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TAXCEUS 20 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): DOCETAXEL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Taxceus 20 mg/ml concentrate for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each single dose vial contains docetaxel 20 mg/ml
Each 1 ml single dose vial contains 20 mg docetaxel.
Each 4 ml single dose vial contains 80 mg docetaxel.
Each 7 ml single dose vial contains 140 mg docetaxel.
Each 8 ml single dose vial contains 160 mg docetaxel.
Excipient with known effect: Ethanol anhydrous 395 mg/ml
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Concentrate for solution for infusion
The concentrate is a clear, pale yellow solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Breast cancer
Taxceus 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).
Taxceus 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.
Taxceus 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.
Taxceus 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.
Taxceus 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
Taxceus is indicated for the treatment of patients with locally advanced or metastatic
non-small cell lung cancer after failure of prior chemotherapy.
Taxceus 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
Taxceus in combination with prednisone or prednisolone is indicated for the
treatment of patients with hormone refractory metastatic prostate cancer.
Gastric adenocarcinoma
Taxceus 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

Taxceus 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).
Posology
For breast, non-small cell lung, gastric, and head and neck cancers, premedication
consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg
BID) for 3 days starting 1 day prior to docetaxel administration, unless
contraindicated, can be used (see section 4.4). 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 1-hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive and node-negative breast cancer,
the recommended dose of docetaxel is 75 mg/m² administered 1-hour after
doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks for 6 cycles
(TAC regimen) (see also Dose adjustments during treatment). For the treatment of
patients with locally advanced or metastatic breast cancer, the recommended dose of
docetaxel is 100 mg/m² in monotherapy. In first-line treatment, docetaxel 75 mg/m² is
given in combination therapy with doxorubicin (50 mg/m²).
In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m²
every three weeks, with trastuzumab administered weekly. In the pivotal study the
initial docetaxel infusion was started the day following the first dose of trastuzumab.
The subsequent docetaxel doses were administered immediately after completion of
the trastuzumab infusion, if the preceding dose of trastuzumab was well tolerated. For
trastuzumab dose and administration, see trastuzumab Summary of Product
Characteristics.
In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m²
every three weeks, combined with capecitabine at 1250 mg/m² twice daily (within
30 minutes after a meal) for 2 weeks followed by a 1-week rest period. For

capecitabine dose calculation according to body surface area, see capecitabine
Summary of Product Characteristics.
Non-small cell lung cancer
In chemotherapy naïve patients treated for non-small cell lung cancer, the
recommended dose regimen is docetaxel 75 mg/m² immediately followed by cisplatin
75 mg/m² over 30 – 60 minutes. For treatment after failure of prior platinum-based
chemotherapy, the recommended dose is 75 mg/m² as a single agent.
Prostate cancer
The recommended dose of docetaxel is 75 mg/m². Prednisone or prednisolone 5 mg
orally twice daily is administered continuously (see section 5.1).
Gastric adenocarcinoma
The recommended dose of docetaxel is 75 mg/m² as a 1-hour infusion, followed by
cisplatin 75 mg/m², as a 1- to 3-hour infusion (both on day 1 only), followed by
5-fluorouracil 750 mg/m² per day given as a 24-hour continuous infusion for 5 days,
starting at the end of the cisplatin infusion.
Treatment is repeated every three weeks. Patients must receive premedication with
antiemetics and appropriate hydration for cisplatin administration. Prophylactic
G-CSF should be used to mitigate the risk of haematological toxicities (see also Dose
adjustments during treatment).
Head and neck cancer
Patients must receive premedication with antiemetics and appropriate hydration (prior
to and after cisplatin administration). Prophylactic G-CSF may be used to mitigate the
risk of haematological toxicities. All patients on the docetaxel-containing arm of the
TAX 323 and TAX 324 studies, received prophylactic antibiotics.
-

Induction chemotherapy followed by radiotherapy (TAX 323)
For the induction treatment of inoperable locally advanced squamous cell
carcinoma of the head and neck (SCCHN), the recommended dose of
docetaxel is 75 mg/m² as a 1-hour infusion followed by cisplatin 75 mg/m²
over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion
at 750 mg/m² per day for five days. This regimen is administered every
3 weeks for 4 cycles. Following chemotherapy, patients should receive
radiotherapy.

-

Induction chemotherapy followed by chemoradiotherapy (TAX 324)
For the induction treatment of patients with locally advanced (technically
unresectable, low probability of surgical cure, and aiming at organ
preservation) squamous cell carcinoma of the head and neck (SCCHN), the
recommended dose of docetaxel is 75 mg/m² as a 1-hour intravenous infusion
on day 1, followed by cisplatin 100 mg/m² administered as a 30-minute to
3-hour infusion, followed by 5-fluorouracil 1,000 mg/m²/day as a continuous
infusion from day 1 to day 4. This regimen is administered every 3 weeks for

3 cycles. Following chemotherapy, patients should receive
chemoradiotherapy.
For cisplatin and 5-fluorouracil dose modifications, see the corresponding Summary
of Product Characteristics.
Dose adjustments during treatment
General
Docetaxel should be administered when the neutrophil count is ≥ 1,500 cells/mm³. In
patients who experienced either febrile neutropenia, neutrophil count < 500 cells/mm³
for more than one week, severe or cumulative cutaneous reactions or severe
peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be
reduced from 100 mg/m² to 75 mg/m² and/or from 75 to 60 mg/m². If the patient
continues to experience these reactions at 60 mg/m², the treatment should be
discontinued.
Adjuvant therapy for breast cancer
Primary G-CSF prophylaxis should be considered in patients who receive docetaxel,
doxorubicin and cyclophosphamide (TAC) adjuvant therapy for breast cancer.
Patients who experience febrile neutropenia and/or neutropenic infection should have
their docetaxel dose reduced to 60 mg/m² in all subsequent cycles (see sections 4.4
and 4.8). Patients who experience Grade 3 or 4 stomatitis should have their dose
decreased to 60 mg/m².
In combination with cisplatin
For patients who are dosed initially at docetaxel 75 mg/m² in combination with
cisplatin and whose nadir of platelet count during the previous course of therapy is
< 25,000 cells/mm³, or in patients who experience febrile neutropenia, or in patients
with serious non-haematologic toxicities, the docetaxel dose in subsequent cycles
should be reduced to 65 mg/m². For cisplatin dose adjustments, see the corresponding
Summary of Product Characteristics.
In combination with capecitabine


For capecitabine dose modifications, see capecitabine Summary of Product
Characteristics.



For patients developing the first appearance of Grade 2 toxicity, which
persists at the time of the next docetaxel/capecitabine treatment, delay
treatment until resolved to Grade 0 – 1, and resume at 100 % of the original
dose.



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



For any subsequent appearances of toxicities, or any Grade 4 toxicities,
discontinue the docetaxel dose.

For trastuzumab dose modifications, see trastuzumab Summary of Product
Characteristics
In combination with cisplatin and 5-fluorouracil
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection
occurs despite G—CSF use, the docetaxel dose should be reduced from 75 to
60 mg/m². If subsequent episodes of
complicated neutropenia occur the docetaxel dose should be reduced from 60 to
45 mg/m². In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced
from 75 to 60 mg/m². Patients should not be retreated with subsequent cycles of
docetaxel until neutrophils recover to a level > 1,500 cells/mm³ and platelets recover
to a level > 100,000 cells/mm³. Discontinue treatment if these toxicities persist (see
section 4.4).
Recommended dose modifications for toxicities in patients treated with docetaxel in
combination with cisplatin and 5-fluorouracil (5-FU):

Toxicity
Diarrhoea grade 3
Diarrhoea grade 4
Stomatitis/mucositis
grade 3
Stomatitis/mucositis
grade 4

Dose adjustment
First episode: reduce 5-FU dose by 20 %.
Second episode: then reduce docetaxel dose by 20 %.
First episode: reduce docetaxel and 5-FU doses by 20 %.
Second episode: discontinue treatment.
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 %.
First episode: stop 5-FU only, at all subsequent cycles.
Second episode: reduce docetaxel dose by 20 %.

For cisplatin and 5-fluorouracil dose adjustments, see the corresponding Summary of
Product Characteristics.
In the pivotal SCCHN studies patients who experienced complicated neutropenia
(including prolonged neutropenia, febrile neutropenia, or infection), it was
recommended to use G-CSF to provide prophylactic coverage (e.g., day 6 – 15) in all
subsequent cycles.
Special populations:
Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients
who have both elevations of transaminase (ALT and/or AST) greater than 1.5 times
the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5
times the ULN, the recommended dose of docetaxel is 75 mg/m² (see sections 4.4 and
5.2). For those patients with serum bilirubin > ULN and/or ALT and AST > 3.5 times
the ULN associated with alkaline phosphatase > 6 times the ULN, no dose-reduction
can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with
gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or
AST > 1.5 × ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin
> 1 x ULN; for these patients, no dose-reductions can be recommended and docetaxel
should not be used unless strictly indicated. No data are available in patients with
hepatic impairment treated by docetaxel in combination in the other indications.
Paediatric population
The safety and efficacy of Taxceus in nasopharyngeal carcinoma in children aged
1 month to less than 18 years have not yet been established.
There is no relevant use of Taxceus 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 patients
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 listed in
section 6.1.
Patients with baseline neutrophil count of < 1,500 cells/mm³.
Patients with severe liver impairment (see sections 4.2 and 4.4).
Contraindications for other medicinal products also apply, when combined with
docetaxel.

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/mm³ (see section 4.2).
In the case of severe neutropenia (< 500 cells/mm³ for seven days or more) during a course of
docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of
appropriate symptomatic measures are recommended (see section 4.2).
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.
Respiratory disorders

Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung
disease, pulmonary fibrosis and respiratory failure have been reported and may be associated
with fatal outcome. Cases of radiation pneumonitis have been reported in patients receiving
concomitant radiotherapy.
If new or worsening pulmonary symptoms develop, patients should be closely monitored,
promptly investigated, and appropriately treated. Interruption of docetaxel therapy is
recommended until diagnosis is available. Early use of supportive care measures may help
improve the condition. The benefit of resuming docetaxel treatment must be carefully
evaluated.
Patients with liver impairment
In patients treated with docetaxel at 100 mg/m² as single agent who have serum transaminase
levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline
phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe
adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage
which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia.
Therefore, the recommended dose of docetaxel in those patients with elevated liver function
test (LFTs) is 75 mg/m² and LFTs should be measured at baseline and before each cycle (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.
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.
Eye disorders

Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel. Patients
with impaired vision should undergo a prompt and complete ophthalmologic examination. In
case CMO is diagnosed, docetaxel treatment should be discontinued and appropriate
treatment initiated (see section 4.8).
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).
The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole,
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin and voriconazole) should be avoided (see section 4.5).
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 (CHF)
Patients should be monitored for symptoms of congestive heart failure during therapy and
during the follow up period. In patients treated with the TAC regimen for node positive breast
cancer, the risk of CHF has been shown to be higher during the first year after treatment (see
sections 4.8 and 5.1).
Leukaemia
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of
delayed myelodysplasia or myeloid leukaemia requires haematological follow-up.
Patients with 4+ nodes
As the benefit observed in patient with 4+ nodes was not statistically significant on
disease-free survival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC
in patients with 4+ nodes was not fully demonstrated at the final analysis (see section 5.1).
Elderly patients
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 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.
Excipients
This medicinal product contains 50 vol % ethanol anhydrous (alcohol), i.e. up to 395 mg
ethanol anhydrous per vial, equivalent to 10 ml of beer or 4 ml wine per vial.
Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding women, in children and in high-risk
groups such as patients with liver disease, or epilepsy.
Consideration should be given to possible effects on the central nervous system.
The amount of alcohol in this medicinal product may alter the effects of other medicinal
products.
The amount of alcohol in this medicinal product may impair the patient’s ability to drive or
use machines (see section 4.7).

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, ketoconazole and erythromycin. 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.
In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel
adverse reactions may increase, as a result of reduced metabolism. If the
concomitant use of a strong CYP3A4 inhibitor (e.g., ketoconazole,
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir,
saquinavir, telithromycin and voriconazole) cannot be avoided, a close clinical
surveillance is warranted and a dose-adjustment of docetaxel may be suitable
during the treatment with the strong CYP3A4 inhibitor (see section 4.4). In a
pharmacokinetic study with 7 patients, the co-administration of docetaxel with
the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in
docetaxel clearance by 49 %.
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 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.
4.6

Fertility, pregnancy and lactation
Pregnancy
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 age receiving docetaxel should be advised to avoid becoming
pregnant, and to inform the treating physician immediately should this occur.
Breast-feeding
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.
Contraception in males and females
An effective method of contraception should be used during treatment.
Fertility
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.

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. The
amount of ethanol in Taxceus may impair the ability to drive or use machines (see
section 4.4).

4.8

Undesirable effects
Summary of the safety profile for all indications
The adverse reactions considered to be possibly or probably related to the
administration of docetaxel have been obtained in:
• 1312 and 121 patients who received 100 mg/m² and 75 mg/m² of
docetaxel as a single agent respectively.
• 258 patients who received docetaxel in combination with doxorubicin.
• 406 patients who received docetaxel in combination with cisplatin.
• 92 patients treated with docetaxel in combination with trastuzumab.
• 255 patients who received docetaxel in combination with capecitabine.
• 332 patients who received docetaxel in combination with prednisone or
prednisolone (clinically important treatment related adverse events are
presented).
• 1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively)
who received docetaxel in combination with doxorubicin and
cyclophosphamide (clinically important treatment related adverse events
are presented).
• 300 gastric adenocarcinoma patients (221 patients in the phase III part of
the study and 79 patients in the phase II part) who received docetaxel in
combination with cisplatin and 5-fluorouracil (clinically important
treatment related adverse events are presented).
• 174 and 251 head and neck cancer patients who received docetaxel in
combination with cisplatin and 5-fluorouracil (clinically important
treatment related adverse events are presented).
These reactions were described using the NCI Common Toxicity Criteria
(grade 3 = G3; grade3 - 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 the
available data).
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
The most commonly reported adverse reactions of docetaxel alone are:
neutropenia (which was reversible and not cumulative; the median day to nadir
was 7 days and the median duration of severe neutropenia (< 500 cells/mm³)
was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and
asthenia. The severity of adverse events of docetaxel may be increased when
docetaxel is given in combination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in
≥ 10 % are displayed. There was an increased incidence of SAEs (40 % versus
31 %) and Grade 4 AEs (34 % versus 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
generalised rash/erythema (see section 4.4).
Nervous system disorders
The development of severe peripheral neurotoxicity requires a reduction of
dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are
characterised by 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).

Tabulated list of adverse reactions in breast cancer for Docetaxel 100 mg/m²
single agent
MedDRA
system organ
classes

Very common
adverse
reactions

Common adverse
reactions

Infections and
infestations

Infections (G3/4:
5.7 %; including
sepsis and
pneumonia, fatal
in 1.7 %)
Neutropenia (G4:
76.4 %);
Anaemia (G3/4:
8.9 %);
Febrile
neutropenia
Hypersensitivity
(G3/4: 5.3 %)

Infection
associated with G4
neutropenia (G3/4:
4.6 %)

Blood and
lymphatic
system
disorders

Immune system
disorders

Uncommon
adverse
reactions

Thrombocytopenia
(G4: 0.2 %)

Metabolism and Anorexia
nutrition
disorders
Nervous system Peripheral
disorders
sensory
neuropathy
(G3: 4.1 %);
Peripheral motor
neuropathy (G3/4:
4 %)
Dysgeusia
(severe: 0.07 %)
Cardiac
disorders

Arrhythmia (G3/4:
0.7 %)

Vascular
disorders

Hypotension;
Hypertension;
Haemorrhage

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Cardiac failure

Dyspnoea
(severe: 2.7 %)

Stomatitis (G3/4:
5.3 %);

Constipation
(severe 0.2 %);

Oesophagitis
(severe: 0.4 %)

MedDRA
system organ
classes

Very common
adverse
reactions

Common adverse
reactions

Diarrhoea (G3/4:
4 %);
Nausea (G3/4:
4 %);
Vomiting (G3/4:
3 %)
Skin and
Alopecia;
subcutaneous
Skin reaction
tissue disorders (G3/4: 5.9 %);
Nail disorders
(severe 2.6 %)
Musculoskeletal Myalgia (severe:
and connective 1.4 %)
tissue disorders

Abdominal pain
(severe 1 %);
Gastrointestinal
haemorrhage
(severe 0.3 %)

General
disorders and
administration
site conditions

Infusion site
reaction;
Non-cardiac chest
pain (severe:
0.4 %)

Fluid retention
(severe: 6.5 %);
Asthenia (severe:
11.2 %);
Pain

Investigations

Uncommon
adverse
reactions

Arthralgia

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

Description of selected adverse reactions in breast cancer for Docetaxel
100 mg/m² single agent
Blood and lymphatic system disorders
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia.
Nervous system disorders
Reversibility data are available among 35.3 % of patients who developed
neurotoxicity following docetaxel treatment at 100 mg/m² as single agent. The
events were spontaneously reversible within 3 months.
Skin and subcutaneous tissue disorders

Very rare: one case of alopecia non-reversible at the end of the study. 73 % of
the cutaneous reactions were reversible within 21 days.
General disorders and administration site conditions
The median cumulative dose to treatment discontinuation was more than
1,000 mg/m² and the median time to fluid retention reversibility was
16.4 weeks (range 0 to 42 weeks). The onset of moderate and severe retention
is delayed (median cumulative dose: 818.9 mg/m²) in patients with
premedication compared with patients without premedication (median
cumulative dose: 489.7 mg/m²); however, it has been reported in some patients
during the early courses of therapy.
Tabulated list of adverse reactions in non-small cell lung cancer for Docetaxel
75 mg/m² single agent
MedDRA system
organ classes

Very common adverse
reactions

Infections and
infestations
Blood and
lymphatic system
disorders

Infections (G3/4: 5 %)

Immune system
disorders
Metabolism and
nutrition disorders
Nervous system
disorders
Cardiac disorders
Vascular
disorders
Gastrointestinal
disorders

Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
General disorders
and
administration site
conditions
Investigations

Neutropenia (G4: 54.2 %);
Anaemia (G3/4: 10.8 %);
Thrombocytopenia (G4:
1.7 %)

Common adverse
reactions

Febrile neutropenia

Hypersensitivity (no
severe)
Anorexia
Peripheral sensory
neuropathy (G3/4: 0.8 %)

Peripheral motor
neuropathy (G3/4: 2.5 %)
Arrhythmia (no severe)
Hypotension

Nausea (G3/4: 3.3 %);
Constipation
Stomatitis (G3/4: 1.7 %);
Vomiting (G3/4: 0.8 %);
Diarrhoea (G3/4: 1.7 %)
Alopecia;
Nail disorders (severe:
Skin reaction (G3/4: 0.8 %) 0.8 %)
Myalgia

Asthenia (severe: 12.4 %);
Fluid retention (severe:
0.8 %);
Pain
G3/4 Blood bilirubin
increased
(<2 %)

Tabulated list of adverse reactions in breast cancer for Docetaxel 75 mg/m² in
combination with doxorubicin
MedDRA
system organ
classes

Very common
adverse reactions

Infections and
infestations
Blood and
lymphatic
system
disorders

Infection (G3/4:
7.8 %)
Neutropenia (G4:
91.7 %);
Anaemia (G3/4:
9.4 %);
Febrile neutropenia;
Thrombocytopenia
(G4: 0.8 %)

Common
Uncommon
adverse reactions adverse
reactions

Immune system
disorders
Metabolism and
nutrition
disorders
Nervous system Peripheral sensory
disorders
neuropathy (G3:
0.4 %)

Hypersensitivity
(G3/4: 1.2 %)
Anorexia

Cardiac
disorders

Cardiac failure;
Arrhythmia (no
severe)

Vascular
disorders
Gastrointestinal
disorders

Skin and
subcutaneous
tissue disorders

Peripheral motor
neuropathy (G3/4:
0.4 %)

Hypotension
Nausea (G3/4:
5 %);
Stomatitis (G3/4:
7.8 %);
Diarrhoea (G3/4:
6.2 %);
Vomiting (G3/4:
5 %);
Constipation
Alopecia;
Nail disorders
(severe 0.4 %);
Skin reaction (no
severe)

Musculoskeletal
and connective
tissue disorders
General
Asthenia (severe:

Myalgia

Infusion site

MedDRA
system organ
classes

Very common
adverse reactions

Common
Uncommon
adverse reactions adverse
reactions

disorders and
administration
site conditions

8.1 %);
Fluid retention
(severe: 1.2 %);
Pain

reaction

Investigations

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

G3/4 AST
increased
(< 1 %);
G3/4 ALT
increased
(< 1 %)

Tabulated list of adverse reactions in non-small cell lung cancer for Docetaxel
75 mg/m² in combination with cisplatin
MedDRA
system organ
classes
Infections and
infestations
Blood and
lymphatic
system
disorders

Very common
adverse reactions

Infection (G3/4:
5.7 %)
Neutropenia (G4:
51.5 %);
Anaemia (G3/4:
6.9 %);
Thrombocytopenia
(G4:0.5 %)
Immune system Hypersensitivity
disorders
(G3/4: 2.5 %)
Metabolism and Anorexia
nutrition
disorders
Nervous system Peripheral sensory
disorders
neuropathy (G3:
3.7 %);
Peripheral motor
neuropathy (G3/4:
2 %)
Cardiac
disorders
Vascular
disorders

Common
adverse
reactions

Uncommon
adverse
reactions

Febrile
neutropenia

Arrhythmia
(G3/4: 0.7 %)
Hypotension
(G3/4:
0.7 %)

Cardiac failure

MedDRA
system organ
classes

Very common
adverse reactions

Common
adverse
reactions

Uncommon
adverse
reactions

Gastrointestinal
disorders

Nausea (G3/4:
Constipation
9.6 %);
Vomiting (G3/4:
7.6 %);
Diarrhoea (G3/4:
6.4 %);
Stomatitis (G3/4:
2 %)
Skin and
Alopecia;
subcutaneous
Nail disorders
tissue disorders (severe 0.7 %);
Skin reaction (G3/4:
0.2 %)
Musculoskeletal Myalgia (severe:
and connective 0.5 %)
tissue disorders
General
Asthenia (severe:
Infusion site
disorders and
9.9 %);
reaction;
administration
Fluid retention
Pain
site conditions
(severe:
0.7 %);
Fever (G3/4: 1.2 %)
Investigations
G3/4 Blood
bilirubin
increased
(2.1 %);
G3/4 ALT
increased
(1.3 %)

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

Tabulated list of adverse reactions in breast cancer for Docetaxel 100 mg/m² in
combination with trastuzumab
MedDRA system
organ classes

Very 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
Anorexia

Metabolism and
nutrition disorders
Psychiatric

Insomnia

Common adverse
reactions

MedDRA system
organ classes
disorders
Nervous system
disorders
Eye disorders
Cardiac disorders
Vascular disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
General disorders
and administration
site conditions

Investigations

Very common adverse
reactions

Common adverse
reactions

Paresthesia; Headache;
Dysgeusia; Hypoaesthesia
Lacrimation increased;
Conjunctivitis
Cardiac failure
Lymphoedema
Epistaxis;
Pharyngolaryngeal pain;
Nasopharyngitis;
Dyspnoea; Cough;
Rhinorrhoea
Nausea; Diarrhoea;
Vomiting; Constipation;
Stomatitis; Dyspepsia;
Abdominal pain
Alopecia; Erythema; Rash;
Nail disorders
Myalgia; Arthralgia; Pain in
extremity; Bone pain; Back
pain
Asthenia; Oedema
Lethargy
peripheral; Pyrexia;
Fatigue; Mucosal
inflammation; Pain;
Influenza like illness; Chest
pain; Chills
Weight increased

Description of selected adverse reactions in breast cancer for Docetaxel
100 mg/m² in combination with trastuzumab
Blood and lymphatic system disorders
Very common: Haematological toxicity was increased in patients receiving
trastuzumab and docetaxel, compared with docetaxel alone (32 % grade 3/4
neutropenia versus 22 %, using NCI-CTC criteria). Note that this is likely to
be an underestimate since docetaxel alone at a dose of 100 mg/m² is known to
result in neutropenia in 97 % of patients, 76 % grade 4, based on nadir blood
counts. The incidence of febrile neutropenia/neutropenic sepsis was also
increased in patients treated with Herceptin plus docetaxel (23 % versus 17 %
for patients treated with docetaxel alone).
Cardiac disorders
Symptomatic cardiac failure was reported in 2.2 % of the patients who
received docetaxel plus trastuzumab compared to 0 % of patients given
docetaxel alone. In the docetaxel plus trastuzumab arm, 64 % had received a

prior anthracycline as adjuvant therapy compared with 55 % in the docetaxel
arm alone.
Tabulated list of adverse reactions in breast cancer for Docetaxel 75 mg/m² in
combination with capecitabine
MedDRA system
organ classes
Infections and
infestations
Blood and
lymphatic system
disorders
Metabolism and
nutrition disorders
Nervous system
disorders
Eye disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Skin and
subcutaneous
tissue disorders

Musculoskeletal
and connective
tissue disorders
General disorders
and
administration
site conditions

Investigations

Very common adverse
reactions

Common adverse
reactions

Neutropenia (G3/4: 63 %);
Anaemia (G3/4: 10 %)

Oral candidiasis (G3/4:
< 1 %)
Thrombocytopenia (G3/4:
3 %)

Anorexia (G3/4: 1 %);
Decreased appetite
Dysgeusia (G3/4: <1 %);
Paraesthesia (G3/4: <1 %)
Lacrimation increased
Pharyngolaryngeal pain
(G3/4: 2 %)

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
Hand-foot syndrome
(G3/4: 24 %);
Alopecia (G3/4: 6 %);
Nail disorders (G3/4: 2 %)
Myalgia (G3/4: 2 %);
Arthralgia (G3/4: 1 %)
Asthenia (G3/4: 3 %);
Pyrexia (G3/4: 1 %);
Fatigue/ weakness (G3/4:
5 %);
Oedema peripheral (G3/4:
1 %)

Dehydration (G3/4: 2 %)
Dizziness;
Headache (G3/4: < 1 %);
Neuropathy peripheral
Dyspnoea (G3/4: 1 %);
Cough (G3/4: < 1 %);
Epistaxis (G3/4: < 1 %)
Abdominal pain upper;
Dry mouth

Dermatitis;
Rash erythematous (G3/4:
< 1 %); Nail
discolouration;
Onycholysis (G3/4: 1 %)
Pain in extremity (G3/4:
<1 %);
Back pain (G3/4: 1 %)
Lethargy;
Pain

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

Tabulated list of adverse reactions in prostate cancer for Docetaxel 75 mg/m²
in combination with prednisone or prednisolone
MedDRA
system organ
classes

Very common adverse
reactions

Infections and
infestations
Blood and
lymphatic system
disorders
Immune system
disorders
Metabolism and
nutrition
disorders
Nervous system
disorders

Infection (G3/4: 3.3 %)
Neutropenia (G3/4: 32 %);
Anaemia (G3/4: 4.9 %)

Peripheral sensory
neuropathy
(G3/4: 1.2 %);
Dysgeusia (G3/4: 0 %)

Peripheral motor
neuropathy (G3/4: 0 %)

Lacrimation increased
(G3/4: 0.6 %)
Cardiac left ventricular
function
decrease (G3/4: 0.3 %)
Epistaxis (G3/4: 0 %);
Dyspnoea (G3/4: 0.6 %);
Cough (G3/4: 0 %)

Cardiac disorders

Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
General disorders
and
administration
site conditions

Thrombocytopenia; (G3/4:
0.6 %);
Febrile neutropenia
Hypersensitivity (G3/4:
0.6 %)

Anorexia (G3/4: 0.6 %)

Eye disorders

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Common adverse
reactions

Nausea (G3/4: 2.4 %);
Diarrhoea (G3/4: 1.2 %);
Stomatitis/Pharyngitis
(G3/4: 0.9 %);
Vomiting (G3/4: 1.2 %)
Alopecia;
Nail disorders (no severe)

Exfoliative rash (G3/4:
0.3 %)
Arthralgia (G3/4: 0.3 %);
Myalgia (G3/4: 0.3 %)

Fatigue (G3/4: 3.9 %);
Fluid retention (severe:
0.6 %)

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

Infections and
infestations

Infection (G3/4:
2.4 %);
Neutropenic
infection
(G3/4: 2.6 %)
Anaemia (G3/4:
3 %);
Neutropenia (G3/4:
59.2 %);
Thrombocytopenia
(G3/4: 1.6 %);
Febrile neutropenia
(G3/4: NA)

Blood and
lymphatic
system
disorders

Immune system
disorders

Common
adverse
reactions

Hypersensitivity
(G3/4: 0.6 %)

Metabolism and
nutrition
disorders
Nervous system
disorders

Anorexia (G3/4:
1.5 %)
Dysgeusia (G3/4:
0.6 %);
Peripheral sensory
neuropathy (G3/4:
<0.1 %)

Peripheral motor
neuropathy
(G3/4: 0 %)

Eye disorders

Conjunctivitis
(G3/4: <0.1 %)

Lacrimation
increased (G3/4:
<0.1 %);
Arrhythmia
(G3/4: 0.2 %)

Hot flush (G3/4:
0.5 %)

Hypotension
(G3/4: 0 %);
Phlebitis (G3/4:
0 %)
Cough (G3/4:
0 %)

Nausea (G3/4:
5.0 %);
Stomatitis (G3/4:
6.0 %);
Vomiting (G3/4:
4.2 %);

Abdominal pain
(G3/4: 0.4 %)

Cardiac
disorders
Vascular
disorders

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Uncommon
adverse
reactions

Syncope (G3/4:
0 %);
Neurotoxicity
(G3/4: 0 %);
Somnolence
(G3/4: 0 %)

Lymphoedema
(G3/4: 0 %)

MedDRA
system organ
classes

Very common
adverse reactions

Diarrhoea (G3/4:
3.4 %);
Constipation
(G3/4: 0.5 %)
Skin and
Alopecia (G3/4:
subcutaneous
<0.1 %);
tissue disorders Skin disorder
(G3/4: 0.6 %);
Nail disorders
(G3/4: 0.4 %)
Musculoskeletal Myalgia (G3/4:
and connective 0.7 %);
tissue disorders Arthralgia (G3/4:
0.2 %)
Reproductive
Amenorrhoea
system and
(G3/4: NA)
breast disorders
General
Asthenia (G3/4:
disorders and
10.0 %);
administration
Pyrexia (G3/4:
site conditions
NA);
Oedema peripheral
(G3/4: 0.2 %)
Investigations

Common
adverse
reactions

Uncommon
adverse
reactions

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

Description of selected adverse reactions for adjuvant therapy with Docetaxel
75 mg/m² in combination with doxorubicin and cyclophosphamide in patients
with node-positive (TAX316) and node-negative (GEICAM 9805) breast
cancer
Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in
10 patients out of the 84 patients with peripheral sensory neuropathy at the end
of the chemotherapy in the node-positive breast cancer study (TAX316).
Cardiac disorders
In study TAX316, 26 patients (3.5 %) in the TAC arm and 17 patients (2.3 %)
in the FAC arm experienced congestive heart failure. All except one patient in
each arm were diagnosed with CHF more than 30 days after the treatment
period. Two patients in the TAC arm and 4 patients in the FAC arm died
because of cardiac failure.

In GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %)
in FAC arm developed congestive heart failure during the follow-up period.
One patient in TAC arm died because of dilated cardiomyopathy.
Skin and subcutaneous tissue disorders
In study TAX316, alopecia persisting into the follow-up period after the end of
chemotherapy was reported in 687 of 744 TAC patients and 645 of 736 FAC
patients.
At the end of the follow-up period (actual median follow-up time of
96 months), alopecia was observed to be ongoing in 29 TAC patients (3.9 %)
and 16 FAC patients (2.2 %).
In GEICAM 9805 study, alopecia persisted into the follow-up period (median
follow-up time of 10 years and 5 months) and was observed to be ongoing in
49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in FAC arm. Alopecia
related to study drug started or worsened during the follow-up period in
42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm.
Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing during follow-up in 121 patients out
of the 202 patients with amenorrhoea at the end of the chemotherapy in study
TAX316.
In GEICAM 9805 study, amenorrhoea persisted into the follow-up period (median
follow-up time of 10 years and 5 months) and was observed to be ongoing in
18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm.

General disorders and administration site conditions
In study TAX316, peripheral oedema was observed to be ongoing in
19 patients out of the 119 patients with peripheral oedema in the TAC arm and
4 patients out of the 23 patients with peripheral oedema in the FAC arm.
In study GEICAM 9805, lymphoedema was observed to be ongoing in 4 of the
5 patients in TAC arm and in 1 of the 2 patients in FAC arm at the end of the
chemotherapy, and did not resolve during the follow-up period (median
follow-up time of 10 years and 5 months). Asthenia persisted into the followup period (median follow-up time of 10 years and 5 months) and was observed
to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in
FAC arm.
Acute leukaemia / Myelodysplastic syndrome
After 10 years of follow up in study TAX316, acute leukaemia was reported in
4 of 744 TAC patients and in 1 of 736 FAC patients. Myelodysplastic
syndrome was reported in 2 of 744 TAC patients and in 1 of 736 FAC patients.
After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred
in 1 of 532 (0.2 %) patients in TAC arm. No cases were reported in patients in
FAC arm. No patient was diagnosed with myelodysplastic syndrome in either
treatment groups.
Neutropenic complications
Table below shows that the incidence of Grade 4 neutropenia, febrile
neutropenia and neutropenic infection was decreased in patients who received

primary G-CSF prophylaxis after it was made mandatory in the TAC arm –
GEICAM study.
Neutropenic complications in patients receiving TAC with or without primary
G-CSF prophylaxis (GEICAM 9805)

Neutropenia
(Grade 4)
Febrile
neutropenia
Neutropenic
infection
Neutropenic
infection (Grade
3 - 4)

Without primary
G-CSF prophylaxis
(n = 111)
n (%)

With primary
G-CSF prophylaxis
(n = 421)
n (%)

104 (93.7)

135 (32.1)

28 (25.2)

23 (5.5)

14 (12.6)

21 (5.0)

2 (1.8)

5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil:
MedDRA
system organ
classes
Infections and
infestations
Blood and
lymphatic
system disorders

Immune system
disorders
Metabolism and
nutrition
disorders
Nervous system
disorders
Eye disorders
Ear and labyrinth
disorders
Cardiac
disorders

Very common adverse
reactions

Common adverse
reactions

Neutropenic infection;
Infection (G3/4: 11.7 %)
Anaemia (G3/4: 20.9 %);
Neutropenia (G3/4:
83.2 %);
Thrombocytopenia (G3/4:
8.8 %); Febrile
neutropenia
Hypersensitivity (G3/4:
1.7 %)
Anorexia (G3/4: 11.7 %)

Peripheral sensory
neuropathy (G3/4: 8.7 %)

Dizziness (G3/4: 2.3 %);
Peripheral motor neuropathy
(G3/4: 1.3 %)
Lacrimation increased
(G3/4: 0 %)
Hearing impaired (G3/4:
0 %)
Arrhythmia (G3/4: 1.0 %)

MedDRA
system organ
classes
Gastrointestinal
disorders

Very common adverse
reactions

Common adverse
reactions

Diarrhoea (G3/4: 19.7 %);
Nausea (G3/4: 16 %);
Stomatitis (G3/4: 23.7 %);
Vomiting (G3/4: 14.3 %)

Skin and
subcutaneous
tissue disorders

Alopecia (G3/4: 4.0 %)

Constipation (G3/4: 1.0 %);
Gastrointestinal pain (G3/4:
1.0 %);
Oesophagitis/dysphagia/
odynophagia (G3/4: 0.7 %)
Rash pruritus (G3/4: 0.7 %);
Nail disorders (G3/4:
0.7 %);
Skin exfoliation (G3/4: 0 %)

General
disorders and
administration
site conditions

Lethargy (G3/4: 19.0 %);
Fever (G3/4: 2.3 %);
Fluid retention (severe/
life-threatening: 1 %)

Description of selected adverse reactions in gastric adenocarcinoma cancer for
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil
Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2 % and 13.5 %
of patients respectively, regardless of G-CSF use. G-CSF was used for
secondary prophylaxis in 19.3 % of patients (10.7 % of the cycles). Febrile
neutropenia and neutropenic infection occurred respectively in 12.1 % and
3.4 % of patients when patients received prophylactic G-CSF, in 15.6 % and
12.9 % of patients without prophylactic G-CSF (see section 4.2).

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


Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA
system organ
classes

Very common
adverse reactions

Infections and
infestations

Infection (G3/4:
6.3 %); Neutropenic
infection

Neoplasms
benign,
malignant and
unspecified
(incl cysts and
polyps)
Blood and
lymphatic
system
disorders

Immune system
disorders
Metabolism and
nutrition
disorders
Nervous system
disorders

Eye disorders
Ear and
labyrinth
disorders
Cardiac
disorders
Vascular
disorders
Gastrointestinal
disorders

Common adverse
reactions

Uncommon
adverse
reactions

Cancer pain (G3/4:
0.6 %)

Neutropenia (G3/4:
76.3 %);
Anaemia (G3/4:
9.2 %);
Thrombocytopenia
(G3/4: 5.2 %)

Febrile neutropenia

Hypersensitivity (no
severe)
Anorexia (G3/4:
0.6 %)
Dysgeusia/Parosmia; Dizziness
Peripheral sensory
neuropathy (G3/4:
0.6 %)
Lacrimation increased;
Conjunctivitis
Hearing impaired

Myocardial ischemia
(G3/4: 1.7 %)

Nausea
(G3/4:0.6 %);
Stomatitis (G3/4:
4.0 %);
Diarrhoea (G3/4:
2.9 %);
Vomiting (G3/4:

Venous disorder (G3/4:
0.6 %)
Constipation;
Oesophagitis/dysphagia/
odynophagia (G3/4:
0.6 %);
Abdominal pain;
Dyspepsia;
Gastrointestinal

Arrhythmia
(G3/4:
0.6 %)

MedDRA
system organ
classes

Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
General
disorders and
administration
site conditions

Very common
adverse reactions

Common adverse
reactions

0.6 %)

haemorrhage
(G3/4: 0.6 %)
Rash pruritic;
Dry skin;
Skin exfoliative
(G3/4: 0.6 %)
Myalgia (G3/4: 0.6 %)

Alopecia
(G3/4: 10.9 %)

Lethargy (G3/4:
3.4 %);
Pyrexia (G3/4:
0.6 %);
Fluid retention;
Oedema

Investigations


Uncommon
adverse
reactions

Weight increased

Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA
system organ
classes

Very common adverse
reactions

Common
adverse
reactions

Infections and
infestations
Neoplasms
benign,
malignant and
unspecified
(incl cysts and
polyps)
Blood and
lymphatic
system
disorders

Infection (G3/4: 3.6 %)

Neutropenic
infection
Cancer pain
(G3/4: 1.2 %)

Immune system
disorders
Metabolism and
nutrition
disorders
Nervous system
disorders

Uncommon
adverse
reactions

Neutropenia
(G3/4: 83.5 %);
Anaemia
(G3/4: 12.4 %);
Thrombocytopenia
(G3/4: 4.0 %);
Febrile neutropenia
Hypersensitivity
Anorexia (G3/4:
12.0 %)
Dysgeusia/Parosmia
(G3/4: 0.4 %);

Dizziness
(G3/4: 2.0 %);

MedDRA
system organ
classes

Very common adverse
reactions

Common
adverse
reactions

Peripheral sensory
neuropathy
(G3/4: 1.2 %)

Peripheral
motor
neuropathy
(G3/4: 0.4 %)
Lacrimation
increased

Eye disorders
Ear and
labyrinth
disorders
Cardiac
disorders
Vascular
disorders
Gastrointestinal
disorders

Skin and
subcutaneous
tissue disorders
Musculoskeletal
and connective
tissue disorders
General
disorders and
administration
site conditions
Investigations

Uncommon
adverse
reactions

Conjunctivitis

Hearing impaired
(G3/4: 1.2 %)
Arrhythmia
(G3/4: 2.0 %)

Nausea (G3/4: 13.9 %);
Stomatitis
(G3/4: 20.7 %);
Vomiting
(G3/4: 8.4 %);
Diarrhoea (G3/4:
6.8 %);
Oesophagitis/dysphagia/
odynophagia
(G3/4: 12.0 %);
Constipation
(G3/4:0.4 %)
Alopecia (G3/4: 4.0 %);
Rash pruritic

Ischemia
myocardial
Venous disorder

Dyspepsia
(G3/4: 0.8 %);
Gastrointestinal
pain (G3/4:
1.2 %);
Gastrointestinal
haemorrhage
(G3/4: 0.4 %)

Dry skin;
Desquamation
Myalgia
(G3/4: 0.4 %)

Lethargy (G3/4: 4.0 %);
Pyrexia (G3/4: 3.6 %);
Fluid retention
(G3/4: 1.2 %);
Oedema (G3/4: 1.2 %)
Weight decreased

Weight
increased

Post-marketing experience
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
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. Cases of cystoid macular oedema
(CMO) have been reported in patients treated with docetaxel.
Ear and labyrinth disorders
Rare cases of ototoxicity, hearing impaired and/or hearing loss have been
reported.
Cardiac disorders
Rare cases of myocardial infarction have been reported.
Vascular disorders
Venous thromboembolic events have rarely been reported.
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome and cases of interstitial
pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and
respiratory failure sometimes fatal have rarely been reported. Rare cases of
radiation pneumonitis have been reported in patients receiving concomitant
radiotherapy.
Gastrointestinal disorders
Rare 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 preexisting 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 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. Cases of persisting alopecia have been reported.
Renal and urinary disorders
Renal insufficiency and renal failure have been reported. In about 20 % of
these cases there were no risk factors for acute renal failure such as
concomitant nephrotoxic medicinal products and gastrointestinal disorders.
General disorders and administration site conditions
Recall phenomena including radiation recall, injection site recall and sunburn
recall 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.
Metabolism and nutrition disorders
Cases of hyponatraemia have been reported, mostly associated with
dehydration, vomiting and pneumonia.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme
www.mhra.gov.uk/yellowcard.
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: L01CD02
Mechanism of action
Docetaxel is an antineoplastic agent which acts by promoting the assembly of
tubulin into stable microtubules and inhibits their disassembly which leads to a
marked decrease of free tubulin. The binding of docetaxel to microtubules
does not alter the number of protofilaments.
Docetaxel has been shown in vitro to disrupt the microtubular network in cells
which is essential for vital mitotic and interphase cellular functions.
Pharmacodynamic effects
Docetaxel was found to be cytotoxic in vitro against various murine and
human tumour cell lines and against freshly excised human tumour cells in
clonogenic assays. Docetaxel achieves high intracellular concentrations with a
long cell residence time. In addition, docetaxel was found to be active on some
but not all cell lines over expressing the p-glycoprotein which is encoded by
the multidrug resistance gene. In vivo, docetaxel is schedule independent and
has a broad spectrum of experimental antitumour activity against advanced
murine and human grafted tumours.
Clinical efficacy and safety
Breast cancer
Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant
therapy
Patients with operable node-positive breast cancer (TAX 316)
Data from a multicenter open label randomised 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 randomised to receive either docetaxel 75 mg/m²
administered 1 hour after doxorubicin 50 mg/m² and cyclophosphamide
500 mg/m² (TAC arm), or doxorubicin 50 mg/m² followed by fluorouracil
500 mg/m² and cyclosphosphamide 500 mg/m² (FAC arm). Both regimens
were administered once every 3 weeks for 6 cycles. Docetaxel was
administered as a 1-hour infusion, all other medicinal products were given as
intravenous bolus on day one. G-CSF was administered as secondary
prophylaxis to patients who experienced complicated neutropenia (febrile
neutropenia, prolonged neutropenia, or infection). Patients on the TAC arm
received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily
for 10 days starting on day 5 of each cycle, or equivalent. In both arms, after
the last cycle of chemotherapy, patients with positive estrogen and/or
progesterone receptors received tamoxifen 20 mg daily for up to 5 years.
Adjuvant radiation therapy was prescribed according to guidelines in place at
participating institutions and was given to 69 % of patients who received TAC

and 72 % of patients who received FAC. Two interim analyses and one final
analysis were performed. The first interim analysis was planned 3 years after
the date when half of study enrolment was done. The second interim analysis
was done after 400 DFS events had been recorded overall, which led to a
median follow-up of 55 months. The final analysis was performed when all
patients had reached their 10-year follow-up visit (unless they had a DFS event
or were lost to follow-up before). Disease-free survival (DFS) was the primary
efficacy endpoint and Overall survival (OS) was the secondary efficacy
endpoint.
A final analysis was performed with an actual median follow up of 96 months.
Significantly longer disease-free survival for the TAC arm compared to the
FAC arm was demonstrated. Incidence of relapses at 10 years was reduced in
patients receiving TAC compared to those who received FAC (39 % versus
45 %, respectively) i.e. an absolute risk reduction by 6 % (p = 0.0043). Overall
survival at 10 years was also significantly increased with TAC compared to
FAC (76 % versus 69 %, respectively) i.e. an absolute reduction of the risk of
death by 7 % (p = 0.002). As the benefit observed in patients with 4+ nodes
was not statistically significant on DFS and OS, the positive benefit/risk ratio
for TAC in patients with 4+ nodes was not fully demonstrated at the final
analysis.
Overall, the study results demonstrate a positive benefit risk ratio for TAC
compared to FAC.
TAC-treated patient subsets according to prospectively defined major
prognostic factors were analysed:

Patient
subset

Disease free survival
Number Hazard 95% CI p =
of
ratio*
patients

Overall survival
Hazard 95% CI p =
ratio*

No of
positive
nodes
0.74
0.61-0.90 0.0020
Overall 745
0.80
0.68-0.93 0.0043
0.62
1-3
467
0.72
0.58-0.91 0.0047
0.46-0.82 0.0008
4+
278
0.87
0.70-1.09 0.2290
0.87
0.67-1.12 0.2746
*a hazard ratio of less than 1 indicates that TAC is associated with a longer
disease-free survival and overall survival compared to FAC
Patients with operable node-negative breast cancer eligible to receive
chemotherapy (GEICAM 9805)
Data from a multicenter open label randomised trial support the use of
docetaxel for the adjuvant treatment of patients with operable node-negative
breast cancer eligible to receive chemotherapy. 1060 patients were randomised
to receive either docetaxel 75 mg/m² administered 1 hour after doxorubicin
50 mg/m² and cyclophosphamide 500 mg/m² (539 patients in TAC arm), or
doxorubicin 50 mg/m² followed by fluorouracil 500 mg/m² and

cyclosphosphamide 500 mg/m² (521 patients in FAC arm), as adjuvant
treatment of operable node-negative breast cancer patients with high risk of
relapse according to 1998 St. Gallen criteria (tumour size > 2 cm and/or
negative ER and PR and/or high histological/nuclear grade (grade 2 to 3) and
/or age < 35 years). Both regimens were administered once every 3 weeks for
6 cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal
products were given intravenously on day 1 every three weeks. Primary
prophylactic G-CSF was made mandatory in TAC arm after 230 patients were
randomised. 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.
One primary analysis and one updated analysis were performed. The primary analysis
was done when all patients had a follow-up of greater than 5 years (median follow-up
time of 77 months). The updated analysis was performed when all patients had
reached their 10-year (median follow up time of 10 years and 5 months) follow-up
visit (unless they had a DFS event or were lost to follow-up previously). Disease-free
survival (DFS) was the primary efficacy endpoint and Overall survival (OS) was the
secondary efficacy endpoint.

At the median follow-up time of 77 months, significantly longer disease-free
survival for the TAC arm compared to the FAC arm was demonstrated.
TAC-treated patients had a 32 % reduction in the risk of relapse compared to
those treated with FAC (hazard ratio = 0.68, 95 % CI (0.49 – 0.93), p = 0.01).
At the median follow up time of 10 years and 5 months, TAC-treated patients
had a 16.5 % reduction in the risk of relapse compared to those treated with
FAC (hazard ratio = 0.84, 95 % CI (0.65 – 1.08), p = 0.1646). DFS data were
not statistically significant but were still associated with a positive trend in
favour of TAC.
At the median follow-up time of 77 months, overall survival (OS) was longer
in the TAC arm with TAC-treated patients having a 24 % reduction in the risk
of death compared to FAC (hazard ratio = 0.76, 95 % CI (0.46 – 1.26, p =
0.29). However, the distribution of OS was not significantly different between
the 2 groups.
At the median follow up time of 10 years and 5 months, TAC-treated patients
had a 9 % reduction in the risk of death compared to FAC-treated patients
(hazard ratio = 0.91, 95% CI (0.63 – 1.32)).
The survival rate was 93.7% in the TAC arm and 91.4 % in the FAC arm, at
the 8-year follow-up timepoint, and 91.3 % in the TAC arm and 89 % in the
FAC arm, at the 10-year follow-up timepoint.
The positive benefit risk ratio for TAC compared to FAC remained
unchanged.

TAC-treated patient subsets according to prospectively defined major
prognostic factors were analysed in the primary analysis (at the median
follow-up time of 77 months) (see table below):
Subset Analyses–Adjuvant Therapy in Patients with Node-negative Breast
Cancer Study
(Intent-to-Treat Analysis)
Patient subset

Number of
patients in TAC
group
539

Disease free survival
Hazard ratio*
95 % CI

0.68
0.49 – 0.93
Overall
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
Grade 1 (includes
64
0.79
0.24 – 2.6
grade not assessed)
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:

Subgroups
Meeting relative
indication for
chemotherapy a
No
Yes

TAC

FAC

(n = 539)

(n = 521)

Hazard ratio
(TAC/FAC)
(95% CI)

18/214
(8.4 %)
48/325
(14.8 %)

26/227
(11.5 %)
69/294
(23.5 %)

0.796 (0.434 –
1.459)
0.606 (0.42 –
0.877)

p-value

0.4593
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 tumour size > 5 cm
The estimated hazard ratio was using Cox proportional hazard model with
treatment group as the factor.
Docetaxel 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 versus doxorubicin 14 months, p = 0.38) or time to progression
(docetaxel 27 weeks versus doxorubicin 23 weeks, p = 0.54), docetaxel
increased response rate (52 % versus 37 %, p = 0.01) and shortened time to
response (12 weeks versus 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 % versus 12 %, p < 0.0001),
prolonged time to progression (19 weeks versus 11 weeks, p = 0.0004) and
prolonged overall survival (11 months versus 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, randomised 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 randomised 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 in combination with doxorubicin

One large randomised phase III study, involving 429 previously untreated
patients with metastatic disease, has been performed with doxorubicin
(50 mg/m²) in combination with docetaxel (75 mg/m²) (AT arm) versus
doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²)
(AC arm). Both regimens were administered on day 1 every 3 weeks.


Time to progression (TTP) was significantly longer in the AT arm versus
AC arm, p = 0.0138. The median TTP was 37.3 weeks (95 %CI:
33.4 - 42.1) in AT arm and 31.9 weeks (95 %CI : 27.4 - 36.0) in AC arm.



Overall response rate (ORR) was significantly higher in the AT arm
versus AC arm, p = 0.009. The ORR was 59.3 % (95 %CI: 52.8 - 65.9) in
AT arm versus 46.5 % (95 %CI: 39.8 - 53.2) in AC arm.

In this study, AT arm showed a higher incidence of severe neutropenia (90 %
versus 68.6 %), febrile neutropenia (33.3 % versus 10 %), infection (8 %
versus 2.4 %), diarrhoea (7.5 % versus 1.4 %), asthenia (8.5 % versus 2.4 %),
and pain (2.8 % versus 0 %) than AC arm. On the other hand, AC arm showed
a higher incidence of severe anaemia (15.8 % versus 8.5 %) than AT arm, and,
in addition, a higher incidence of severe cardiac toxicity: congestive heart
failure (3.8 % versus 2.8 %), absolute LVEF decrease ≥ 20 % (13.1 % versus
6.1 %), absolute LVEF decrease ≥ 30 % (6.2 % versus 1.1 %). Toxic deaths
occurred in 1 patient in the AT arm (congestive heart failure) and in 4 patients
in the AC arm (1 due to septic shock and 3 due to congestive heart failure). In
both arms, quality of life measured by the EORTC questionnaire was
comparable and stable during treatment and follow-up.
Docetaxel 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 randomised to receive docetaxel (100 mg/m²)
with or without trastuzumab; 60 % of patients received prior
anthracycline-based adjuvant chemotherapy. Docetaxel plus trastuzumab was
efficacious in patients whether or not they had received prior adjuvant
anthracyclines. The main test method used to determine HER2 positivity in
this pivotal study was immunohistochemistry (IHC). A minority of patients
were tested using fluorescence in-situ hybridisation (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
summarised in the following table:

Parameter

Docetaxel plus
trastuzumab1
n = 92
61 %
(50 – 71)

Docetaxel1
n = 94

Response rate
34 %
(95 % CI)
(25 – 45)
Median Duration of
response
11.4
5.1
(months)
(9.2 – 15.0)
(4.4 – 6.2)
(95 % CI)
Median TTP (months)
10.6
5.7
(95 % CI)
(7.6 – 12.9)
(5.0 – 6.5)
Median Survival (months)
30.5²
22.1²
(95 % CI)
(26.8 – ne)
(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
Docetaxel in combination with capecitabine
Data from one multicenter, randomised, controlled phase III clinical study
support the use of docetaxel in combination with capecitabine for treatment of
patients with locally advanced or metastatic breast cancer after failure of
cytotoxic chemotherapy, including an anthracycline. In this study, 255 patients
were randomised to treatment with docetaxel (75 mg/m² as a 1-hour
intravenous infusion every 3 weeks) and capecitabine (1250 mg/m² twice daily
for 2 weeks followed by 1-week rest period). 256 patients were randomised to
treatment with docetaxel alone (100 mg/m² as a 1-hour intravenous infusion
every 3 weeks). Survival was superior in the docetaxel +capecitabine
combination arm (p=0.0126). Median survival was 442 days (docetaxel +
capecitabine) versus 352 days (docetaxel alone). The overall objective
response rates in the all-randomised population (investigator assessment) were
41.6 % (docetaxel + capecitabine) versus 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) versus 128 days (docetaxel alone).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression
(12.3 weeks versus 7 weeks) and overall survival were significantly longer for
docetaxel at 75 mg/m² compared to Best Supportive Care. The 1-year survival
rate was also significantly longer in docetaxel (40 %) versus BSC (16 %).
There was less use of morphinic analgesic (p < 0.01), non--morphinic
analgesics (p < 0.01), other disease related medicinal products (p = 0.06) and
radiotherapy (p < 0.01) in patients treated with docetaxel at 75 mg/m²
compared to those with BSC.

The overall response rate was 6.8 % in the evaluable patients, and the median
duration of response was 26.1 weeks.
Docetaxel in combination with platinum agents in chemotherapy-naïve
patients
In a phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC,
with KPS of 70 % or greater, and who did not receive previous chemotherapy
for this condition, were randomised to either docetaxel (T) 75 mg/m² as a
1-hour infusion immediately followed by cisplatin (Cis) 75 mg/ m² over
30 - 60 minutes every 3 weeks (TCis), docetaxel 75 mg/ m² as a 1-hour
infusion in combination with carboplatin (AUC 6 mg/ml min) over 30 –
60 minutes every 3 weeks, or vinorelbine (V) 25 mg/ m² administered over
6 - 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/ m²
administered on day 1 of cycles repeated every 4 weeks (VCis).
Survival data, median time to progression and response rates for two arms of
the study are illustrated in the following table:

Overall survival
(Primary end-point):
Median survival
(months)

TCis
n = 408

VCis
n = 404

Statistical analysis

11.3

10.1

46

41

21

14

Hazard Ratio: 1.122
[97.2 % CI: 0.937;
1.342]*
Treatment difference:
5.4 %
[95 % CI: -1.1; 12.0]
Treatment difference:
6.2 % [95 % CI: 0.2;
12.3]

22.0

23.0

1-year Survival (%)
2-year Survival (%)

Median time to
progression
(weeks):
Overall response rate
(%):

Hazard Ratio: 1.032
[95 % CI: 0.876; 1.216]
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.
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 randomised multicenter phase III study. A total of
1006 patients with KPS ≥ 60 were randomised to the following treatment
groups:
• Docetaxel 75 mg/m² every 3 weeks for 10 cycles.
• Docetaxel 30 mg/m² administered weekly for the first 5 weeks in a 6-week
cycle for 5 cycles.
• Mitoxantrone 12 mg/m² every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone or
prednisolone 5 mg twice daily, continuously.
Patients who received docetaxel every three weeks demonstrated significantly
longer overall survival compared to those treated with mitoxantrone. The
increase in survival seen in the docetaxel weekly arm was not statistically
significant compared to the mitoxantrone control arm. Efficacy endpoints for
the docetaxel arms versus the control arm are summarised in the following
table:
Endpoint

Docetaxel
every 3 weeks
335
18.9
(17.0 – 21.2)
0.761
(0.619 – 0.936)
0.0094

Docetaxel
every week
334
17.4
(15.7 – 19.0)
0.912
(0.747 – 1.113)
0.3624

Number of patients
Median survival
(months)
95 % CI
Hazard ratio
95 % CI
p-value†*
Number of patients
291
282
PSA** response rate
45.4
47.9
(%)
(39.5 – 51.3)
(41.9 – 53.9)
95 % CI
0.0005
< 0.0001
p-value*
Number of patients
153
154
Pain response rate
34.6
31.2
(%)
(27.1 – 42.7)
(24.0 – 39.1)
95 % CI
0.0107
0.0798
p-value*
Number of patients
141
134
Tumor response rate
12.1
8.2
(%)
(7.2 – 18.6)
(4.2 – 14.2)
95 % CI
0.1112
0.5853
p-value*

Stratified log rank test
*Threshold for statistical significance = 0.0175
**PSA: Prostate-Specific Antigen

Mitoxantrone
every 3 weeks
337
16.5
(14.4 – 18.6)
---300
31.7
(26.4 – 37.3)
-157
21.7
(15.5 – 28.9)
-137
6.6
(3.0 – 12.1)
--

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, randomised 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/m² on day 1) in combination with cisplatin (C) (75 mg/m² on day 1)
and 5-fluorouracil (F) (750 mg/m² per day for 5 days) or cisplatin (100 mg/m²
on day 1) and 5-fluorouracil (1,000 mg/m² 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 favour of the TCF arm. Overall survival was also significantly
longer (p = 0.0201) in favour of the TCF arm with a risk reduction of mortality
of 22.7 %. Efficacy results are summarised in the following table:
Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma
Endpoint
Median TTP (months)
(95 % CI)
Hazard ratio
(95 % CI)
*p-value
Median survival (months)
(95 % CI)
2-year estimate (%)
Hazard ratio
(95 % CI)
*p-value
Overall response rate (CR+PR) (%)
p-value
Progressive disease as best overall
response (%)
*Unstratified logrank test

TCF
CF
n = 221
n = 224
5.6
3.7
(4.86 – 5.91)
(3.45 – 4.47)
1.473
(1.189 – 1.825)
0.0004
9.2
8.6
(8.38 – 10.58) (7.16 – 9.46)
18.4
8.8
1.293
(1.041 – 1.606)
0.0201
36.7

25.4
0.0106

16.7

25.9

Subgroup analyses across age, gender and race consistently favoured 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 favour 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, randomised study (TAX323). In this study,
358 patients with inoperable locally advanced SCCHN, and WHO
performance status 0 or 1, were randomised to one of two treatment arms.
Patients on the docetaxel arm received docetaxel (T) 75 mg/m² followed by
cisplatin (P) 75 mg/m² followed by 5-fluorouracil (F) 750 mg/m² 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/m² followed by
5-fluorouracil (F) 1,000 mg/m² 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 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
versus 8.3 months respectively) with an overall median follow up time of 33.7

months. Median overall survival was also significantly longer in favour of the
TPF arm compared to the PF arm (median OS: 18.6 versus 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
Cis+5-FU
n = 177
n = 181
11.4
8.3
(10.1 – 14.0)
(7.4 - 9.1)
0.70
(0.55 – 0.89)
0.0042
18.6
14.5
(15.7 – 24.0)
(11.6 - 18.7)
0.72
(0.56 – 0.93)
0.0128
67.8
53.6
(60.4 – 74.6)
(46.0 - 61.0)
0.006

Median progression free survival (months)
(95 %CI)
Adjusted hazard ratio
(95 %CI)
*p-value
Median survival (months)
(95 %CI)
Hazard ratio
(95 %CI)
**p-value
Best overall response to chemotherapy (%)
(95 %CI)
***p-value
Best overall response to study treatment
[chemotherapy +/- radiotherapy] (%)
72.3
58.6
(95 %CI)
(65.1 – 78.8)
(51.0 - 65.8)
***p-value
0.006
Median duration of response to chemotherapy
n = 128
n = 106
±
15.7
11.7
radiotherapy (months)
(13.4 – 24.6)
(10.2-17.4)
(95 %CI)
0.72
Hazard ratio
(0.52 – 0.99)
(95 %CI)
0.0457
**p-value
A hazard ratio of less than 1 favours 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 favour 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.
• 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 randomised, 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 randomised 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 3-hour intravenous
infusion, followed by the continuous intravenous infusion of 5-fluorouracil
(F) 1,000 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 3-hour intravenous infusion on day 1 followed by the
continuous intravenous infusion of 5-fluorouracil (F) 1,000 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 1-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:
Efficacy of docetaxel in the induction treatment of patients with locally
advanced SCCHN (Intent-to-Treat Analysis)
Endpoint

Docetaxel + Cis +
5-FU
n=225
70.6
(49.0 – NA)

Cis + 5-FU
n=246

Median overall survival
30.1
(months)
(20.9 – 51.5)
(95 % CI)
0.70
Hazard ratio
(0.54 – 0.90)
(95 % CI)
0.0058
*p-value
Median PFS (months)
35.5
13.1
(95 % CI)
(19.3 – NA)
(10.6 – 20.2)
Hazard ratio
0.71
(95 % CI)
(0.56 – 0.90)
**p-value
0.004
Best overall response (CR +
71.8
64.2
PR) to chemotherapy (%)
(65.8 – 77.2)
(57.9 – 70.2)
(95 % CI)
0.070
***p-value
Best overall response (CR +
76.5
71.5
PR) to study treatment
(70.8 – 81.5)
(65.5 – 77.1)
[chemotherapy +/0.209
chemoradiotherapy] (%)
(95 % CI)
*** p-value
A hazard ratio of less than 1 favours 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
Paediatric population
The European Medicines Agency has waived the obligation to submit the
results of studies with Docetaxel in all subsets of the paediatric population in
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 (see section 4.2 for information on paediatric use).

5.2

Pharmacokinetic properties
Absorption

The pharmacokinetics of docetaxel have been evaluated in cancer patients after
administration of 20 - 115 mg/m² 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.
Distribution
Following the administration of a 100 mg/m² dose given as a 1-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/m² and 113 l, respectively. Inter individual variation in total body
clearance was approximately 50 %. Docetaxel is more than 95 % bound to plasma
proteins.
Elimination
A study of 14C-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.
Special populations
Age and gender
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.
Hepatic impairment
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).
Fluid retention
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.
Combination therapy

Doxorubicin
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 co-administration.
Capecitabine
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 (Cmax and AUC) and no effect by docetaxel on the pharmacokinetics of a
relevant capecitabine metabolite 5’-DFUR.
Cisplatin
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.
Cisplatin and 5-fluorouracil
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.
Prednisone and dexamethasone
The effect of prednisone on the pharmacokinetics of docetaxel administered with
standard dexamethasone premedication has been studied in 42 patients.
Prednisone
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

Citric acid anhydrous
Povidone
Polysorbate 80
Ethanol anhydrous
6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.

6.3

Shelf life

Unopened vial:
24 months.
After opening of the vial:
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.
Once added to the infusion bag:
From a microbiological point of view, reconstitution/dilution must take place in controlled
and aseptic conditions and the medicinal product should be used immediately. If not used
immediately, in-use storage times and conditions are the responsibility of the user.
Once added into the infusion bag containing the recommended solutions for infusion (50
mg/ml (5 %) glucose solution for infusion or 9 mg/ml (0.9 %) sodium chloride solution for
infusion), the diluted docetaxel solution (maximum concentration 0.74 mg/ml), if stored
below 25 °C, in non PVC bags, is stable for 8 hours. It should be used within 8 hours
(including the one hour infusion intravenous administration).
In addition, physical and chemical in-use stability of the infusion solution prepared as
recommended has been demonstrated for 3 days when stored between 2 to 8 °C protected
from light.

Docetaxel infusion solution is supersaturated, therefore it may crystallise over time. If crystals
appear, the solution must no longer be used and should be discarded.

6.4

Special precautions for storage
Store below 25 °C.
Do not refrigerate or freeze.
Store in the original package in order to protect from light.
For storage conditions after opening of the vials and of the diluted medicinal product,
see section 6.3.

6.5

Nature and contents of container

Colourless glass vial (type I) closed with a bromobutyl rubber stopper (type I) sealed
with aluminium cap with polypropylene disc. Vial will be packed with or without a
protective plastic overwrap.
Pack sizes:
1 x 1 ml single dose vial
1 x 4 ml single dose vial
1 x 7 ml single dose vial
1 x 8 ml single dose vial
Not all pack sizes may be marketed.
6.6

Special precautions for disposal

Taxceus is an antineoplastic agent and, as with other potentially toxic compounds,
caution should be exercised when handling it and preparing Taxceus solutions.
Cytotoxic agents should be prepared for administration only by personnel who have
been trained in the safe handling of such preparations. Refer to local cytotoxic
guidelines before commencing. The use of gloves is recommended.
If Taxceus concentrate or infusion solution should come into contact with skin, wash
immediately and thoroughly with soap and water. If Taxceus concentrate or infusion
solution should come into contact with mucous membranes, wash immediately and
thoroughly with water.
Preparation of the solution for infusion
More than one vial of Taxceus 20 mg/ml concentrate for solution for infusion may be
necessary to obtain the required dose for individual patients. Based on the required
dose for the patient expressed in mg, aseptically withdraw the corresponding volume
of 20 mg/ml docetaxel from the appropriate number of vials using graduated syringes

fitted with a needle. For example, a dose of 140 mg docetaxel would require 7 ml of
Taxceus 20 mg/ml concentrate for solution for infusion.
For doses below 192 mg of docetaxel, inject the required volume of Taxceus
20 mg/ml concentrate for solution for infusion into a 250 ml infusion bag or bottle
containing either 250 ml of 50 mg/ml (5 %) glucose solution for infusion or 9 mg/ml
(0.9 %) sodium chloride solution for infusion. For doses exceeding 192 mg of
docetaxel more than 250 ml of the infusion solution is required, as the maximum
concentration of docetaxel is 0.74 mg per ml of infusion solution.
Mix the infusion bag or bottle manually using a rocking motion.
For storage conditions of the diluted medicinal product, see section 6.3.
The diluted solution should be used within 8 hours and should be aseptically
administered as a 1-hour infusion at room temperature and normal lighting conditions.
Administration
For instructions on administration see section 4.2.
As with all parenteral products, this medicinal product should be visually inspected
prior to use and 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

medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
Tel.: +49 4103 8006-0
Fax: +49 4103 8006-100

8

MARKETING AUTHORISATION NUMBER(S)
PL 11587/0074

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 02/08/2010

10

DATE OF REVISION OF THE TEXT
06/05/2016

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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