Skip to Content

DOCETAXEL 20 MG/1 ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): DOCETAXEL ANHYDROUS

View full screen / Print PDF » Download PDF ⇩

PDF Transcript

SUMMARY OF PRODUCT CHARACTERISTICS

1

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

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate contains 20 mg docetaxel anhydrous.
One vial of 1 ml of concentrate contains 20 mg of docetaxel.
One vial of 4 ml of concentrate contains 80 mg of docetaxel.
One vial of 8 ml of concentrate contains 160 mg of docetaxel.
Excipients with known effect:
Each vial of 1 ml of concentrate contains 0.57 ml of ethanol 96% (0.46 g).
Each vial of 4 ml of concentrate contains 2.28 ml of ethanol 96% (1.83 g).
Each vial of 8 ml of concentrate contains 4.56 ml of ethanol 96% (3.66 g).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Concentrate for solution for infusion.
The concentrate is a clear viscous, colourless to brownish-yellow sterile
solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Breast cancer
Docefim 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).
Docefim 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.
Docefim 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.
Docefim 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.
Docefim 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
Docefim is indicated for the treatment of patients with locally advanced or
metastatic non-small cell lung cancer after failure of prior chemotherapy.
Docefim 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
Docefim in combination with prednisone or prednisolone is indicated for the
treatment of patients with hormone refractory metastatic prostate cancer.
Gastric adenocarcinoma
Docefim 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
Docefim in combination with cisplatin and 5 - fluorouracil is indicated for the
induction treatment of patients with locally advanced squamous cell carcinoma
of the head and neck.

4.2

Posology and method of administration
The use of docetaxel should be confined to units specialised in the
administration of cytotoxic chemotherapy and it should only be administered
under the supervision of a physician qualified in the use of anticancer
chemotherapy (see section 6.6).
Recommended dose
For breast, non-small cell lung, gastric, and head and neck cancers,
premedication consisting of an oral corticosteroid, such as dexamethasone 16
mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel
administration, unless contraindicated, can be used (see section 4.4).
Prophylactic G CSF may be used to mitigate the risk of haematological
toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone
the recommended premedication regimen is oral dexamethasone 8 mg, 12
hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.4).
Docetaxel is administered as a one-hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive and node-negative breast
cancer, the recommended dose of docetaxel is 75 mg/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 3hour infusion, followed by 5-fluorouracil 1000 mg/m2/day as a continuous
infusion from day 1 to day 4. This regimen is administered every 3 weeks for
3
cycles.
Following
chemotherapy,
patients
should
receive
chemoradiotherapy.
For cisplatin and 5-fluorouracil dose modifications, see the corresponding
summary of product characteristics.
Dose adjustments during treatment
General
Docetaxel should be administered when the neutrophil count is ≥ 1,500
cells/mm3.
In patients who experienced either febrile neutropenia, neutrophil count < 500
cells/mm3 for more than one week, severe or cumulative cutaneous reactions
or severe peripheral neuropathy during docetaxel therapy, the dose of
docetaxel should be reduced from 100 mg/m2 to 75 mg/m2 and/or from 75 to
60 mg/m². If the patient continues to experience these reactions at 60 mg/m²,
the treatment should be discontinued.
Adjuvant therapy for breast cancer
Primary G-CSF prophylaxis should be considered in patients who receive
docetaxel, doxorubicin and cyclophosphamide (TAC) adjuvant therapy for
breast cancer. Patients who experience febrile neutropenia and/or neutropenic
infection should have their docetaxel dose reduced to 60 mg/m2 in all
subsequent cycles (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

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

For cisplatin and 5-fluorouracil dose adjustments, see the corresponding
summary of product characteristics.

In the pivotal SCCHN studies patients who experienced complicated
neutropenia (including prolonged neutropenia, febrile neutropenia, or
infection), it was recommended to use G CSF to provide prophylactic
coverage (eg, day 6 15) in all subsequent cycles.
Special populations
Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent,
patients who have both elevations of transaminase (ALT and/or AST) greater
than 1.5 times the upper limit of the normal range (ULN) and alkaline
phosphatase greater than 2.5 times the ULN, the recommended dose of
docetaxel is 75 mg/m2 (see sections 4.4 and 5.2). For those patients with serum
bilirubin > ULN and/or ALT and AST > 3.5 times the ULN associated with
alkaline phosphatase > 6 times the ULN, no dose-reduction can be
recommended and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients
with gastric adenocarcinoma, the pivotal clinical study excluded patients with
ALT and/or AST > 1.5 × ULN associated with alkaline phosphatase > 2.5 ×
ULN, and bilirubin > 1 x ULN; for these patients, no dose-reductions can be
recommended and docetaxel should not be used unless strictly indicated. No
data are available in patients with hepatic impairment treated by docetaxel in
combination in the other indications.
Paediatric population
The safety and efficacy of docetaxel in nasopharyngeal carcinoma in children
aged 1 month to less than 18 years have not yet been established.
There is no relevant use of docetaxel in the paediatric population in the
indications breast cancer, non-small cell lung cancer, prostate cancer, gastric
carcinoma and head and neck cancer, not including type II and III less
differentiated nasopharyngeal carcinoma.

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.
Docetaxel must not be used in patients with baseline neutrophil count of <
1,500 cells/mm3.
Docetaxel must not be used in patients with severe liver impairment (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 section 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).
Older people
There are limited data available in patients > 70 years of age on docetaxel use in
combination with doxorubicin and cyclophosphamide.
Of the 333 patients treated with docetaxel every three weeks in a prostate cancer
study, 209 patients were 65 years of age or greater and 68 patients were older than
75 years. In patients treated with docetaxel every three weeks, the incidence of related
nail changes occurred at a rate ≥ 10% higher in patients who were 65 years of age or
greater compared to younger patients. The incidence of related fever, diarrhoea,
anorexia, and peripheral oedema occurred at rates ≥ 10% higher in patients who were
75 years of age or greater versus less than 65 years.
Among the 300 (221 patients in the phase III part of the study and 79 patients in the
phase II part) patients treated with docetaxel in combination with cisplatin and
5-fluorouracil in the gastric cancer study, 74 were 65 years of age or older and
4 patients were 75 years of age or older. The incidence of serious adverse events was
higher in 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 approximately 55 vol % ethanol (alcohol), i.e. up to
0.457 g (0.57 ml) ethanol 96 % per 1 ml vial, equivalent to 12 ml of beer or 5 ml wine
per 1 ml vial, 1.828 g (2.28 ml) ethanol 96 % per 4 ml vial, equivalent to 48 ml of
beer or 20 ml wine per 4 ml vial, or 3.66g (4.56 ml) ethanol 96 % per vial of 8 ml fill
volume, equivalent to 96 ml beer or 40ml wine per 8 ml vial.

Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding women, children and high-risk
groups such as patients with liver disease, or epilepsy.
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.
4.5

Interaction with other medicinal products and other forms of interaction
In vitro studies have shown that the metabolism of docetaxel may be modified
by the concomitant administration of compounds which induce, inhibit or are
metabolised by (and thus may inhibit the enzyme competitively) cytochrome
P450-3A such as ciclosporine, terfenadine, ketoconazole, erythromycin and
troleandomycin. As a result, caution should be exercised when treating
patients with these medicinal products as concomitant therapy since there is a
potential for a significant interaction.
Docetaxel is highly protein bound (> 95%). Although the possible in vivo
interaction of docetaxel with concomitantly administered medicinal product
has not been investigated formally, in vitro interactions with tightly proteinbound agents such as erythromycin, diphenhydramine, propranolol,
propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate
did not affect protein binding of docetaxel. In addition, dexamethasone did not
affect protein binding of docetaxel. Docetaxel did not influence the binding of
digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were
not influenced by their co administration. Limited data from a single
uncontrolled study were suggestive of an interaction between docetaxel and
carboplatin. When combined to docetaxel, the clearance of carboplatin was
about 50% higher than values previously reported for carboplatin
monotherapy.
Docetaxel pharmacokinetics in the presence of prednisone was studied in
patients with metastatic prostate cancer. Docetaxel is metabolised by CYP3A4
and prednisone is known to induce CYP3A4. No statistically significant effect
of prednisone on the pharmacokinetics of docetaxel was observed.
Clinical cases consistent with an increase in docetaxel toxicity were reported
when it was combined with ritonavir. The mechanism behind this interaction
is a CYP3A4 inhibition, the main isoenzyme involved in docetaxel
metabolism by ritonavir. Based on extrapolation from a pharmacokinetic study
with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if

patients require co-administration of a strong CYP3A4 inhibitor such as azole
antifungals, ritonavir and some macrolides (clarithromycin, telithromycin).

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.
Fertility
An effective method of contraception should be used during treatment.
In non clinical studies, docetaxel has genotoxic effects and may alter male
fertility (see section 5.3). Therefore, men being treated with docetaxel are
advised not to father a child during and up to 6 months after treatment and to
seek advice on conservation of sperm prior to treatment.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.

4.8

Undesirable effects

Summary of the safety profile for all indications

The adverse reactions considered to be possibly or probably related to the
administration of docetaxel have been obtained in:
• 1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as
a single agent respectively.
• 258 patients who received docetaxel in combination with doxorubicin.
• 406 patients who received docetaxel in combination with cisplatin.
• 92 patients treated with docetaxel in combination with trastuzumab.
• 255 patients who received docetaxel in combination with capecitabine.
• 332 patients who received docetaxel in combination with prednisone or
prednisolone (clinically important treatment related adverse events are
presented).
• 1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who
received docetaxel in combination with doxorubicin and cyclophosphamide
(clinically important treatment related adverse events are presented).
• 300 gastric adenocarcinoma patients (221 patients in the phase III part of the
study and 79 patients in the phase II part) who received docetaxel in
combination with cisplatin and 5-fluorouracil (clinically important treatment
related adverse events are presented).
• 174 and 251 head and neck cancer patients who received docetaxel in
combination with cisplatin and 5-fluorouracil (clinically important treatment
related adverse events are presented).
These reactions were described using the NCI Common Toxicity Criteria
(grade 3 = G3; grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA
terms.
Frequencies are defined as:
very common
common
uncommon
rare
very rare
not known

(≥ 1/10)
(≥ 1/100 to < 1/10)
≥ 1/1000 to < 1/100)
(≥ 1/10,000 to < 1/1000)
(< 1/10000)
(cannot be estimated from available data)

Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
The most commonly reported adverse reactions of docetaxel alone are: neutropenia
(which was reversible and not cumulative; the median day to nadir was 7 days and the
median duration of severe neutropenia (< 500 cells/mm3) was 7 days), anaemia,
alopecia, nausea, vomiting, stomatitis, diarrhoea and asthenia. The severity of adverse
events of docetaxel may be increased when docetaxel is given in combination with
other chemotherapeutic agents.
For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are
displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4
AEs (34% vs. 23%) in the trastuzumab combination arm compared to docetaxel
monotherapy.

For combination with capecitabine, the most frequent treatment-related undesirable
effects (≥ 5%) reported in a phase III study in breast cancer patients failing
anthracycline treatment are presented (see capecitabine summary of product
characteristics).
The following adverse reactions are frequently observed with docetaxel:
Immune system disorders
Hypersensitivity reactions have generally occurred within a few minutes following the
start of the infusion of docetaxel and were usually mild to moderate. The most
frequently reported symptoms were flushing, rash with or without pruritus, chest
tightness, back pain, dyspnoea and fever or chills. Severe reactions were characterised
by hypotension and/or bronchospasm or generalized rash/erythema (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

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

Uncommon
adverse reactions

MedDRA system
organ classes

Blood and
lymphatic system
disorders

Immune system
disorders
Metabolism and
nutrition disorders
Nervous system
disorders

Very common
adverse reactions
1.7%)
Neutropenia (G4:
76.4%);
Anaemia (G3/4:
8.9%);
Febrile neutropenia
Hypersensitivity
(G3/4: 5.3%)
Anorexia

Uncommon
adverse reactions

Thrombocytopenia
(G4: 0.2%)

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

Cardiac disorders
Vascular disorders

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Common adverse
reactions

Arrhythmia (G3/4:
0.7%)
Hypotension;
Hypertension;
Haemorrhage

Cardiac failure

Constipation
(severe: 0.2%);
Abdominal pain
(severe: 1%);
Gastrointestinal
haemorrhage
(severe: 0.3%)

Oesophagitis
(severe: 0.4%)

Dyspnoea (severe:
2.7%)

Stomatitis (G3/4:
5.3%);
Diarrhoea (G3/4:
4%);
Nausea (G3/4: 4%);
Vomiting (G3/4:
3%)
Skin and
Alopecia;
subcutaneous tissue Skin reaction (G3/4:
disorders
5.9%);
Nail disorders
(severe: 2.6%)
Musculoskeletal
Myalgia (severe:
and connective
1.4%)
tissue disorders
General disorders
Fluid retention
and administration (severe: 6.5%);
site conditions
Asthenia (severe:
11.2%);

Arthralgia

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

MedDRA system
organ classes

Very common
adverse reactions

Common adverse
reactions

Uncommon
adverse reactions

Pain
Investigations

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

Description of selected adverse reactions in breast cancer for 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 breast cancer for docetaxel 75mg/m² single
agent:
MedDRA system organ
classes

Very common adverse
reactions

Infections and infestations
Blood and lymphatic
system disorders

Infections (G3/4: 5%)
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4:
1.7%)

Common adverse
reactions

Febrile neutropenia

Immune system disorders
Metabolism and nutrition
disorders
Nervous system disorders

Cardiac disorders
Vascular disorders
Gastrointestinal disorders

Skin and subcutaneous
tissue disorders

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

Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhea (G3/4: 1.7%)
Alopecia;
Skin reaction (G3/4: 0.8%)

Musculoskeletal and
connective tissue disorders
General disorders and
Asthenia (severe 12.4%);
administration site
Fluid retention (severe
conditions
0.8%);
Pain
Investigations

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

Nail disorders (severe
0.8%)
Myalgia

G3/4 Blood bilirubin
increased (<2%)

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

Very common
adverse reactions

Infections and
infestations
Blood and the
lymphatic system
disorders

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

Immune system
disorders
Metabolism and
nutrition
disorders
Nervous system

Common adverse
reactions

Hypersensitivity
(G3/4: 1.2 %)
Anorexia

Peripheral sensory

Peripheral motor

Uncommon
adverse
reactions

disorders

neuropathy (G3:
0.4%)

Cardiac disorders

Vascular disorders
Gastrointestinal
disorders

Skin and
subcutaneous tissue
disorders

Musculoskeletal
and connective
tissue disorders
General disorders
and administration
site conditions

Investigations

neuropathy (G3/4:
0.4%)
Cardiac failure;
Arrhythmia (no
severe)
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)
Myalgia

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

Infusion site
reaction

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 breast cancer for docetaxel 75 mg/m² in
combination with cisplatin
MedDRA system
organ classes

Very common
adverse reactions

Infections and
infestations
Blood and
lymphatic system
disorders

Infection (G3/4:
5.7%)
Neutropenia (G4:
51.5%);
Anaemia (G3/4:
6.9%);
Thrombocytopenia
(G4: 0.5%)
Hypersensitivity
(G3/4: 2.5%)
Anorexia

Immune system
disorders
Metabolism and
nutrition disorders
Nervous system
disorders

Cardiac disorders
Vascular disorders
Gastrointestinal
disorders

Common adverse
reactions

Uncommon
adverse reactions

Febrile neutropenia

Peripheral sensory
neuropathy (G3:
3.7%);
Peripheral motor
neuropathy (G3/4:
2%)
Arrhythmia (G3/4: Cardiac failure
0.7%)
Hypotension (G3/4:
0.7%)
Constipation

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

MedDRA system
organ classes

Very common
adverse reactions

Investigations

Common adverse
reactions

Uncommon
adverse reactions

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 disorders

Insomnia

Common adverse
reactions

MedDRA system organ
classes

Very common adverse
reactions

Nervous system disorders

Paresthesia; Headache;
Dysgeusia; Hypoaesthesia
Lacrimation increased;
Conjunctivitis

Eye disorders
Cardiac disorders
Vascular disorders
Respiratory, thoracic and
mediastinal disorders

Common adverse
reactions

Cardiac failure

Lymphoedema
Epistaxis;
Pharyngolaryngeal pain;
Nasopharyngitis;
Dyspnoea;
Cough; Rhinorrhoea
Gastrointestinal disorders Nausea; Diarrhoea;
Vomiting; Constipation;
Stomatitis; Dyspepsia;
Abdominal pain
Skin and subcutaneous
Alopecia; Erythema; Rash;
tissue disorders
Nail disorders
Musculoskeletal and
Myalgia; Arthralgia; Pain
connective tissue disorders in extremity; Bone pain;
Back pain
General disorders and
Asthenia; Oedema
Lethargy
administration site
peripheral; Pyrexia;
conditions
Fatigue; Mucosal
inflammation; Pain;
Influenza like illness; Chest
pain; Chills
Investigations
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 75mg/m² in
combination with capecitabine:
MedDRA system organ
classes

Very common adverse
reactions

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

Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Anorexia (G3/4: 1%);
Decreased appetite
Dysgeusia (G3/4: <1%);
Paraesthesia (G3/4: <1%)

Eye disorders
Respiratory, thoracic and
mediastinal disorders

Lacrimation increased
Pharyngolaryngeal pain
(G3/4: 2%)

Gastrointestinal disorders

Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4:
2%);
Dyspepsia
Hand-foot syndrome
(G3/4:
24%)
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)

Skin and subcutaneous
tissue disorders

Musculoskeletal and
connective tissue
disorders
General disorders and
administration site
conditions

Investigations

Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/ weakness (G3/4:
5%);
Oedema peripheral (G3/4:
1%);

Common adverse
reactions
Oral candidiasis (G3/4:
<1%)
Thrombocytopenia (G3/4:
3%)
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 breast 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

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

Immune system disorders
Metabolism and nutrition
disorders
Nervous system disorders

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

Respiratory, thoracic and
mediastinal disorders

Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective bone 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

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
%);

Common adverse
reactions

Uncommon
adverse reactions

MedDRA system
organ classes

Very common
adverse reactions

Common adverse
reactions

Uncommon
adverse reactions

Neutropenic
infection.
(G3/4:2.6%)
Blood and
lymphatic system
disorders

Immune system
disorders
Metabolism and
nutrition disorders
Nervous system
disorders

Eye disorders

Anaemia (G3/4: 3
%);
Neutropenia (G3/4:
59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4:NA)
Hypersensitivity
(G3/4:0.6%)
Anorexia (G3/4:
1.5%)
Dysgeusia (G3/4: 0. Peripheral motor
6%);
neuropathy (G3/4:
Peripheral sensory 0%);
neuropathy (G3/4:
<0.1 %)
Conjunctivitis
(G3/4:<0.1%)

Cardiac disorders

Vascular disorders
Hot flush
(G3/4:0.5%)
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

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

Lacrimation
increased (G3/4:
0.1%)
Arrhythmia (G3/4:
0. 2%);
Hypotension (G3/4: ;
0%)
Lymphoedema
Phlebitis (G3/4:0%) (G3/4: 0%)
Cough (G3/4: 0%)

Nausea (G3/4:
Abdominal pain
5.0%);
(G3/4: 0.4%)
Stomatitis (G3/4:
6.0%);
Vomiting (G3/4:
4.2%);
Diarrhoea (G3/4:
3.4%);
Constipation (G3/4:
0.5%)
Skin and
Alopecia
subcutaneous tissue (G3/4:<0.1%);

MedDRA system
organ classes

Very common
adverse reactions

disorders

Skin disorder
(G3/4: 0.6%);
Nail disorders
(G3/4: 0.4%)
Myalgia (G3/4:
0.7%);
Arthralgia (G3/4:
0.2%)
Amenorrhoea
(G3/4:NA)

Musculoskeletal
and connective
tissue disorders
Reproductive
system and breast
disorders
General disorders
and administration
site conditions

Common adverse
reactions

Uncommon
adverse reactions

Asthenia (G3/4:
10.0%);
Pyrexia (G3/4:NA)
Oedema peripheral
(G3/4: 0.2%)

Investigations

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

Description of selected adverse reactions for adjuvant therapy with docetaxel 75
mg/m² in combination with doxorubicin and cyclophosphamide in patients with nodepositive (TAX 316) 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.
Skin and subcutaneous tissue disorders
In study TAX 316, alopecia persisting into the follow-up period after the end of
chemotherapy was reported in 687 TAC patients and 645 FAC patients
At the end of the follow-up period, alopecia was observed to be ongoing in 29 TAC
patients (4.2%) and 16 FAC patients (2.4%).
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.

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 GEICAM9805,
lymphoedema was observed to be ongoing in 4 of the 5 patients with lymphoedema at
the end of the chemotherapy.
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.
At a median follow-up time of 77 months, acute leukaemia occurred in 1 of 532
(0.2%) patients who received docetaxel, doxorubicin, and cyclophosphamide in
the GEICAM 9805 study. No cases were reported in patients who received
fluorouracil, doxorubicin and cyclophosphamide. No patient was diagnosed with
myelodysplastic syndrome in either treatment groups.
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 GCSF prophylaxis (GEICAM 9805)
Without primary
G-CSF prophylaxis
(n = 111)
n (%)

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

Neutropenia (Grade 4)

104 (93.7)

135 (32.1)

Febrile neutropenia

28 (25.2)

23 (5.5)

Neutropenic infection

14 (12.6)

21 (5.0)

Neutropenic infection
(Grade 3-4)

2 (1.8)

5 (1.2)

Tabulated list of adverse reactions in gastric adenocarcinoma cancer for docetaxel
75 mg/m² in combination with cisplatin and 5-fluorouracil
MedDRA system organ
classes

Very common adverse
reactions

Infections and infestations

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%)

Blood and lymphatic
system disorders

Immune system disorders
Metabolism and nutrition
disorders
Nervous system disorders

Peripheral sensory
neuropathy (G3/4: 8.7%)

Eye disorders
Ear and labyrinth disorders
Cardiac disorders
Gastrointestinal disorders

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%)

General disorders and
administration site
conditions

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

Common adverse
reactions

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

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 Very common
organ classes
adverse reactions
Infections and
infestations

Uncommon
adverse reactions

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

Neoplasms
benign, malignant
and unspecified
(incl cysts and
polyps)
Blood and
Neutropenia (G3/4:
lymphatic system 76.3%);
disorders
Anaemia (G3/4:
9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Immune system
disorders
Metabolism and
Anorexia (G3/4:
nutrition disorders 0.6%)
Nervous system
Dysgeusia/Parosmia;
disorders
Peripheral sensory
neuropathy (G3/4:
0.6%)
Eye disorders
Ear and labyrinth
disorders
Cardiac disorders
Vascular disorders
Gastrointestinal
disorders

Common adverse
reactions

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

Cancer pain (G3/4:
0.6%)

Febrile neutropenia

Hypersensitivity (no
severe)

Dizziness

Lacrimation increased;
Conjunctivitis
Hearing impaired
Myocardial ischemia Arrhythmia (G3/4:
(G3/4:1.7%)
0.6%)
Venous disorder
(G3/4: 0.6%)
Constipation;
Esophagitis/dysphagia/
odynophagia (G3/4:
0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal
haemorrhage (G3/4:
0.6%)

MedDRA system Very common
organ classes
adverse reactions

Common adverse
reactions

Skin and
subcutaneous
tissue disorders

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

Alopecia (G3/4:
10.9%)

Musculoskeletal
and connective
tissue disorders
General disorders Lethargy (G3/4:
and administration 3.4%);
site conditions
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 Uncommon
reactions
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

Eye disorders

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

Dizziness (G3/4:
2.0%);
Peripheral motor
neuropathy (G3/4:
0.4%)
Lacrimation
increased

Conjunctivitis

MedDRA system
organ classes

Very common
adverse reactions

Ear and labyrinth
disorders
Cardiac disorders

Hearing impaired
(G3/4: 1.2%)

Common adverse Uncommon
reactions
adverse reactions

Arrhythmia (G3/4: Ischemia
2.0%)
myocardial
Vascular disorders
Venous disorder
Gastrointestinal
Nausea (G3/4: 13.9%); Dyspepsia (G3/4:
disorders
Stomatitis (G3/4:
0.8%);
20.7%);
Gastrointestinal
Vomiting (G3/4:
pain (G3/4: 1.2%);
8.4%);
Gastrointestinal
Diarrhoea (G3/4:
haemorrhage
6.8%);
(G3/4: 0.4%)
Esophagitis/dysphagia/
odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Skin and
Alopecia (G3/4:
Dry skin ;
subcutaneous
4.0%);
Desquamation
tissue disorders
Rash pruritic
Musculoskeletal,
Myalgia (G3/4:
connective tissue
0.4%)
bone disorders
General disorders Lethargy (G3/4:
and administration 4.0%);
site conditions
Pyrexia (G3/4: 3.6%);
Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)
Investigations
Weight decreased
Weight increased
Post-marketing experience
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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 pre-existing
liver disorders, have been reported.
Skin and subcutaneous tissue disorders
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as
erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, have
been reported with docetaxel. In some 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
Radiation recall phenomena have rarely been reported.
Fluid retention has not been accompanied by acute episodes of oliguria or
hypotension. Dehydration and pulmonary oedema have rarely been reported.
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 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 GCSF 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 randomized study support the use of
docetaxel for the adjuvant treatment of patients with operable node-positive
breast cancer and KPS ≥ 80%, between 18 and 70 years of age. After
stratification according to the number of positive lymph nodes (1-3, 4+), 1491
patients were randomized to receive either docetaxel 75 mg/m2 administered
1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC
arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and
cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens were administered
once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour
infusion, all other medicinal products were given as intravenous bolus on day
one. G CSF was administered as secondary prophylaxis to patients who
experienced complicated neutropenia (febrile neutropenia, prolonged
neutropenia, or infection). Patients on the TAC arm received antibiotic
prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days starting
on day 5 of each cycle, or equivalent. In both arms, after the last cycle of
chemotherapy, patients with positive estrogen and/or progesterone receptors
received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy
was prescribed according to guidelines in place at participating institutions and
was given to 69% of patients who received TAC and 72% of patients who
received FAC.
Two interim analyses and one final analysis were performed. The first interim
analysis was planned 3 years after the date when half of study 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 t the final
analysis.
Overall, the study results demonstrate a positive benefit risk ratio for TAC
compared to FAC.
TAC-treated patient subsets according to prospectively defined major
prognostic factors were analyzed:
Disease free survival
Overall survival
Patient subset Number Hazard 95% CI p =
Hazard 95%
of
ratio*
ratio*
CI
patients
No of positive
nodes
Overall
745
0.80
0.680.0043 0.74
0.610.93
0.90
1-3
467
0.72
0.580.0047 0.62
0.460.91
0.82
4+
278
0.87
0.700.2290 0.87
0.671.09
1.12
*a hazard ratio of less than 1 indicates that TAC is associated with
disease-free survival and overall survival compared to FAC

p=

0.0020
0.0008
0.2746
a longer

Patients with operable node-negative breast cancer eligible to receive
chemotherapy (GEICAM 9805)
Data from a multicenter open label randomized trial support the use of
docetaxel for the adjuvant treatment of patients with operable node-negative
breast cancer eligible to receive chemotherapy.
1060 patients were randomized 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 andlor 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 intraveinously on day 1 every three
weeks. Primary prophylactic G-CSF was made mandatory in TAC arm after
230 patients were randomized. The incidence of Grade 4 neutropenia, febrile
neutropenia and neutropenic infection was decreased in patients who received
primary G-CSF prophylaxis (see section 4.8). In both arms, after the last cycle
of chemotherapy, patients with ER+ and/or PgR+ tumours received tamoxifen
20 mg once a day for up to 5 years. Adjuvant radiation therapy was
administered according to guidelines in place at participating institutions and
was given to 57.3% of patients who received TAC and 51.2% of patients who
received FAC.
Median duration of follow-up was 77 months. Significantly longer diseasefree survival for the TAC arm compared to the FAC arm was demonstrated.
TAC-treated patients had a 32% reduction in the risk of relapse compared to
those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93), p = 0.01).
Overall survival (OS) was also longer in the TAC arm with TAC-treated
patients having a 24% reduction in the risk of death compared to FAC (hazard
ratio = 0.76, 95% CI (0.46-1.26, p = 0.29). However, the distribution of OS
was not significantly different between the 2 groups.
TAC-treated patient subsets according to prospectively defined major
prognostic factors were analyzed (see table below):
Subset Analyses-Adjuvant Therapy in Patients with Node-negative Breast
Cancer Study (Intent-to-Treat Analysis)

Patient subset

Number
of
patients
in
TAC group
539

Disease Free Survival
Hazard ratio*
95% CI
0.68

0.49-0.93

260
279

0.67
0.67

0.43-1.05
0.43-1.05

Age category 2
<35 years
≥35 years

42
497

0.31
0.73

0.11-0.89
0.52-1.01

Hormonal
receptor status
Negative
Positive

195
344

0.7
0.62

0.45-1.1
0.4-0.97

Overall
Age category 1
<50 years
≥50 years

Tumour size
≤2 cm
>2 cm

285
254

0.69
0.68

0.43-1.1
0.45-1.04

Histological grade
Grade1
(includes
grade not assessed)
Grade 2
Grade 3

64

0.79

0.24-2.6

216
259

0.77
0.59

0.46-1.3
0.39-0.9

Menopausal status
Pre-Menopausal
Post-Menopausal

285
254

0.64
0.72

0.40-1
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

TAC
(n=539)

FAC
(n=521)

18/214

26/227

(8.4%)

(11.5%)

48/325

69/294

(14.8%)

(23.5%)

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

p-value

Meeting relative indication
for chemotherapya

No

Yes

0.796 (0.434 - 1.459)

0.4593

0.606 (0.42 - 0.877)

0.0072

TAC = docetaxel, doxorubicin and cyclophosphamide
FAC = 5-fluorouracil, doxorubicin and cyclophospamide
CI = confidence interval; ER = estrogen receptor
PR = progesterone receptor
a

ER/PR-negative or Grade 3 or 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 vs. doxorubicin 14 months, p = 0.38) or time to progression (docetaxel
27 weeks vs. doxorubicin 23 weeks, p = 0.54), docetaxel increased response
rate (52% vs. 37%, p = 0.01) and shortened time to response (12 weeks vs. 23
weeks, p = 0.007). Three docetaxel patients (2%) discontinued the treatment
due to fluid retention, whereas 15 doxorubicin patients (9%) discontinued due
to cardiac toxicity (three cases of fatal congestive heart failure).
In anthracycline-failure patients, docetaxel was compared to the combination
of mitomycin C and vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every
3 weeks). Docetaxel increased response rate (33% vs. 12%, p < 0.0001),
prolonged time to progression (19 weeks vs. 11 weeks, p = 0.0004) and
prolonged overall survival (11 months vs. 9 months, p = 0.01).
During these two phase III studies, the safety profile of docetaxel was
consistent with the safety profile observed in phase II studies (see section 4.8).
An open-label, multicenter, randomized phase III study was conducted to
compare docetaxel monotherapy and paclitaxel in the treatment of advanced
breast cancer in patients whose previous therapy should have included an
anthracycline. A total of 449 patients were randomized to receive either
docetaxel monotherapy 100 mg/m² as a 1 hour infusion or paclitaxel 175
mg/m² as a 3 hour infusion. Both regimens were administered every 3 weeks.
Without affecting the primary endpoint, overall response rate (32% vs 25%, p
= 0.10), docetaxel prolonged median time to progression (24.6 weeks vs 15.6
weeks; p < 0.01) and median survival (15.3 months vs 12.7 months; p = 0.03).
More grade 3/4 adverse events were observed for docetaxel monotherapy
(55.4%) compared to paclitaxel (23.0%).
Docetaxel in combination with doxorubicin
One large randomized phase III study, involving 429 previously untreated
patients with metastatic disease, has been performed with doxorubicin (50

mg/m²) in combination with docetaxel (75 mg/m²) (AT arm) versus
doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²)
(AC arm). Both regimens were administered on day 1 every 3 weeks.

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

Overall response rate (ORR) was significantly higher in the AT arm
versus AC arm, p = 0.009. The ORR was 59.3% (95% CI: 52.8 - 65.9) in AT
arm versus 46.5% (95% CI: 39.8 - 53.2) in AC arm.
In this study, AT arm showed a higher incidence of severe neutropenia (90%
versus 68.6%), febrile neutropenia (33.3% versus 10%), infection (8% versus
2.4%), diarrhoea (7.5% versus 1.4%), asthenia (8.5% versus 2.4%), and pain
(2.8% versus 0%) than AC arm. On the other hand, AC arm showed a higher
incidence of severe anaemia (15.8% versus 8.5%) than AT arm, and, in
addition, a higher incidence of severe cardiac toxicity: congestive heart failure
(3.8% versus 2.8%), absolute LVEF decrease ≥ 20% (13.1% versus 6.1%),
absolute LVEF decrease ≥ 30% (6.2% versus 1.1%). Toxic deaths occurred in
1 patient in the AT arm (congestive heart failure) and in 4 patients in the AC
arm (1 due to septic shock and 3 due to congestive heart failure).
In both arms, quality of life measured by the EORTC questionnaire was
comparable and stable during treatment and follow up.
Docetaxel in combination with trastuzumab
Docetaxel in combination with trastuzumab was studied for the treatment of
patients with metastatic breast cancer whose tumours overexpress HER2, and
who previously had not received chemotherapy for metastatic disease. One
hundred eighty six patients were randomized to receive docetaxel (100 mg/m2)
with or without trastuzumab; 60% of patients received prior anthracyclinebased adjuvant chemotherapy. Docetaxel plus trastuzumab was efficacious in
patients whether or not they had received prior adjuvant anthracyclines. The
main test method used to determine HER2 positivity in this pivotal study was
immunohistochemistry (IHC). A minority of patients were tested using
fluorescence in situ hybridization (FISH). In this study, 87% of patients had
disease that was IHC 3+, and 95% of patients entered had disease that was
IHC 3+ and/or FISH positive. Efficacy results are summarized in the
following table:
Parameter

Response rate
(95% CI)
Median
duration
response (months)
(95% CI)

Docetaxel
trastuzumab1
n = 92
61%
(50-71)

plus Docetaxel1
n = 94
34%
(25-45)

of
11.4
(9.2-15.0)

5.1
(4.4-6.2)

Median TTP (months)
10.6
(95% CI)
(7.6-12.9)
Median survival (months) 30.52
(95% CI)
(26.8-ne)
TTP = time to progression; “ne” indicates that it
was not yet reached.
1
2

5.7
(5.0-6.5)
22.12
(17.6-28.9)
could not be estimated or it

Full analysis set (intent-to-treat)
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) vs. 352 days (docetaxel alone). The overall objective response
rates in the all randomised population (investigator assessment) were 41.6%
(docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to
progressive disease was superior in the docetaxel + capecitabine combination
arm (p < 0.0001). The median time to progression was 186 days (docetaxel +
capecitabine) vs. 128 days (docetaxel alone).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3
weeks versus 7 weeks) and overall survival were significantly longer for
docetaxel at 75 mg/m² compared to Best Supportive Care. The 1 year survival
rate was also significantly longer in docetaxel (40%) versus BSC (16%).
There was less use of morphinic analgesic (p < 0.01), non-morphinic
analgesics (p < 0.01), other disease-related medicinal products (p = 0.06) and
radiotherapy (p < 0.01) in patients treated with docetaxel at 75 mg/m²
compared to those with BSC.
The overall response rate was 6.8% in the evaluable patients, and the median
duration of response was 26.1 weeks.
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:
TCis
n = 408

VCis
n = 404

Statistical analysis

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

11.3

10.1

1-year Survival (%)

46

41

2-year Survival (%)

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]

Median time to progression
(weeks):

22.0

23.0

Hazard ratio: 1.032
[95% CI: 0.876; 1.216]
Overall response rate (%):
31.6
24.5
Treatment difference: 7.1%
[95% CI: 0.7; 13.5]
*: Corrected for multiple comparisons and adjusted for stratification factors
(stage of disease and region of treatment), based on evaluable patient
population.
Secondary end points included change of pain, global rating of quality of life
by EuroQoL-5D, Lung Cancer Symptom Scale, and changes in Karnosfky
performance status. Results on these end-points were supportive of the
primary end-points results.
For docetaxel/carboplatin combination, neither equivalent nor non-inferior
efficacy could be proven compared to the reference treatment combination
VCis.
Prostate cancer
The safety and efficacy of docetaxel in combination with prednisone or
prednisolone in patients with hormone refractory metastatic prostate cancer

were evaluated in a randomized multicenter phase III study. A total of 1006
patients with KPS ≥ 60 were randomized to the following treatment groups:


Docetaxel 75 mg/m2 every 3 weeks for 10 cycles.



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



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

All 3 regimens were administered in combination with prednisone or
prednisolone 5 mg twice daily, continuously.
Patients who received docetaxel every three weeks demonstrated significantly
longer overall survival compared to those treated with mitoxantrone. The
increase in survival seen in the docetaxel weekly arm was not statistically
significant compared to the mitoxantrone control arm. Efficacy endpoints for
the docetaxel arms versus the control arm are summarized in the following
table:
Endpoint

Docetaxel
every 3 weeks

Docetaxel
every week

Mitoxantrone
every 3 weeks

Number of patients
Median
survival
(months)
95% CI
Hazard ratio
95% CI
p-value†*

335
18.9

334
17.4

337
16.5

(17.0-21.2)
0.761
(0.619-0.936)
0.0094

(15.7-19.0)
0.912
(0.747-1.113)
0.3624

(14.4-18.6)
----

Number of patients
PSA** response rate
(%)
95% CI
p-value*

291
45.4

282
47.9

300
31.7

(39.5-51.3)
0.0005

(41.9-53.9)
<0.0001

(26.4-37.3)
----

Number of patients
Pain response rate
(%)
95% CI
p-value*
Number of patients
Tumour
response
rate (%)
95% CI
p-value*

153
34.6
(27.1-42.7)
0.0107

154
31.2
(24.0-39.1)
0.0798

157
21.7
(15.5-28.9)
--

141
12.1

134
8.2

137
6.6

(7.2-18.6)
0.1112

(4.2-14.2)
0.5853

(3.0-12.1)
--

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

Given the fact that docetaxel every week presented a slightly better safety
profile than docetaxel every 3 weeks, it is possible that certain patients may
benefit from docetaxel every week.
No statistical differences were observed between treatment groups for Global
Quality of Life.
Gastric adenocarcinoma
A multicenter, open-label, randomized study was conducted to evaluate the
safety and efficacy of docetaxel for the treatment of patients with metastatic
gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal
junction, who had not received prior chemotherapy for metastatic disease. A
total of 445 patients with KPS > 70 were treated with either docetaxel (T) (75
mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and 5fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on
day 1) and 5 fluorouracil (1000 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
favor of the TCF arm. Overall survival was also significantly longer (p =
0.0201) in favor of the TCF arm with a risk reduction of mortality of 22.7%.
Efficacy results are summarized in the following table:
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
n = 221
5.6
(4.86-5.91)
1.473
(1.189-1.825)
0.0004
9.2
(8.38-10.58)
18.4
1.293
(1.041-1.606)
0.0201
36.7
0.0106
16.7

CF
n = 224
3.7
(3.45-4.47)

8.6
(7.16-9.46)
8.8

25.4
25.9

Subgroup analyses across age, gender and race consistently favored the TCF
arm compared to the CF arm.
A survival update analysis conducted with a median follow-up time of 41.6
months no longer showed a statistically significant difference although always
in favour of the TCF regimen and showed that the benefit of TCF over CF is
clearly observed between 18 and 30 months of follow up.
Overall, quality of life (QoL) and clinical benefit results consistently indicated
improvement in favor of the TCF arm. Patients treated with TCF had a longer
time to 5% definitive deterioration of global health status on the QLQ C30
questionnaire (p = 0.0121) and a longer time to definitive worsening of
Karnofsky performance status (p = 0.0088) compared to patients treated with
CF.
Head and neck cancer


Induction chemotherapy followed by radiotherapy (TAX323)

The safety and efficacy of docetaxel in the induction treatment of patients with
squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a
phase III, multicenter, open-label, randomized study (TAX323). In this study,
358 patients with inoperable locally advanced SCCHN, and WHO perfomance
status 0 or 1, were randomized to one of two treatment arms. Patients on the
docetaxel arm received docetaxel (T) 75 mg/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) 1000 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 vs. 8.3 months
respectively) with an overall median follow up time of 33.7 months. Median
overall survival was also significantly longer in favor of the TPF arm
compared to the PF arm (median OS: 18.6 vs. 14.5 months respectively) with
a 28% risk reduction of mortality, p = 0.0128. Efficacy results are presented in
the table below:
Efficacy of docetaxel in the induction treatment of patients with
inoperable locally advanced SCCHN (Intent-to-Treat Analysis)
ENDPOINT

Docetaxel +
Cis + 5-FU
n = 177
11.4
(10.1-14.0)
0.70
(0.55-0.89)
0.0042
18.6
(15.7-24.0)
0.72
(0.56-0.93)
0.0128
67.8
(60.4-74.6)
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

Cis + 5-FU
n = 181
8.3
(7.4-9.1)

14.5
(11.6-18.7)

53.6
(46.0-61.0)

58.6

(95% CI)
(65.1-78.8)
(51.0-65.8)
***p-value
0.006
Median
duration
of
response
to n = 128
n = 106
15.7
11.7
chemotherapy ± radiotherapy (months)
(13.4-24.6)
(10.2-17.4)
(95% CI)
Hazard ratio
0.72
(95% CI)
(0.52-0.99)
**p-value
0.0457
A hazard ratio of less than 1 favors docetaxel + cisplatin + 5-FU
*Cox model (adjustment for Primary tumour site, T and N clinical stages and
PSWHO)
**Logrank test
*** Chi-square test
Quality of life parameters
Patients treated with TPF experienced significantly less deterioration of their
Global health score compared to those treated with PF (p = 0.01, using the
EORTC QLQ C30 scale).
Clinical benefit parameters
The performance status scale, for head and neck (PSS-HN) subscales designed
to measure understandability of speech, ability to eat in public, and normalcy
of diet, was significantly in favor of TPF as compared to PF.
Median time to first deterioration of WHO performance status was
significantly longer in the TPF arm compared to PF. Pain intensity score
improved during treatment in both groups indicating adequate pain
management.


Induction chemotherapy followed by chemoradiotherapy (TAX324)

The safety and efficacy of docetaxel in the induction treatment of patients with
locally advanced squamous cell carcinoma of the head and neck (SCCHN)
was evaluated in a randomized, multicenter open-label, phase III study
(TAX324). In this study, 501 patients, with locally advanced SCCHN, and a
WHO performance status of 0 or 1, were randomized to one of two arms. The
study population comprised patients with technically unresectable disease,
patients with low probability of surgical cure and patients aiming at organ
preservation. The efficacy and safety evaluation solely addressed survival
endpoints and the success of organ preservation was not formally addressed.
Patients on the docetaxel arm received docetaxel (T) 75 mg/m² by intravenous
infusion on day 1 followed by cisplatin (P) 100 mg/m² administered as a 30
minute to three-hour intravenous infusion, followed by the continuous
intravenous infusion of 5 fluorouracil (F) 1000 mg/m²/day from day 1 to day
4. The cycles were repeated every 3 weeks for 3 cycles. All patients who did
not have progressive disease were to receive chemoradiotherapy (CRT) as per

protocol (TPF/CRT). Patients on the comparator arm received cisplatin (P)
100 mg/m² as a 30 minute to three hour intravenous infusion on day 1
followed by the continuous intravenous infusion of 5 fluorouracil (F) 1000
mg/m²/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3
cycles. All patients who did not have progressive disease were to receive CRT
as per protocol (PF/CRT).
Patients in both treatment arms were to receive 7 weeks of CRT following
induction chemotherapy with a minimum interval of 3 weeks and no later than
8 weeks after start of the last cycle (day 22 to day 56 of last cycle). During
radiotherapy, carboplatin (AUC 1.5) was given weekly as a one hour
intravenous infusion for a maximum of 7 doses. Radiation was delivered with
megavoltage equipment using once daily fractionation (2 Gy per day, 5 days
per week for 7 weeks, for a total dose of 70 - 72 Gy). Surgery on the primary
site of disease and/or neck could be considered at anytime following
completion of CRT. All patients on the docetaxel-containing arm of the study
received prophylactic antibiotics. The primary efficacy endpoint in this study,
overall survival (OS) was significantly longer (log-rank test, p = 0.0058) with
the docetaxel-containing regimen compared to PF (median OS: 70.6 versus
30.1 months respectively), with a 30% risk reduction in mortality compared to
PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54 - 0.90) with
an overall median follow up time of 41.9 months. The secondary endpoint,
PFS, demonstrated a 29% risk reduction of progression or death and a 22
month improvement in median PFS (35.5 months for TPF and 13.1 for PF).
This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90;
log-rank test p = 0.004. Efficacy results are presented in the table below:
Efficacy of docetaxel in the induction treatment of patients with locally
advanced SCCHN (Intent-to-Treat Analysis)

Endpoint

Docetaxel +
Cis +
5-FU
Cis + 5-FU
n = 255
n = 246
Median overall survival (months)
70.6
30.1
(95% CI)
(49.0-NA)
(20.9-51.5)
Hazard ratio:
0.70
(95% CI)
(0.54-0.90)
*p-value
0.0058
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 + PR) to 71.8
64.2
chemotherapy (%)
(65.8-77.2)
(57.9-70.2)
(95% CI)
***p-value
0.070
Best overall response (CR + PR) to 76.5
71.5
study treatment [chemotherapy +/- (70.8-81.5)
(65.5-77.1)
chemoradiotherapy] (%)
(95%CI)
***p-value
0.209
A hazard ratio of less than 1 favors docetaxel + cisplatin + fluorouracil
*un-adjusted log-rank test
**un-adjusted log-rank test, not adjusted for multiple comparisons
***Chi square test, not adjusted for multiple comparisons
NA-not applicable
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, prostated cancer, gastric carcinoma
and head and neck cancer, not including type II and III less differentiated
nasopharyngeal carcinoma (see section 4.2 for information on paediatric use).

5.2

Pharmacokinetic properties
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 one-hour
infusion a mean peak plasma level of 3.7 µg/ml was obtained with a
corresponding AUC of 4.6 h.µg/ml. Mean values for total body clearance and
steady-state volume of distribution were 21 l/h/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 inpairment
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
Polysorbate 80
Ethanol 96%
Citric acid monohydrate

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
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 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 as recommended into the infusion bag (PP) or infusion bottle
(PE), the docetaxel infusion solution, if stored below 25°C, is stable for 8
hours in infusion bottle or for 6 hours in infusion bag. It should be used within
6-8 hours (including the one hour infusion IV administration).
In addition, physical and chemical in-use stability of the infusion solution
prepared as recommended has been demonstrated in non-PVC bags up to 48
hours when stored between 2 to 8°C.

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

6.4

Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Store in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container
2 ml colourless type-I glass vial, closed with a 13 mm grey chlorobutyl rubber stopper
and a green flip-off seal consisting of an aluminium shell and a green plastic flip-off
button. The rubber stopper is coated with a Teflon® barrier film.
Each box contains one vial with 1 ml fill volume
6 ml colourless type-I glass vial, closed with a 20 mm grey chlorobutyl rubber stopper
and an orange flip-off seal consisting of an aluminium shell and an orange plastic flipoff button. The rubber stopper is coated with a Teflon® barrier film.
Each box contains one vial with 4 ml fill volume.
10 ml colourless type-I glass vial, closed with a 20 mm grey chlorobutyl rubber
stopper and a red flip-off seal consisting of an aluminium shell and a red plastic flipoff button. The rubber stopper is coated with a Teflon® barrier film.
Each box contains one vial with 8 ml fill volume.
6.6

Special precautions for disposal
Docetaxel is an antineoplastic agent and, as with other potentially toxic compounds,
caution should be exercised when handling it and preparing Docetaxel solutions. The
use of gloves is recommended.
If Docetaxel concentrate or infusion solution should come into contact with skin,
wash immediately and thoroughly with soap and water. If Docetaxel concentrate or
infusion solution should come into contact with mucous membranes, wash
immediately and thoroughly with water.

Preparation for the intravenous administration
Preparation of the infusion solution
DO NOT use other docetaxel medicinal products consisting of more than one
vial (concentrate and solvent) with this medicinal product (Docetaxel 20 mg/ml
concentrate for solution for infusion, which contains only 1 vial).
Docetaxel 20 mg/ml concentrate for solution for infusion requires NO prior
dilution with a solvent and is ready to add to the infusion solution.
Each vial is of single use and should be used immediately.
Allow the required number of boxes of Docetaxel concentrate for solution for
infusion to stand below 25°C for 5 minutes before use.
More than one vial of Docetaxel concentrate for solution for infusion may be
necessary to obtain the required dose for the patient. Aseptically withdraw the
required amount of Docetaxel concentrate for solution for infusion using a calibrated
syringe.

In Docetaxel 20 mg /ml vial the concentration of docetaxel is 20 mg/ml.
The required volume of Docetaxel concentrate for solution for infusion must be
injected into a 250 ml infusion bag or bottle containing either glucose solution 50
mg/ml (5%) or sodium chloride 9 mg/ml (0.9%) solution for infusion.
If a dose greater than 190 mg of docetaxel is required, use a larger volume of the
infusion vehicle so that a concentration of 0.74 mg/ml docetaxel is not exceeded.
Mix the infusion bag or bottle manually using a rocking motion.
The infusion bag solution should be used within 8 hours below 25°C including the
one hour infusion to the patient.
As with all parenteral products, Docetaxel infusion solution should be visually
inspected prior to use, solutions containing a precipitate should be discarded.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER

Seacross Pharmaceuticals Limited
Bedford Business Centre,
61 - 63 St. Peter’s Street,
Bedford MK40 2PR,

United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 41013/0008

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/07/2011

10

DATE OF REVISION OF THE TEXT
23/03/2016

Expand Transcript

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.

Hide