docetaxel.
Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair
male fertility.
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Concentrate vial:
polysorbate 80
citric acid.
Solvent vial:
ethanol 95%
water for injections.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
36
6.3 Shelf-life
2 years.
Premix solution: The premix solution contains 10 mg/ml docetaxel and should be used
immediately after preparation. However the chemical and physical stability of the premix solution
has been demonstrated for 8 hours when stored either between 2°C and 8°C or at room
temperature (below 25°C).
Infusion solution: the infusion solution should be used within 4 hours at room temperature (below
25°C).
6.4 Special precautions for storage
Do not store above 25°C or below 2°C.
Store in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Each blister pack contains:
one single-dose vial of concentrate and,
one single-dose vial of solvent.
Docetaxel Winthrop 20 mg/0.5 ml concentrate for solution for infusion vial
7 ml clear glass Type I vial with a green flip-off cap.
This vial contains 0.5 ml of a 40 mg/ml solution of docetaxel in polysorbate 80 (fill volume:
24.4 mg/0.61 ml). This fill volume has been established during the development of Docetaxel
Winthrop to compensate for liquid loss during preparation of the premix due to foaming, adhesion to
the walls of the vial and "dead-volume". This overfill ensures that after dilution with the entire
contents of the accompanying solvent for Docetaxel Winthrop vial, there is a minimal extractable
premix volume of 2 ml containing 10 mg/ml docetaxel which corresponds to the labelled amount of 20
mg/0.5 ml per vial.
Solvent vial
7 ml clear glass Type I vial with a transparent colourless flip-off cap.
Solvent vial contains 1.5 ml of a 13% w/w solution of ethanol 95% in water for injections (fill volume:
1.98 ml). The addition of the entire contents of the solvent vial to the contents of the Docetaxel
Winthrop 20 mg/0.5 ml concentrate for solution for infusion vial ensures a premix concentration of
10 mg/ml docetaxel.
6.6 Special precautions for disposal and other handling
Docetaxel Winthrop is an antineoplastic agent and, as with other potentially toxic compounds, caution
should be exercised when handling it and preparing Docetaxel Winthrop solutions. The use of gloves
is recommended.
If Docetaxel Winthrop concentrate, premix solution or infusion solution should come into contact with
skin, wash immediately and thoroughly with soap and water. If Docetaxel Winthrop concentrate,
premix solution or infusion solution should come into contact with mucous membranes, wash
immediately and thoroughly with water.
37
Preparation for the intravenous administration
a)
Preparation of the Docetaxel Winthrop premix solution (10 mg docetaxel/ml)
If the vials are stored under refrigeration, allow the required number of Docetaxel Winthrop boxes to
stand at room temperature (below 25°C) for 5 minutes.
Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Winthrop vial by partially inverting the vial.
Inject the entire contents of the syringe into the corresponding Docetaxel Winthrop vial.
Remove the syringe and needle and mix manually by repeated inversions for at least 45 seconds. Do
not shake.
Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then check that
the solution is homogenous and clear (foaming is normal even after 5 minutes due to the presence of
polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after preparation.
However the chemical and physical stability of the premix solution has been demonstrated for 8 hours
when stored either between 2°C and 8°C or at room temperature (below 25°C).
b)
Preparation of the infusion solution
More than one premix vial may be necessary to obtain the required dose for the patient. Based on the
required dose for the patient expressed in mg, aseptically withdraw the corresponding premix volume
containing 10 mg/ml docetaxel from the appropriate number of premix vials using graduated syringes
fitted with a needle. For example, a dose of 140 mg docetaxel would require 14 ml docetaxel premix
solution.
Inject the required premix volume into a 250 ml infusion bag or bottle containing either 5% glucose
solution or sodium chloride 9 mg/ml (0.9%) solution for infusion.
If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so
that a concentration of 0.74 mg/ml docetaxel is not exceeded.
Mix the infusion bag or bottle manually using a rocking motion.
The Docetaxel Winthrop infusion solution should be used within 4 hours and should be aseptically
administered as a 1-hour infusion under room temperature (below 25°C) and normal lighting
conditions.
As with all parenteral products, Docetaxel Winthrop premix solution and infusion solution should be
visually inspected prior to use, solutions containing a precipitate should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Aventis Pharma S.A., 20 avenue Raymond Aron, 92165 Antony Cedex, France
8. MARKETING AUTHORISATION NUMBER
EU/1/07/384/001
38
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 20 April 2007
10. DATE OF REVISION OF THE TEXT
39
1.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
256
The following information is intended for medical or healthcare professionals only:
PREPARATION GUIDE FOR USE WITH DOCETAXEL WINTHROP 160 mg/8 ml
CONCENTRATE FOR SOLUTION FOR INFUSION
It is important that you read the entire contents of this procedure prior to the preparation of the
Docetaxel Winthrop infusion solution.
Recommendations for the safe handling:
Docetaxel is an antineoplastic agent and, as with other potentially toxic compounds, caution should be
exercised when handling it and preparing its solutions. The use of gloves is recommended.
If Docetaxel Winthrop concentrate or infusion solution should come into contact with skin, wash
immediately and thoroughly with soap and water. If it should come into contact with mucous
membranes, wash immediately and thoroughly with water.
Preparation of the intravenous administration :
Preparation of the infusion solution
DO NOT use other docetaxel medicinal products consisting of 2 vials (concentrate and solvent)
with this medicinal product (Docetaxel Winthrop 160 mg/8 ml concentrate for solution for
infusion, which contains only 1 vial).
Docetaxel Winthrop 160 mg/8 ml concentrate for solution for infusion requires NO prior
dilution with a solvent and is ready to add to the infusion solution.
Each vial is for single use and should be used immediately after opening. If not used
immediately, in-use storage times and conditions are the responsibility of the user. More than
one vial of concentrate for solution for infusion may be necessary to obtain the required dose for
the patient. For example, a dose of 140 mg docetaxel would require 7 ml docetaxel concentrate
for solution.
Aseptically withdraw the required amount of concentrate for solution for infusion with a
calibrated syringe.
In Docetaxel Winthrop 160 mg/8 ml vial the concentration of docetaxel is 20 mg/ml.
Then, inject via a single injection (one shot) into a 250 ml infusion bag or bottle containing
either 5% glucose solution or sodium chloride 9 mg/ml (0.9%) solution for infusion. If a dose
greater than 190 mg of docetaxel is required, use a larger volume of the infusion vehicle so that
a concentration of 0.74 mg/ml docetaxel is not exceeded.
Mix the infusion bag or bottle manually using a rocking motion.
From a microbiological point of view, reconstitution /dilution must take place in controlled and
aseptic conditions and the infusion solution should be used immediately. If not used
immediately, in-use storage times and conditions are the responsibility of the user.
Once added as recommended into the infusion bag, the docetaxel infusion solution, if stored
below 25°C, is stable for 6 hours. It should be used within 6 hours (including the one hour
infusion IV administration).
In addition, physical and chemical in-use stability of the infusion solution prepared as
recommended has been demonstrated in non-PVC bags up to 48 hours when stored between
2°C to 8°C.
Docetaxel infusion solution is supersaturated, therefore may crystallize over time. If crystals
appear, the solution must no longer be used and shall be discarded.
As with all parenteral products, infusion solution should be visually inspected prior to use,
solutions containing a precipitate should be discarded.
Disposal:
All materials that have been utilised for dilution and administration should be disposed of according to
standard procedures.
257
 


Source: European Medicines Agency



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