ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Docetaxel Teva 20 mg concentrate and solvent for solution for infusion
Each single-dose vial of Docetaxel Teva concentrate contains 20 mg docetaxel (anhydrous). Each ml
of concentrate contains 27.73 mg docetaxel.
Excipients
:
Each vial of concentrate contains 25.1% (w/w) anhydrous ethanol.
For a full list of excipients, see section 6.1.
Concentrate and solvent for solution for infusion.
The concentrate is a clear viscous, yellow to brown-yellow solution.
The solvent is a colourless solution.
Breast cancer
Docetaxel Teva in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant
treatment of patients with:
•
operable node-positive breast cancer
•
operable node-negative breast cancer
For patients with operable node-negative breast cancer, adjuvant treatment should be restricted to
patients eligible to receive chemotherapy according to internationally established criteria for primary
therapy of early breast cancer (see section 5.1).
Docetaxel Teva in combination with doxorubicin is indicated for the treatment of patients with locally
advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this
condition.
Docetaxel Teva monotherapy is indicated for the treatment of patients with locally advanced or
metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have
included an anthracycline or an alkylating agent.
Docetaxel Teva in combination with trastuzumab is indicated for the treatment of patients with
metastatic breast cancer whose tumours overexpress HER2 and who previously have not received
chemotherapy for metastatic disease.
Docetaxel Teva 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
2
Docetaxel Teva is indicated for the treatment of patients with locally advanced or metastatic non-small
cell lung cancer after failure of prior chemotherapy.
Docetaxel Teva in combination with cisplatin is indicated for the treatment of patients with
unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not
previously received chemotherapy for this condition.
Prostate cancer
Docetaxel Teva in combination with prednisone or prednisolone is indicated for the treatment of
patients with hormone refractory metastatic prostate cancer.
Gastric adenocarcinoma
Docetaxel Teva in combination with cisplatin and 5-fluorouracil is indicated for the treatment of
patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal
junction, who have not received prior chemotherapy for metastatic disease.
Head and neck cancer
Docetaxel Teva in combination with cisplatin and 5-fluorouracil is indicated for the induction
treatment of patients with locally advanced squamous cell carcinoma of the head and neck.
The use of docetaxel should be confined to units specialised in the administration of cytotoxic
chemotherapy and it should only be administered under the supervision of a physician qualified in the
use of anticancer chemotherapy (see section 6.6).
Recommended dose
For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral
corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to
docetaxel administration, unless contraindicated, can be used (see section 4.4). Prophylactic G-CSF
may be used to mitigate the risk of haematological toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended
premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel
infusion (see section 4.4).
Docetaxel is administered as a one-hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive and node-negative breast cancer, the
recommended dose of docetaxel is 75 mg/m
2
administered 1-hour after doxorubicin 50 mg/m
2
and
cyclophosphamide 500 mg/m
2
every 3 weeks for 6 cycles (TAC regimen) (see also Dose adjustments
during treatment).
For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose
of docetaxel is 100 mg/m
2
in monotherapy. In first-line treatment, docetaxel 75 mg/m
2
is given in
combination therapy with doxorubicin (50 mg/m
2
).
In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m
2
every three weeks,
with trastuzumab administered weekly. In the pivotal study the initial docetaxel infusion was started
the day following the first dose of trastuzumab. The subsequent docetaxel doses were administered
immediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab was
well tolerated. For trastuzumab dose and administration, see trastuzumab summary of product
characteristics.
3
In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m
2
every three weeks,
combined with capecitabine at 1250 mg/m
2
twice daily (within 30 minutes after a meal) for 2 weeks
followed by a 1-week rest period. For capecitabine dose calculation according to body surface area,
see capecitabine summary of product characteristics.
Non-small cell lung cancer
In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen
is docetaxel 75 mg/m
2
immediately followed by cisplatin 75 mg/m
2
over 30-60 minutes. For treatment
after failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m² as a single
agent.
Prostate cancer
The recommended dose of docetaxel is 75 mg/m
2
. Prednisone or prednisolone 5 mg orally twice daily
is administered continuously (see section 5.1).
Gastric adenocarcinoma
The recommended dose of docetaxel is 75 mg/m
2
as a 1-hour infusion, followed by cisplatin
75 mg/m
2
, as a 1-to 3-hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg /m
2
per
day given as a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion.
Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and
appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the
risk of haematological toxicities (See also Dose adjustments during treatment).
Head and neck cancer
Patients must receive premedication with antiemetics and appropriate hydration (prior to and after
cisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of haematological
toxicities. All patients on the docetaxel-containing arm of the TAX 323 and TAX 324 studies,
received prophylactic antibiotics.
•
Induction chemotherapy followed by radiotherapy (TAX 323)
For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head
and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m
2
as a 1 hour infusion
followed by cisplatin 75 mg/m
2
over 1 hour, on day one, followed by 5-fluorouracil as a
continuous infusion at 750 mg/m
2
per day for five days. This regimen is administered every
3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.
•
Induction chemotherapy followed by chemoradiotherapy (TAX 324)
For the induction treatment of patients with locally advanced (technically unresectable, low
probability of surgical cure, and aiming at organ preservation) squamous cell carcinoma of the
head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m
2
as a 1 hour
intravenous infusion on day 1, followed by cisplatin 100 mg/m
2
administered as a 30-minute to
3 hour infusion, followed by 5-fluorouracil 1000 mg/m
2
/day as a continuous infusion from day
1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy,
patients should receive chemoradiotherapy.
For cisplatin and 5-fluorouracil dose modifications, see the corresponding summary of product
characteristics.
Dose adjustments during treatment
General
Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm
3
.
In patients who experienced either febrile neutropenia, neutrophil count <500 cells/mm
3
for more than
one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel
therapy, the dose of docetaxel should be reduced from 100 mg/m
2
to 75 mg/m
2
and/or from
75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment
should be discontinued.
4
Adjuvant therapy for breast cancer
Primary G-CSF prophylaxis should be considered in patients who receive docetaxel, doxorubicin and
cyclophosphamide (TAC) adjuvant therapy for breast cancer. Patients who experience febrile
netutropeania and/or neutropenic infection should have their docetaxel dose reduced to 60 mg/m
2
in all
subsequent cycles (see sections 4.4 and 4.8). Patients who experience Grade 3 or 4 stomatitis should
have their dose decreased to 60 mg/m².
In combination with cisplatin
For patients who are dosed initially at docetaxel 75 mg/m
2
in combination with cisplatin and whose
nadir of platelet count during the previous course of therapy is <25,000 cells/mm
3
, or in patients who
experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxel
dose in subsequent cycles should be reduced to 65 mg/m
2
. For cisplatin dose adjustments, see the
corresponding summary of product characteristics.
In combination with capecitabine
•
For capecitabine dose modifications, see capecitabine summary of product characteristics.
•
For patients developing the first appearance of Grade 2 toxicity, which persists at the time of the
next docetaxel/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume
at 100% of the original dose.
•
For patients developing the second appearance of Grade 2 toxicity, or the first appearance of
Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to
Grade 0-1 and then resume treatment with docetaxel 55 mg/m².
•
For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the
docetaxel dose.
For trastuzumab dose modifications, see trastuzumab summary of product characteristics.
In combination with cisplatin and 5-fluorouracil
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite
G-CSF use, the docetaxel dose should be reduced from 75 to 60 mg/m
2
. If subsequent episodes of
complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m
2
. In case of
Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m
2
. Patients should
not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level
> 1,500 cells/mm
3
and platelets recover to a level > 100,000 cells/mm
3
. Discontinue treatment if these
toxicities persist. (see section 4.4).
Recommended dose modifications for toxicities in patients treated with docetaxel in combination with
cisplatin and 5-fluorouracil (5-FU):
Toxicity
Dose adjustment
First episode: reduce 5-FU dose by 20%.
Diarrhoea grade 3
Diarrhoea grade 4
Second episode: then reduce docetaxel dose by 20%.
First episode: reduce docetaxel and 5-FU doses by 20%.
Stomatitis/mucositis grade 3
Second episode: discontinue treatment.
First episode: reduce 5-FU dose by 20%.
Stomatitis/mucositis grade 4
Second episode: stop 5-FU only, at all subsequent cycles.
Third episode: reduce docetaxel dose by 20%.
First episode: stop 5-FU only, at all subsequent cycles.
Second episode: reduce docetaxel dose by 20%.
For cisplatin and 5-fluorouracil dose adjustments, see the corresponding summary of product
characteristics.
In the pivotal SCCHN studies patients who experienced complicated neutropenia (including prolonged
neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide
prophylactic coverage (eg, day 6-15) in all subsequent cycles.
5
Special populations
Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who have both
elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal
range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of
docetaxel is 75 mg/m
2
(see sections 4.4 and 5.2). For those patients with serum bilirubin >ULN and/or
ALT and AST >3.5 times the ULN associated with alkaline phosphatase >6 times the ULN, no
dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric
adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN
associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x ULN; for these patients, no
dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No
data are available in patients with hepatic impairment treated by docetaxel in combination in the other
indications.
Paediatric population
The safety and efficacy of Docetaxel Teva 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 Teva in the paediatric population in the indications breast
cancer, non-small cell lung cancer, prostrate cancer, gastric carcinoma and head and neck cancer, not
including type II and III less differentiated nasopharyngeal carcinoma.
Elderly
Based on a population pharmacokinetic analysis, there are no special instructions for use in the
elderly. In combination with capecitabine, for patients 60 years of age or more, a starting dose
reduction of capecitabine to 75% is recommended (see capecitabine summary of product
characteristics).
Hypersensitivity to the active substance or to any of the excipients.
Docetaxel must not be used in patients with baseline neutrophil count of <1,500 cells/mm
3
.
Docetaxel must not be used in patients with severe liver impairment since there is no data available
(see sections 4.2 and 4.4).
For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as
dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel
administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well
as the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral
dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).
Haematology
Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median
of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of
complete blood counts should be conducted on all patients receiving docetaxel. Patients should be
retreated with docetaxel when neutrophils recover to a level ≥1,500 cells/mm
3
(see section 4.2).
6
In the case of severe neutropenia (<500 cells/mm
3
for seven days or more) during a course of
docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate
symptomatic measures are recommended (see section 4.2).
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 neutropena 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 neturopenic infection). Patient receiving TAC should be
closely monitored (see sections 4.2 and 4.8).
Hypersensitivity reactions
Patients should be observed closely for hypersensitivity reactions especially during the first and
second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation
of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should
be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised
cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe
hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of
docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions
should not be re-challenged with docetaxel.
Cutaneous reactions
Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema
followed by desquamation has been observed. Severe symptoms such as eruptions followed by
desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see
section 4.2).
Fluid retention
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be
monitored closely.
Patients with liver impairment
In patients treated with docetaxel at 100 mg/m
2
as single agent who have serum transaminase levels
(ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels
greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as
toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia,
infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel
in those patients with elevated liver function test (LFTs) is 75 mg/m
2
and LFTs should be measured at
baseline and before each cycle (see section 4.2).
For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent
with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended
and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric
adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN
associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x UNL; for these patients, no
dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No
7
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.
Others
Contraceptive measures must be taken by both men and women during treatment and for men at least
6 months after cessation of therapy (see section 4.6).
Additional cautions for use in adjuvant treatment of breast cancer
Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or
infection), G-CSF and dose reduction should be considered (see section 4.2).
Gastrointestinal reactions
Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia,
may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated
promptly.
Congestive heart failure
Patients should be monitored for symptoms of congestive heart failure during therapy and during the
follow up period.
Leukaemia
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed
myelodysplasia or myeloid leukaemia requires haematological follow-up.
Patients with 4+ nodes
The benefit/risk ratio for TAC in patients with 4+ nodes was not defined fully at the interim analysis
(see section 5.1).
Elderly
There are limited data available in patients > 70 years of age on docetaxel use in combination with
doxorubicin and cyclophosphamide.
Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study, 209 patients
were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with
docetaxel every three weeks, the incidence of related nail changes occurred at a rate ≥ 10% higher in
patients who were 65 years of age or greater compared to younger patients. The incidence of related
fever, diarrhoea, anorexia, and peripheral oedema occurred at rates ≥ 10% higher in patients who were
75 years of age or greater versus less than 65 years.
8
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.
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 cyclosporine, 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 products has not been investigated formally,
in vitro
interactions with tightly protein-bound drugs such as erythromycin, diphenhydramine, propranolol,
propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein
binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel.
Docetaxel did not influence the binding of digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their
co-administration. Limited data from a single uncontrolled study were suggestive of an interaction
between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was
about 50% higher than values previously reported for carboplatin monotherapy.
Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic
prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4.
No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.
Docetaxel should be administered with caution in patients concomitantly receiving potent CYP3A4
inhibitors (e.g. protease inhibitors like ritonavir, azole antifungals like ketoconazole or itraconazole).
A drug interaction study performed in patients receiving ketoconazole and docetaxel showed that the
clearance of docetaxel was reduced by half by ketoconazole, probably because the metabolism of
docetaxel involves CYP3A4 as a major (single) metabolic pathway. Reduced tolerance of docetaxel
may occur, even at lower doses.
There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be
both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other
cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant
women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.
Women of childbearing potential/contraception:
Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to
inform the treating physician immediately should this occur.
An effective method of contraception should be used during treatment.
In non clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3).
Therefore, men being treated with docetaxel are advised not to father a child during and up to
6 months after treatment and to seek advice on conservation of sperm prior to treatment.
9
Lactation:
Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk.
Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be
discontinued for the duration of docetaxel therapy.
No studies on the effects on the ability to drive and use machines have been performed.
The adverse reactions considered to be possibly or probably related to the administration of docetaxel
have been obtained in:
•
1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent
respectively.
•
258 patients who received docetaxel in combination with doxorubicin.
•
406 patients who received docetaxel in combination with cisplatin.
•
92 patients treated with docetaxel in combination with trastuzumab.
•
255 patients who received docetaxel in combination with capecitabine.
•
332 patients who received docetaxel in combination with prednisone or prednisolone (clinically
important treatment related adverse events are presented).
•
1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received
docetaxel in combination with doxorubicin and cyclophosphamide (clinically important
treatment related adverse events are presented).
•
300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and
79 patients in the phase II part) who received docetaxel in combination with cisplatin and
5-fluorouracil (clinically important treatment related adverse events are presented).
•
174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin
and 5-fluorouracil (clinically important treatment related adverse events are presented).
These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3;
grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA terms. Frequencies are defined as:
very common (≥1/10), common (≥1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); rare (≥1/10,000
to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which was
reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe
neutropenia (<500 cells/mm
3
) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea
and asthenia. The severity of adverse events of docetaxel may be increased when docetaxel is given in
combination with other chemotherapeutic agents.
For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are displayed. There
was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the
trastuzumab combination arm compared to docetaxel monotherapy.
For combination with capecitabine, the most frequent treatment-related undesirable effects (≥ 5%)
reported in a phase III study in breast cancer patients failing anthracycline treatment are presented (see
capecitabine summary of product characteristics).
The following adverse reactions are frequently observed with docetaxel:
10
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 extravasations 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).
11
Docetaxel 100 mg/m² single agent
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infections (G3/4: 5.7%;
including sepsis and
pneumonia, fatal in
1.7%)
Infection associated
with G4 neutropenia
(G3/4: 4.6%)
Blood and lymphatic
system disorders
Neutropenia (G4:
76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia
(G4: 0.2%)
Immune system
disorders
Hypersensitivity (G3/4:
5.3%)
Metabolism and
nutrition disorders
Anorexia
Nerveus system
disorders
Peripheral sensory
neuropathy (G3: 4.1%);
Peripheral motor
neuropathy (G3/4: 4%)
Dysgeusia (severe
0.07%)
Cardiac disorders
Arrhythmia (G3/4:
0.7%)
Cardiac failure
Hypotension;
Hypertension;
Haemorrhage
Vascular disorders
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea (severe 2.7%)
Stomatitis (G3/4: 5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe
0.2%);
Abdominal pain
(severe 1%);
Gastrointestinal
Haemorrhage (severe
0.3%)
Oesophagitis (severe:
0.4%)
Gastrointestinal
disorders
Skin and subcutaneous
tissue disorders
Alopecia;
Skin reaction (G3/4:
5.9%);
Nail disorders (severe
2.6%)
Musculoskeletal,
connective tissue
disorders
Myalgia (severe 1.4%)
Arthralgia
Fluid retention (severe:
6.5%)
Asthenia (severe
11.2%);
Pain
General disorders and
administration site
conditions
Infusion site reaction;
Non-cardiac chest
pain (severe 0.4%)
Investigations
G3/4 Blood bilirubin
increased (< 5%);
12
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
G3/4 Blood alkaline
phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)
Blood and lymphatic system disorders
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia.
Nervous system disorders
Reversibility data are available among 35.3% of patients who developed neurotoxicity following
docetaxel treatment at 100 mg/m² as single agent. The events were spontaneously reversible within
3 months.
Skin and subcutaneous tissue disorders
Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions
were reversible within 21 days.
General disorders and administration site conditions
The median cumulative dose to treatment discontinuation was more than 1,000 mg/m
2
and the median
time to fluid retention reversibility was 16.4 weeks (range 0
to 42 weeks). The onset of moderate and
severe retention is delayed (median cumulative dose: 818.9 mg/m
2
) in patients with premedication
compared with patients without premedication (median cumulative dose: 489.7 mg/m
2
); however, it
has been reported in some patients during the early courses of therapy.
13
Docetaxel 75 mg/m² single agent
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infections (G3/4: 5%)
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Blood and lymphatic system
disorders
Febrile neutropenia
Immune system disorders
Hypersensitivity (no severe)
Metabolism and nutrition disorders Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders
Arrhythmia (no severe)
Vascular disorders
Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue
disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe 0.8%)
Musculoskeletal and connective
tissue disorders
Myalgia
Asthenia (severe 12.4%);
Fluid retention (severe 0.8%);
Pain
General disorders and
administration site conditions
G3/4 Blood bilirubin increased
(< 2%)
Investigations
14
Docetaxel 75 mg/m² in combination with doxorubicin
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 7.8%)
Blood and lymphatic
system disorders
Neutropenia (G4:
91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia
(G4:0.8%)
Immune system
disorders
Hypersensitivity (G3/4:
1.2%)
Metabolism and
nutrition disorders
Anorexia
Nervous system
disorders
Peripheral sensory
neuropathy (G3: 0.4%)
Peripheral motor
neuropathy (G3/4:
0.4%)
Cardiac failure;
Arrhythmia (no severe)
Cardiac disorders
Vascular disorders
Hypotension
Nausea (G3/4: 5%);
Stomatitis (G3/4:
7.8%);
Diarrhoea (G3/4:
6.2%);
Vomiting (G3/4: 5%);
Constipation
Gastrointestinal
disorders
Alopecia;
Nail disorders (severe
0.4%);
Skin reaction (no
severe)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Myalgia
Asthenia (severe
8.1%);
Fluid retention (severe
1.2%);
Pain
General disorders and
administration site
conditions
Infusion site reaction
Investigations
G3/4 Blood bilirubin
increased (< 2.5%);
G3/4 Blood alkaline
phosphatase increased
(< 2.5%)
G3/4 AST increased
(< 1%);
G3/4 ALT increased
(< 1%)
15
Docetaxel 75 mg/m² in combination with cisplatin
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 5.7%)
Blood and lymphatic
system disorders
Neutropenia (G4:
51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia
(G4:0.5%)
Febrile neutropenia
Immune system
disorders
Hypersensitivity (G3/4:
2.5%)
Metabolism and
nutrition disorders
Anorexia
Peripheral sensory
neuropathy (G3: 3.7%);
Peripheral motor
neuropathy (G3/4: 2%)
Nervous system
disorders
Arrhythmia (G3/4:
0.7%)
Cardiac disorders
Cardiac failure
Hypotension (G3/4:
0.7%)
Vascular disorders
Gastrointestinal
disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%);
Constipation
Skin and
subcutaneous tissue
disorders
Alopecia;
Nail disorders (severe
0.7%);
Skin reaction (G3/4:
0.2%)
Musculoskeletal and
connective tissue
disorders
Myalgia (severe: 0.5%)
Asthenia (severe 9.9%);
Fluid retention (severe
0.7%);
Fever (G3/4: 1.2%)
General disorders
and administration
site conditions
Infusion site reaction;
pain
Investigations
G3/4 Blood bilirubin
increased (2.1%);
G3/4 ALT increased
(1.3%)
G3/4 AST increased
(0.5%);
G3/4 Blood alkaline
phosphatase increased
(0.3%)
16
Docetaxel 100 mg/m² in combination with trastuzumab
MedDRA system organ classes
Very common adverse reactions
Common adverse
reactions
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Febrile neutropenia (includes
neutropenia associated with fever
and antibiotic use) or neutropenic
sepsis
Metabolism and nutrition
disorders
Anorexia
Psychiatric disorders
Insomnia
Nervous system disorders
Paresthesia; Headache; Dysgeusia;
Hypoaesthesia
Eye disorders
Lacrimation increased;
Conjunctivitis
Cardiac disorders
Cardiac failure
Vascular disorders
Lymphoedema
Respiratory, thoracic and
mediastinal disorders
Epistaxis; Pharyngolaryngeal pain;
Nasopharyngitis ; Dyspnoea;
Cough; Rhinorrhoea
Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain
Skin and subcutaneous tissue
disorders
Alopecia; Erythema; Rash; Nail
disorders
Musculoskeletal and connective
tissue disorders
Myalgia; Arthralgia; Pain in
extremity; Bone pain; Back pain
General disorders and
administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal
inflammation; Pain; Influenza like
illness; Chest pain; Chills
Lethargy
Investigations
Weight increased
Cardiac disorders
Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus
trastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm,
64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm
alone.
Blood and lymphatic system disorders
Very common: Haematological toxicity was increased in patients receiving trastuzumab and
docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC
criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m
2
is
known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The
incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with
Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).
17
Docetaxel 75 mg/m² in combination with capecitabine
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Oral candidiasis (G3/4: < 1%)
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Blood and lymphatic system
disorders
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Dizziness;
Headache (G3/4: <1%);
Neuropathy peripheral
Nervous system disorders
Dysgeusia (G3/4: <1%);
Paresthesia (G3/4: <1%)
Eye disorders
Lacrimation increased
Dyspnoea (G3/4: 1%);
Cough (G3/4: <1%);
Epistaxis (G3/4: <1%)
Respiratory, thoracic and
mediastinal disorders
Pharyngolaryngeal pain (G3/4:
2%)
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Gastrointestinal disorders
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue
disorders
Hand-foot syndrome (G3/4:
24%)
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4:
<1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective
tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: <1%);
Back pain (G3/4: 1%);
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/ weakness (G3/4: 5%);
Oedema peripheral (G3/4:
1%);
General disorders and
administration site conditions
Lethargy;
Pain
Investigations
Weight decreased;
G3/4 Blood bilirubin increased
(9%)
18
Docetaxel 75 mg/m² in combination with prednisone or prednisolone
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infection (G3/4: 3.3%)
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia (G3/4:
0.6%)
Febrile neutropenia
Immune system disorders
Hypersensitivity (G3/4: 0.6%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 0.6%)
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Nervous system disorders
Peripheral motor neuropathy
(G3/4: 0%)
Lacrimation increased (G 3/4;
0.6%)
Eye disorders
Cardiac disorders
Cardiac left ventricular function
decrease (G3/4: 0.3%)
Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Respiratory, thoracic and
mediastinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4:
0.9%);
Vomiting (G3/4: 1.2%)
Gastrointestinal disorders
Skin and subcutaneous tissue
disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective
tissue disorders
Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and
administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe 0.6%)
19
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
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 2.4%);
Neutropenic infection.
(G3/4: 2.7%)
Anaemia (G3/4: 3%);
Neutropenia (G3/4:
59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4: NA)
Blood and lymphatic
system disorders
Immune system
disorders
Hypersensitivity (G3/4:
0.6%)
Metabolism and
nutrition disorders
Anorexia (G3/4: 1.5%)
Dysgeusia (G3/4:
0.6%);
Peripheral sensory
neuropathy (G3/4:
<0.1%)
Nervous system
disorders
Peripheral motor
neuropathy
(G3/4: 0%);
Syncope (G3/4: 0%)
Neurotoxicity
(G3/4:0%)
Somnolence (G3/4:
0%)
Eye disorders
Conjunctivitis (G3/4:
<0.1%)
Lacrimation increased
(G3/4: <0.1%);
Cardiac disorders
Arrhythmia (G3/4:
0.2%);
Vascular disorders
Hot flush (G3/4: 0.5%)
Hypotension (G3/4:
0%)
Phlebitis (G3/4: 0%)
Lymphoedema (G3/4:
0%)
Respiratory, thoracic
and mediastinal
disorders
Cough (G3/4: 0%)
Nausea (G3/4: 5.0%);
Stomatitis (G3/4:
6.0%);
Vomiting (G3/4:
4.2%);
Diarrhoea (G3/4:
3.4%);
Constipation (G3/4:
0.5%)
Gastrointestinal
disorders
Abdominal pain (G3/4:
0.4%)
Alopecia (G3/4:
<0.1%);
Skin toxicity (G3/4:
0.6%);
Nail disorders (G3/4:
0.4%)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4:
0.2%)
Reproductive system
Amenorrhoea (G3/4:
20
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
and breast disorders
NA)
General disorders and
administration site
conditions
Asthenia (G3/4:
10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral
(G3/4: 0.2%)
Weight increased
(G3/4: 0%)
Weight decreased
(G3/4: 0.2%)
Investigations
Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in 12 patients out of the
83 patients with peripheral sensory neuropathy at the end of the chemotherapy.
Cardiac disorders
Congestive Heart Failure (CHF) has been reported in 18 of 1276 patients during the follow-up period.
In the node positivity study (TAX316) one patient in each treatment arm died due to cardiac failure.
Skin and subcutaneous tissue disorders
Alopecia was observed to be ongoing during follow-up in 25 patients out of the 736 patients with
alopecia at the end of the chemotherapy.
Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing during follow-up in 140 patients out of the 251 patients
with amenorrhoea at the end of the chemotherapy.
General disorders and administration site conditions
Peripheral oedema was observed to be ongoing during follow-up time 18 patients out of the
112 patients with peripheral oedema at the end of the chemotherapy in study TAX 316, whereas
lymphoedema was observed to be ongoing in 4 of the 5 patients with lymphoedema at the end of the
chemotherapy in the study GEICAM 9805.
Acute leukaemia / Myelodysplastic syndrome.
At a median follow-up time of 77 months, acute leukaemia occurred in 1 of 532 (0.2%) patients who
received docetaxel, doxorubicin, and cyclophosphamide in the GEICAM 9805 study. No cases were
reported in patients who received fluorouracil, doxorubicin and cyclophosphamide. No patient was
diagnosed with myelodysplastic syndrome in either treatment groups.
Table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic
infection was decreased in patients who received primary G-CSF prophylaxis after it was made
mandatory in the TAC arm - GEICAM study.
Neutropenic complications in patients receiving TAC with or without primary G-CSF prophylaxis
(GEICAM 9805)
Neutropenia (Grade 4)
Without primary
G-CSF prophylaxis
(n = 111)
n (%)
104 (93.7)
With primary
G-CSF prophylaxis
(n = 421)
n (%)
Febrile neutropenia
28 (25.2)
23 (5.5)
Neutropenic infection
14 (12.6)
21 (5.0)
21
135 (32.1)
Neutropenic infection (Grade 3-4)
2 (1.8)
5 (1.2)
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for gastric adenocarcinoma
cancer:
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Neutropenic infection;
Infection (G3/4: 11.7%)
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4:
8.8%);
Febrile neutropenia.
Blood and lymphatic system
disorders
Immune system disorders
Hypersensitivity (G3/4: 1.7%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 11.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%).
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%).
Lacrimation increased (G3/4:
0%).
Eye disorders
Ear and labyrinth disorders
Hearing impaired (G3/4: 0%).
Cardiac disorders
Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%).
Constipation (G3/4: 1.0 %);
Gastrointestinal pain (G3/4:
1.0%);
Oesophagitis / dysphagia /
odynophagia (G3/4: 0.7%).
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%).
Skin and subcutaneous tissue
disorders
Alopecia (G3/4: 4.0%).
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention (severe/life
threatening: 1%).
General disorders and
administration site conditions
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).
22
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for Head and Neck cancer
•
Induction chemotherapy followed by radiotherapy (TAX 323)
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 6.3%);
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Cancer pain (G3/4:
0.6%)
Neutropenia (G3/4:
76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Blood and lymphatic
system
disorders
Febrile neutropenia
Immune system
disorders
Hypersensitivity (no
severe)
Metabolism and
nutrition disorders
Anorexia (G3/4: 0.6%)
Dysgeusia/Parosmia;
Peripheral sensory
neuropathy
(G3/4:0.6%)
Nervous system
disorders
Dizziness
Lacrimation increased;
Conjunctivitis
Eye disorders
Ear and labyrinth
disorders
Hearing impaired
Cardiac disorders
Myocardial ischemia
(G3/4:1.7%)
Arrhythmia (G3/4:
0.6%)
Venous disorder (G3/4:
0.6%)
Vascular disorders
Constipation;
Oesophagitis/dysphagia/
Odynophagia
(G3/4:0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal
haemorrhage(G3/4:0.6%)
Gastrointestinal
disorders
Nausea (G3/4:0.6%)
Stomatitis (G3/4:
4.0%)
Diarrhoea (G3/4:
2.9%)
Vomiting (G3/4: 0.6%)
Rash pruritic;
Dry skin;
Skin exfoliative
(G3/4:0.6%)
Skin and subcutaneous
tissue disorders
Alopecia (G3/4:
10.9%)
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4:0.6%)
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4:0.6%);
Fluid retention;
Oedema
General disorders and
administration site
conditions
Investigations
Weight increased
23
•
Induction chemotherapy followed by chemoradiotherapy (TAX 324)
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 3.6%)
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Cancer pain (G3/4:
1.2%)
Neutropenia (G3/4:
83.5%);
Anaemia (G3/4:
12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia
Blood and lymphatic
system disorders
Immune system
disorders
Hypersensitivity
Metabolism and
nutrition disorders
Anorexia (G3/4: 12.0%)
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory
neuropathy
(G3/4: 1.2%)
Nervous system
disorders
Dizziness (G3/4: 2.0%);
Peripheral motor
neuropathy (G3/4: 0.4%)
Eye disorders
Lacrimation increased
Conjunctivitis
Ear and labyrinth
disorders
Hearing impaired
(G3/4: 1.2%)
Arrhythmia (G3/4:
2.0%)
Ischemia myocardial
Cardiac disorders
Vascular disorders
Venous disorder
Nausea (G3/4: 13.9%);
Stomatitis (G3/4:
20.7%);
Vomiting (G3/4: 8.4%);
Diarrhoea (G3/4: 6.8%);
Oesophagitis/dysphagia/
Odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Gastrointestinal
disorders
Dyspepsia (G3/4: 0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal
haemorrhage (G3/4:
0.4%)
Skin and subcutaneous
tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritus;
Dry skin;
Desquamation
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.4%)
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)
General disorders and
administration site
conditions
Investigations
Weight decreased
Weight increased
24
Post-marketing experience
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Very rare cases of acute myeloid leukaemia
and myelodysplastic syndrome
have been reported in
association with docetaxel when used in combination with other chemotherapy agents and/or
radiotherapy.
Blood and lymphatic system disorders
Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated
intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been
reported.
Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel
administration. These reactions sometimes appear during the infusion of the medicinal product.
Eye Disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring
during infusion of the medicinal product and in association with hypersensitivity reactions have been
reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or
without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been
rarely reported.
Ear and labyrinth disorders
Rare cases of ototoxicity, hearing impaired and/or hearing loss have been reported.
Cardiac disorders
Rare cases of myocardial infarction have been reported.
Vascular disorders
Venous thromboembolic events have rarely been reported.
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome, interstitial pneumonia and pulmonary fibrosis have rarely been
reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant
radiotherapy.
Gastrointestinal disorders
Rare occurrences of dehydration as a consequence of gastrointestinal events, gastrointestinal
perforation, colitis ischaemic, colitis and neutropenic enterocolitis have been reported. Rare cases of
ileus and intestinal obstruction have been reported.
Hepatobiliary disorders
Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders,
have been reported.
Skin and subcutaneous tissue disorders
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some
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.
25
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.
There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of
overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In
cases of overdose, exacerbation of adverse events may be expected. The primary anticipated
complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and
mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose.
Other appropriate symptomatic measures should be taken, as needed.
5.1 Pharmacodynamicproperties
Pharmacotherapeutic group: Taxanes, ATC Code: L01CD 02
Preclinical data
Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable
microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The
binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown
in vitro
to disrupt the microtubular network in cells which is essential for
vital mitotic and interphase cellular functions.
Docetaxel was found to be cytotoxic
in vitro
against various murine and human tumour cell lines and
against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular
concentrations with a long cell residence time. In addition, docetaxel was found to be active on some
but not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistance
gene.
In vivo
, docetaxel is schedule independent and has a broad spectrum of experimental antitumour
activity against advanced murine and human grafted tumours.
Clinical data
Breast cancer
Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy
Patients with operable node-positive breast cancer (TAX 316)
Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant
treatment of patients with operable node-positive breast cancer and KPS ≥ 80%, between 18 and
70
years of age. After stratification according to the number of positive lymph nodes (1-3, 4+),
1491 patients were randomized to receive either docetaxel 75 mg/m
2
administered 1-hour after
doxorubicin 50 mg/m
2
and cyclophosphamide 500 mg/m
2
(TAC arm), or doxorubicin 50 mg/m
2
followed by fluorouracil 500 mg/m
2
and cyclophosphamide 500 mg/m
2
(FAC arm). Both regimens
were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion;
all other medicinal products were given as intravenous bolus on day one. G-CSF was administered as
secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia,
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
26
according to guidelines in place at participating institutions and was given to 69% of patients who
received TAC and 72% of patients who received FAC.
An interim analysis was performed with a median follow up of 55 months. Significantly longer
disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of
relapses at 5 years was reduced in patients receiving TAC compared to those who received FAC (25%
versus 32%, respectively) i.e. an absolute risk reduction by 7% (p=0.001). Overall survival at 5 years
was also significantly increased with TAC compared to FAC (87% versus 81%, respectively) i.e. an
absolute reduction of the risk of death by 6% (p=0.008). TAC-treated patient subsets according to
prospectively defined major prognostic factors were analyzed:
Disease free survival
Overall survival
Patient subset
Number
of
patients
Hazard
ratio*
95% CI
P=
Hazard
ratio*
95% CI
P=
No of positive
nodes
Overall 745 0.72 0.59-0.88 0.001 0.70 0.53-0.91 0.008
1-3 467 0.61 0.46-0.82 0.0009 0.45 0.29-0.70 0.0002
4+ 278 0.83 0.63-1.08 0.17 0.94 0.66-1.33 0.72
*a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival and
overall survival compared to FAC
The beneficial effect of TAC was not proven in patients with 4 and more positive nodes (37% of the
population) at the interim analysis stage. The effect appears to be less pronounced than in patients with
1-3 positive nodes. The benefit/risk ratio was not defined fully in patients with 4 and more positive
nodes at this analysis stage.
Patients with operable node
-
negative breast cancer eligible to receive chemotherapy (GEICAM 9805)
Data from a multicenter open label randomized trial support the use of Docetaxel 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/m
2
administered 1-hour after doxorubicin
50 mg/m
2
and cyclophosphamide 500 mg/m
2
(539 patients in TAC arm), or doxorubicin 50 mg/m
2
followed by fluorouracil 500 mg/m
2
and cyclosphosphamide 500 mg/m
2
(521 patients in FAC arm), as
adjuvant treatment of operable node-negative breast cancer patients with high risk of relapse according
to 1998 St. Gallen criteria (tumour size >2 cm and/or negative ER and PR and/or high
histological/nuclear grade (grade 2 to 3) and /or age <35 years). Both regimens were administered
once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other drugs
were given intraveinously on day 1 every three weeks. Primary prophylactic G-CSF was made
mandatory in TAC arm after 230 patients were randomized. The incidence of Grade 4 neutropenia,
febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF
prophylaxis (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+
and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant radiation
therapy was administered according to guidelines in place at participating institutions and was given to
57.3% of patients who received TAC and 51.2% of patients who received FAC.
Median duration of follow-up was 77 months. Significantly longer disease-free survival for the TAC
arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the
risk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93),
p = 0.01). Overall survival (OS) was also longer in the TAC arm with TAC-treated patients having a
24% reduction in the risk of death compared to FAC (hazard ratio = 0.76, 95% CI (0.46-1.26,
p = 0.29). However, the distribution of OS was not significantly different between the 2 groups.
TAC-treated patient subsets according to prospectively defined major prognostic factors were
analyzed (see table below):
27
Subset Analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study (Intent-to-
Treat Analysis)
Patient subset
Number of patients
in TAC group
Disease Free Survival
Hazard ratio*
95% CI
Overall
539
0.68
0.49-0.93
Age category 1
<50 years
≥50 years
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
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
216
259
0.79
0.77
0.59
0.24-2.6
0.46-1.3
0.39-0.9
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.
285
254
0.64
0.72
Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallen
chemotherapy criteria – (ITT population) were performed and presented here below
TAC
FAC
Hazard ratio
(TAC/FAC)
Subgroups
(n=539)
(n=521)
(95% CI)
p-value
Meeting relative indication
for chemotherapy
a
No
18/214
(8.4%)
26/227
(11.5%)
0.796
(0.434 - 1.459)
0.4593
Yes
48/325
(14.8%)
69/294
(23.5%)
0.606
(0.42 - 0.877)
0.0072
TAC = docetaxel, doxorubicin and cyclophosphamide
FAC = 5-fluorouracil, doxorubicin and cyclophospamide
CI = confidence interval; ER = estrogen receptor
PR = progesterone receptor
a
ER/PR-negative or Grade 3 or tumor size >5 cm
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.
28
Menopausal status
Pre-Menopausal
Post-Menopausal
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
29
(100 mg/m
2
) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant
chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had
received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in
this pivotal study was immunohistochemistry (IHC). A minority of patients were tested using
fluorescence in-situ hybridization (FISH). In this study, 87% of patients had disease that was IHC 3+,
and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are
summarized in the following table:
Parameter
Docetaxel plus trastuzumab
1
n=92
Docetaxel
1
n=94
Response rate
(95% CI)
61%
(50-71)
34%
(25-45)
Median duration of response
(months)
(95% CI)
11.4
(9.2-15.0)
5.1
(4.4-6.2)
Median TTP (months)
(95% CI)
10.6
(7.6-12.9)
5.7
(5.0-6.5)
22.1
2
(17.6-28.9)
TTP=time to progression; “ne” indicates that it could not be estimated or it was not yet reached.
1
Full analysis set (intent-to-treat)
2
Estimated median survival
30.5
2
(26.8-ne)
Docetaxel in combination with capecitabine
Data from one multicenter, randomised, controlled phase III clinical study support the use of docetaxel
in combination with capecitabine for treatment of patients with locally advanced or metastatic breast
cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this study, 255 patients
were randomised to treatment with docetaxel (75 mg/m
2
as a 1 hour intravenous infusion every
3 weeks) and capecitabine (1250 mg/m
2
twice daily for 2 weeks followed by 1-week rest period).
256 patients were randomised to treatment with docetaxel alone (100 mg/ m
2
as a 1 hour intravenous
infusion every 3 weeks). Survival was superior in the docetaxel +capecitabine combination arm
(p=0.0126). Median survival was 442 days (docetaxel + capecitabine) vs. 352 days (docetaxel alone).
The overall objective response rates in the all-randomised population (investigator assessment) were
41.6% (docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive
disease was superior in the docetaxel + capecitabine combination arm (p<0.0001). The median time to
progression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks)
and overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive
Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).
There was less use of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease
related medications (p=0.06) and radiotherapy (p<0.01) in patients treated with docetaxel at 75 mg/m²
compared to those with BSC.
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/m
2
as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m
2
over
30-60 minutes every 3 weeks (TCis), Docetaxel 75 mg/m
2
as a 1 hour infusion in combination with
30
Median survival (months)
(95% CI)
carboplatin (AUC 6 mg/ml. min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m
2
administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m
2
administered on
day 1 of cycles repeated every 4 weeks (VCis).
Survival data, median time to progression and response rates for two arms of the study are illustrated
in the following table:
TCis
n=408
VCis
n=404
Statistical Aaalysis
Overall survival
(Primary end-point):
Median survival (months)
11.3
10.1
Hazard ratio: 1.122
[97.2% CI: 0.937; 1.342]*
1-year Survival (%)
46
41
Treatment difference: 5.4%
[95% CI: -1.1; 12.0]
2-year Survival (%)
21
14
Treatment difference: 6.2%
[95% CI: 0.2; 12.3]
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/m
2
every 3 weeks for 10 cycles.
•
Docetaxel 30 mg/m
2
administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.
•
Mitoxantrone 12 mg/m
2
every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily,
continuously.
Patients who received docetaxel every three weeks demonstrated significantly longer overall survival
compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly
arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for
the docetaxel arms versus the control arm are summarized in the following table:
Endpoint
Docetaxel
every 3 weeks
Docetaxel
every week
Mitoxantrone
every 3 weeks
Number of patients
Median survival (months)
95% CI
335
18.9
(17.0-21.2)
334
17.4
(15.7-19.0)
337
16.5
(14.4-18.6)
31
Hazard ratio
95% CI
p-value
†
*
0.761
(0.619-0.936)
0.0094
0.912
(0.747-1.113)
0.3624
--
--
--
Number of patients
PSA** response rate (%)
95% CI
p-value*
291
45.4
(39.5-51.3)
0.0005
282
47.9
(41.9-53.9)
<0.0001
300
31.7
(26.4-37.3)
--
Number of patients
Pain response rate (%)
95% CI
p-value*
153
34.6
(27.1-42.7)
0.0107
154
31.2
(24.0-39.1)
0.0798
157
21.7
(15.5-28.9)
--
Number of patients
Tumour response rate
(%)
95% CI
p-value*
141
12.1
(7.2-18.6)
0.1112
134
8.2
(4.2-14.2)
0.5853
137
6.6
(3.0-12.1)
--
†
Stratified log rank test
*Threshold for statistical significance=0.0175
**PSA: Prostate-Specific Antigen
Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every
3 weeks, it is possible that certain patients may benefit from docetaxel every week.
No statistical differences were observed between treatment groups for Global Quality of Life.
Gastric adenocarcinoma
A multicenter, open-label, randomized study, was conducted to evaluate the safety and efficacy of
docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including
adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for
metastatic disease. A total of 445 patients with KPS>70 were treated with either docetaxel (T)
(75 mg/m
2
on day 1) in combination with cisplatin (C) (75 mg/m
2
on day 1) and 5-fluorouracil (F)
(750 mg/m
2
per day for 5 days) or cisplatin (100 mg/m
2
on day 1) and 5-fluorouracil (1000 mg/m
2
per
day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF
arm.
The median number of cycles administered per patient was 6 (with a range of 1-16) for the TCF arm
compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary
endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer
TTP (p=0.0004) in favour of the TCF arm. Overall survival was also significantly longer (p=0.0201)
in favour of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized
in the following table:
Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma
Endpoint
TCF
n=221
CF
n=224
Median TTP (months)
(95%CI)
5.6
(4.86-5.91)
3.7
(3.45-4.47)
Hazard ratio
(95% CI)
*p-value
1.473
(1.189-1.825)
0.0004
Median survival (months)
(95% CI)
2-year estimate (%)
9.2
(8.38-10.58)
18.4
8.6
(7.16-9.46)
8.8
Hazard ratio
(95% CI)
*p-value
1.293
(1.041-1.606)
0.0201
32
Overall response rate (CR+PR) (%)
36.7
25.4
p-value
0.0106
Progressive disease as best overall
Response (%)
16.7
25.9
*Unstratified log rank test
Subgroup analyses across age, gender and race consistently favoured the TCF arm compared to the CF
arm.
A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed
a statistically significant difference although always in favour of the TCF regimen and showed that the
benefit of TCF over CF is clearly observed between 18 and 30 months of follow up.
Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favour
of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global
health status on the QLQ-C30 questionnaire (p=0.0121) and a longer time to definitive worsening of
Karnofsky performance status (p=0.0088) compared to patients treated with CF.
Head and neck cancer
•
Induction chemotherapy followed by radiotherapy (TAX323)
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell
carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label,
randomized study (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN,
and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the
docetaxel arm received docetaxel (T) 75 mg/m
2
followed by cisplatin (P) 75 mg/m
2
followed by
5-fluorouracil (F) 750 mg/m
2
per day as a continuous infusion for 5 days. This regimen was
administered every three weeks for 4 cycles in case at least a minor response (≥ 25% reduction in
bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with
a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not
progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (TPF/RT).
Patients on the comparator arm received cisplatin (P) 100 mg/m
2
followed by 5-fluorouracil (F)
1000 mg/m
2
per day for 5 days. This regimen was administered every three weeks for 4 cycles in case
at least a minor response (≥ 25% reduction in bidimensionally measured tumour size) was observed
after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval
of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to
institutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered either
with a conventional fraction (1.8 Gy - 2.0 Gy once a day, 5 days per week for a total dose of
66 to 70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a
minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for
accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed
following chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic
prophylaxis 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 favour of the TPF arm compared to the PF arm (median OS: 18.6 vs.
14.5 months respectively) with a 28% risk reduction of mortality, p = 0.0128. Efficacy results are
presented in the table below:
Efficacy of docetaxel in the induction treatment of patients
with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)
Endpoint
Docetaxel +
Cis+5-FU
n=177
Cis+5-FU
n=181
Median progression free survival (months)
11.4
8.3
33
(95%CI)
(10.1-14.0)
(7.4-9.1)
Adjusted hazard ratio
(95% CI)
*p-value
0.70
(0.55-0.89)
0.0042
Median survival (months)
(95% CI)
18.6
(15.7-24.0)
14.5
(11.6-18.7)
Hazard ratio
(95% CI)
**p-value
0.72
(0.56-0.93)
0.0128
Best overall response to chemotherapy (%)
(95%CI)
67.8
(60.4-74.6)
53.6
(46.0-61.0)
***p-value
0.006
Best overall response to study treatment
[chemotherapy +/- radiotherapy] (%)
(95%CI)
72.3
(65.1-78.8)
58.6
(51.0-65.8)
***p-value
0.006
Median duration of response to
chemotherapy ± radiotherapy (months)
(95% CI)
n=128
15.7
(13.4-24.6)
n=106
11.7
(10.2-17.4)
Hazard ratio
(95% CI)
**p-value
0.72
(0.52-0.99)
0.0457
A hazard ratio of less than 1 favours docetaxel + cisplatin + 5-FU
*Cox model (adjustment for Primary tumour site, T and N clinical stages and PSWHO)
**Log rank test
*** Chi-square test
Quality of life parameters
Patients treated with TPF experienced significantly less deterioration of their Global health score
compared to those treated with PF (p=0.01, using the EORTC QLQ-C30 scale).
Clinical benefit parameters
The performance status scale, for head and neck (PSS-HN) subscales designed to measure
understandability of speech, ability to eat in public, and normalcy of diet, was significantly in favour
of TPF as compared to PF.
Median time to first deterioration of WHO performance status was significantly longer in the TPF arm
compared to PF. Pain intensity score improved during treatment in both groups indicating adequate
pain management
Induction chemotherapy followed by chemoradiotherapy (TAX324)
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced
squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a 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).
34
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
n=255
Cis+5-FU
n=246
Median overall survival (months)
(95%CI)
70.6
(49.0-NA)
30.1
(20.9-51.5)
Hazard ratio
(95% CI)
*p-value
0.70
(0.54-0.90)
0.0058
Median PFS (months)
(95% CI)
35.5
(19.3-NA)
13.1
(10.6-20.2)
Hazard ratio
(95% CI)
**p-value
0.71
(0.56-0.90)
0.004
Best overall response (CR + PR) to
chemotherapy (%)
(95%CI)
71.8
(65.8-77.2)
64.2
(57.9-70.2)
***p-value
0.070
Best overall response (CR + PR) to study
treatment [chemotherapy +/- radiotherapy]
(%)
(95%CI)
76.5
(70.8-81.5)
71.5
(65.5-77.1)
***p-value 0.209
A hazard ratio of less than 1 favours docetaxel + cisplatin + fluorouracil
* Un-adjusted log-rank test
** Un-adjusted log-rank test, not adjusted for multiple comparisons
*** Chi-square test, not adjusted for multiple comparisons
NA-not applicable
5.2
Pharmacokinetic properties
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of
20-115 mg/m
2
in Phase I studies. The kinetic profile of docetaxel is dose independent and consistent
with a three-compartment pharmacokinetic model with half lives for the α, β and γ phases of 4 min,
36 min and 11.1 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel
from the peripheral compartment. Following the administration of a 100 mg/m
2
dose given as a one
hour infusion a mean peak plasma level of 3.7 μg/ml was obtained with a corresponding AUC of
4.6 h.μg/ml. Mean values for total body clearance and steady-state volume of distribution were
21 l/h/m
2
and 113 l, respectively. Inter individual variation in total body clearance was approximately
50%. Docetaxel is more than 95% bound to plasma proteins.
35
A study of
14
C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in
both the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl
ester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% of
the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is
excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites
and very low amounts of unchanged medicinal product.
A population pharmacokinetic analysis has been performed with docetaxel in 577 patients.
Pharmacokinetic parameters estimated by the model were very close to those estimated from Phase I
studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient. In a small
number of patients (n=23) with clinical chemistry data suggestive of mild to moderate liver function
impairment (ALT, AST ≥1.5 times the ULN associated with alkaline phosphatase ≥2.5 times the
ULN), total clearance was lowered by 27% on average (see section 4.2). Docetaxel clearance was not
modified in patients with mild to moderate fluid retention and there are no data available in patients
with severe fluid retention.
When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma
levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin
and cyclophosphamide were not influenced by their coadministration.
Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice
versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (C
max
and AUC) and no
effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5’-DFUR.
Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following
monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is
similar to that observed with cisplatin alone.
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid
tumours had no influence on the pharmacokinetics of each individual medicinal product.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard
dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the
pharmacokinetics of docetaxel was observed.
5.3 Preclinical safety data
The carcinogenic potential of docetaxel has not been studied.
Docetaxel has been shown to be mutagenic in the
in vitro
micronucleus and chromosome aberration
test in CHO-K1 cells and in the
in vivo
micronucleus test in the mouse. However, it did not induce
mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent
with the pharmacological activity of docetaxel.
Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair
male fertility.
6.1 List of excipients
Concentrate
Polysorbate 80
Ethanol, anhydrous
Solvent
36
Water for injections.
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
•
18 months.
•
Premix solution: Chemical and physical in-use stability has been demonstrated for 8 hours when
stored either between 2°C and 8°C or at room temperature (below 25°C). From a
microbiological point of view, the product should be used immediately. If not used immediately,
in-use storage times and conditions prior to use are the responsibility of the user and would
normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled
and validated aseptic conditions.
•
Infusion solution: Chemical and physical in-use stability has been demonstrated for 4 hours at
room temperature (below 25°C). From a microbiological point of view, the product should be
used immediately. If not used immediately, in-use storage times and conditions prior to use are
the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless
dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage and other handling
Do not store above 25°C.
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Each carton contains:
•
One vial of concentrate and,
•
One vial of solvent
•
Docetaxel Teva 20 mg vial
6 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
This vial contains 0.72 ml of a 27.73 mg/ml solution of docetaxel in polysorbate 80 (fill volume:
24.4 mg/0.88 ml). This fill volume has been established during the development of docetaxel to
compensate for liquid loss during preparation of the premix due to foaming, adhesion to the
walls of the vial and "dead-volume". This overfill ensures that after dilution with the entire
contents of the accompanying solvent for docetaxel vial, there is a minimal extractable premix
volume of 2 ml containing 10 mg/ml docetaxel which corresponds to the labelled amount of
20 mg per vial.
Solvent for Docetaxel Teva 20
mg vial
6 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
Solvent vial contains 1.28 ml of water for injections (fill volume: 1.71 ml). The addition of the
entire contents of the solvent vial to the contents of the Docetaxel Teva 20 mg concentrate for
solution for infusion vial ensures a premix concentration of 10 mg/ml docetaxel.
6.6 Special precautions for disposal and other handling
37
Docetaxel Teva 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 Teva concentrate, premix solution or infusion solution should come into contact with
skin, wash immediately and thoroughly with soap and water. If Docetaxel concentrate, premix solution
or infusion solution should come into contact with mucous membranes, wash immediately and
thoroughly with water.
Preparation for the intravenous administration
a)
Preparation of the Docetaxel Teva premix solution (10 mg docetaxel/ml)
If the vials are stored under refrigeration, allow the required number of Docetaxel Teva boxes to stand
at room temperature (below 25°C) for 5 minutes.
Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Teva vial by partially inverting the vial.
Inject the entire contents of the syringe into the corresponding Docetaxel Teva vial.
Remove the syringe and needle and mix manually by repeated inversions for at least 45 seconds. Do
not shake.
Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then check that
the solution is homogenous and clear (foaming is normal even after 5 minutes due to the presence of
polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after preparation.
However the chemical and physical stability of the premix solution has been demonstrated for 8 hours
when stored either between 2°C and 8°C or at room temperature (below 25°C).
b)
Preparation of the infusion solution
More than one premix vial may be necessary to obtain the required dose for the patient. Based on the
required dose for the patient expressed in mg, aseptically withdraw the corresponding premix volume
containing 10 mg/ml docetaxel from the appropriate number of premix vials using graduated syringes
fitted with a needle. For example, a dose of 140 mg docetaxel would require 14 ml docetaxel premix
solution.
Inject the required premix volume into a non-PVC 250 ml infusion bag containing either 5% glucose
solution or sodium chloride 9 mg/ml (0.9%) solution for infusion.
If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so
that a concentration of 0.74 mg/ml docetaxel is not exceeded.
Mix the infusion bag or bottle manually using a rocking motion.
The Docetaxel Teva infusion solution should be used within 4 hours and should be aseptically
administered as a 1-hour infusion under room temperature (below 25°C) and normal lighting
conditions.
As with all parenteral products, Docetaxel Teva premix solution and infusion solution should be
visually inspected prior to use, solutions containing a precipitate should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
38
8. MARKETING AUTHORISATION NUMBER
EU/1/09/611/001
26 January 2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
39
1.
Docetaxel Teva 80 mg concentrate and solvent for solution for infusion
Each single dose vial of Docetaxel Teva concentrate contains 80 mg docetaxel (anhydrous). Each ml
of concentrate contains 27.73 mg docetaxel.
Excipients
:
Each vial of concentrate contains 25.1% (w/w) anhydrous ethanol.
For a full list of excipients, see section 6.1.
Concentrate and solvent for solution for infusion.
The concentrate is a clear viscous, yellow to brown-yellow solution.
The solvent is a colourless solution.
4.1 Therapeuticindications
Breast cancer
Docetaxel Teva 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 resticted to
patients eligible to receive chemotherapy according to internationally established crieteria from
primary therapy of early breast cancer (see section 5.1).
Docetaxel Teva in combination with doxorubicin is indicated for the treatment of patients with locally
advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this
condition.
Docetaxel Teva monotherapy is indicated for the treatment of patients with locally advanced or
metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have
included an anthracycline or an alkylating agent.
Docetaxel Teva in combination with trastuzumab is indicated for the treatment of patients with
metastatic breast cancer whose tumours overexpress HER2 and who previously have not received
chemotherapy for metastatic disease.
Docetaxel Teva 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
40
Docetaxel Teva is indicated for the treatment of patients with locally advanced or metastatic non-small
cell lung cancer after failure of prior chemotherapy.
Docetaxel Teva in combination with cisplatin is indicated for the treatment of patients with
unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not
previously received chemotherapy for this condition.
Prostate cancer
Docetaxel Teva in combination with prednisone or prednisolone is indicated for the treatment of
patients with hormone refractory metastatic prostate cancer.
Gastric adenocarcinoma
Docetaxel Teva in combination with cisplatin and 5-fluorouracil is indicated for the treatment of
patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal
junction, who have not received prior chemotherapy for metastatic disease.
Head and neck cancer
Docetaxel Teva in combination with cisplatin and 5-fluorouracil is indicated for the induction
treatment of patients with locally advanced squamous cell carcinoma of the head and neck.
The use of docetaxel should be confined to units specialised in the administration of cytotoxic
chemotherapy and it should only be administered under the supervision of a physician qualified in the
use of anticancer chemotherapy (see section 6.6).
Recommended dose
For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral
corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to
docetaxel administration, unless contraindicated, can be used (see section 4.4). Prophylactic G-CSF
may be used to mitigate the risk of haematological toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended
premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel
infusion (see section 4.4).
Docetaxel is administered as a one-hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive and node-negative breast cancer, the
recommended dose of docetaxel is 75 mg/m
2
administered 1-hour after doxorubicin 50 mg/m
2
and
cyclophosphamide 500 mg/m
2
every 3 weeks for 6 cycles (TAC regimen) (see also Dose adjustments
during treatment).
For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose
of docetaxel is 100 mg/m
2
in monotherapy. In first-line treatment, docetaxel 75 mg/m
2
is given in
combination therapy with doxorubicin (50 mg/m
2
).
In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m
2
every three weeks,
with trastuzumab administered weekly. In the pivotal study the initial docetaxel infusion was started
the day following the first dose of trastuzumab. The subsequent docetaxel doses were administered
immediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab was
well tolerated. For trastuzumab dose and administration, see trastuzumab summary of product
characteristics.
41
In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m
2
every three weeks,
combined with capecitabine at 1250 mg/m
2
twice daily (within 30 minutes after a meal) for 2 weeks
followed by a 1-week rest period. For capecitabine dose calculation according to body surface area,
see capecitabine summary of product characteristics.
Non-small cell lung cancer
In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen
is docetaxel 75 mg/m
2
immediately followed by cisplatin 75 mg/m
2
over 30-60 minutes. For treatment
after failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m² as a single
agent.
Prostate cancer
The recommended dose of docetaxel is 75 mg/m
2
. Prednisone or prednisolone 5 mg orally twice daily
is administered continuously (see section 5.1).
Gastric adenocarcinoma
The recommended dose of docetaxel is 75 mg/m
2
as a 1 hour infusion, followed by cisplatin 75 mg/m
2
,
as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg /m
2
per day given as
a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion.
Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and
appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the
risk of haematological toxicities (See also Dose adjustments during treatment).
Head and neck cancer
Patients must receive premedication with antiemetics and appropriate hydration (prior to and after
cisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of haematological
toxicities. All patients on the docetaxel-containing arm of the TAX 323 and TAX 324 studies,
received prophylactic antibiotics.
•
Induction chemotherapy followed by radiotherapy (TAX 323)
For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head
and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m
2
as a 1 hour infusion
followed by cisplatin 75 mg/m
2
over 1 hour, on day one, followed by 5-fluorouracil as a
continuous infusion at 750 mg/m
2
per day for five days. This regimen is administered every
3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.
•
Induction chemotherapy followed by chemoradiotherapy (TAX 324)
For the induction treatment of patients with locally advanced (technically unresectable, low
probability of surgical cure, and aiming at organ preservation) squamous cell carcinoma of the
head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m
2
as a 1 hour
intravenous infusion on day 1, followed by cisplatin 100 mg/m
2
administered as a 30-minute to
3 hour infusion, followed by 5-fluorouracil 1000 mg/m
2
/day as a continuous infusion from day
1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy,
patients should receive chemoradiotherapy.
For cisplatin and 5-fluorouracil dose modifications, see the corresponding summary of product
characteristics.
Dose adjustments during treatment
General
Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm
3
.
In patients who experienced either febrile neutropenia, neutrophil count <500 cells/mm
3
for more than
one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel
therapy, the dose of docetaxel should be reduced from 100 mg/m
2
to 75 mg/m
2
and/or from
75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment
should be discontinued.
42
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/m
2
in all
subsequent cycles (see sections 4.4 and 4.8). Patients who experience Grade 3 or 4 stomatitis should
have their dose decreased to 60 mg/m².
In combination with cisplatin
For patients who are dosed initially at docetaxel 75 mg/m
2
in combination with cisplatin and whose
nadir of platelet count during the previous course of therapy is <25,000 cells/mm
3
, or in patients who
experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxel
dose in subsequent cycles should be reduced to 65 mg/m
2
. For cisplatin dose adjustments, see the
corresponding summary of product characteristics.
In combination with capecitabine
•
For capecitabine dose modifications, see capecitabine summary of product characteristics.
•
For patients developing the first appearance of Grade 2 toxicity, which persists at the time of the
next docetaxel/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume
at 100% of the original dose.
•
For patients developing the second appearance of Grade 2 toxicity, or the first appearance of
Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to
Grade 0-1 and then resume treatment with docetaxel 55 mg/m².
•
For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the
docetaxel dose.
For trastuzumab dose modifications, see trastuzumab summary of product characteristics.
In combination with cisplatin and 5-fluorouracil
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite
G-CSF use, the docetaxel dose should be reduced from 75 to 60 mg/m
2
. If subsequent episodes of
complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m
2
. In case of
Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m
2
. Patients should
not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level
> 1,500 cells/mm
3
and platelets recover to a level > 100,000 cells/mm
3
. Discontinue treatment if these
toxicities persist. (see section 4.4).
Recommended dose modifications for toxicities in patients treated with docetaxel in combination with
cisplatin and 5-fluorouracil (5-FU):
Toxicity
Dose adjustment
First episode: reduce 5-FU dose by 20%.
Diarrhoea grade 3
Diarrhoea grade 4
Second episode: then reduce docetaxel dose by 20%.
First episode: reduce docetaxel and 5-FU doses by 20%.
Stomatitis/mucositis grade 3
Second episode: discontinue treatment.
First episode: reduce 5-FU dose by 20%.
Stomatitis/mucositis grade 4
Second episode: stop 5-FU only, at all subsequent cycles.
Third episode: reduce docetaxel dose by 20%.
First episode: stop 5-FU only, at all subsequent cycles.
Second episode: reduce docetaxel dose by 20%.
For cisplatin and 5-fluorouracil dose adjustments, see the corresponding summary of product
characteristics.
In the pivotal SCCHN studies patients who experienced complicated neutropenia (including prolonged
neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide
prophylactic coverage (eg, day 6-15) in all subsequent cycles.
43
Special populations
Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who have both
elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal
range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of
docetaxel is 75 mg/m
2
(see sections 4.4 and 5.2). For those patients with serum bilirubin >ULN and/or
ALT and AST >3.5 times the ULN associated with alkaline phosphatase >6 times the ULN, no
dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric
adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN
associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x ULN; for these patients, no
dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No
data are available in patients with hepatic impairment treated by docetaxel in combination in the other
indications.
Paediatric population
The safety and efficacy of Docetaxel Teva 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 Teva in the paediatric population in the indications breast
cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not
including type II and III less differentiated nasopharyngeal carcinoma.
Elderly
Based on a population pharmacokinetic analysis, there are no special instructions for use in the
elderly. In combination with capecitabine, for patients 60 years of age or more, a starting dose
reduction of capecitabine to 75% is recommended (see capecitabine summary of product
characteristics).
Hypersensitivity to the active substance or to any of the excipients.
Docetaxel must not be used in patients with baseline neutrophil count of <1,500 cells/mm
3
.
Docetaxel must not be used in patients with severe liver impairment since there is no data available
(see sections 4.2 and 4.4).
For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as
dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel
administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well
as the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral
dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).
Haematology
Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median
of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of
complete blood counts should be conducted on all patients receiving docetaxel. Patients should be
retreated with docetaxel when neutrophils recover to a level ≥1,500 cells/mm
3
(see section 4.2).
44
In the case of severe neutropenia (<500 cells/mm
3
for seven days or more) during a course of
docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate
symptomatic measures are recommended (see section 4.2).
In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile
neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic
G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of
complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection).
Patients receiving TCF should be closely monitored, (see sections 4.2 and 4.8).
In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC),
febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received
primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive
adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile
neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be
closely monitored (see sections 4.2 and 4.8).
Hypersensitivity reactions
Patients should be observed closely for hypersensitivity reactions especially during the first and
second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation
of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should
be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised
cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe
hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of
docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions
should not be re-challenged with docetaxel.
Cutaneous reactions
Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema
followed by desquamation has been observed. Severe symptoms such as eruptions followed by
desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see
section 4.2).
Fluid retention
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be
monitored closely.
Patients with liver impairment
In patients treated with docetaxel at 100 mg/m
2
as single agent who have serum transaminase levels
(ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels
greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as
toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia,
infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel
in those patients with elevated liver function test (LFTs) is 75 mg/m
2
and LFTs should be measured at
baseline and before each cycle (see section 4.2).
For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent
with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended
and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric
adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN
associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x UNL; for these patients, no
dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No
45
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.
Others
Contraceptive measures must be taken by both men and women during treatment and for ment at least
6 months after cessation of therapy (see section 4.6).
Additional cautions for use in adjuvant treatment of breast cancer
Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or
infection), G-CSF and dose reduction should be considered (see section 4.2).
Gastrointestinal reactions
Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia,
may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated
promptly.
Congestive heart failure
Patients should be monitored for symptoms of congestive heart failure during therapy and during the
follow up period.
Leukaemia
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed
myelodysplasia or myeloid leukaemia requires haematological follow-up.
Patients with 4+ nodes
The benefit/risk ratio for TAC in patients with 4+ nodes was not defined fully at the interim analysis
(see section 5.1).
Elderly
There are limited data available in patients > 70 years of age on docetaxel use in combination with
doxorubicin and cyclophosphamide.
Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study, 209 patients
were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with
docetaxel every three weeks, the incidence of related nail changes occurred at a rate ≥ 10% higher in
patients who were 65 years of age or greater compared to younger patients. The incidence of related
fever, diarrhoea, anorexia, and peripheral oedema occurred at rates ≥ 10% higher in patients who were
75 years of age or greater versus less than 65 years.
46
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.
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 cyclosporine, 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 products has not been investigated formally,
in vitro
interactions with tightly protein-bound drugs such as erythromycin, diphenhydramine, propranolol,
propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein
binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel.
Docetaxel did not influence the binding of digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their
co-administration. Limited data from a single uncontrolled study were suggestive of an interaction
between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was
about 50% higher than values previously reported for carboplatin monotherapy.
Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic
prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4.
No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.
Docetaxel should be administered with caution in patients concomitantly receiving potent CYP3A4
inhibitors (e.g. protease inhibitors like ritonavir, azole antifungals like ketoconazole or itraconazole).
A drug interaction study performed in patients receiving ketoconazole and docetaxel showed that the
clearance of docetaxel was reduced by half by ketoconazole, probably because the metabolism of
docetaxel involves CYP3A4 as a major (single) metabolic pathway. Reduced tolerance of docetaxel
may occur, even at lower doses.
There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be
both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other
cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant
women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.
Women of childbearing potential / contraception:
Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to
inform the treating physician immediately should this occur.
An effective method of contraception should be used during treatment.
In non clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3).
Therefore, men being treated with docetaxel are advised not to father a child during and up to
6 months after treatment and to seek advice on conservation of sperm prior to treatment.
47
Lactation:
Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk.
Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be
discontinued for the duration of docetaxel therapy.
No studies on the effects on the ability to drive and use machines have been performed.
The adverse reactions considered to be possibly or probably related to the administration of docetaxel
have been obtained in:
•
1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent
respectively.
•
258 patients who received docetaxel in combination with doxorubicin.
•
406 patients who received docetaxel in combination with cisplatin.
•
92 patients treated with docetaxel in combination with trastuzumab.
•
255 patients who received docetaxel in combination with capecitabine.
•
332 patients who received docetaxel in combination with prednisone or prednisolone (clinically
important treatment related adverse events are presented).
•
1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received
docetaxel in combination with doxorubicin and cyclophosphamide (clinically important
treatment related adverse events are presented).
•
300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and
79 patients in the phase II part) who received docetaxel in combination with cisplatin and
5-fluorouracil (clinically important treatment related adverse events are presented).
•
174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin
and 5-fluorouracil (clinically important treatment related adverse events are presented).
These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3;
grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA terms. Frequencies are defined as:
very common (≥1/10), common (≥1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); rare (≥1/10,000
to < 1/1,000); very rare (< 1/10,000; not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which was
reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe
neutropenia (<500 cells/mm
3
) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea
and asthenia. The severity of adverse events of docetaxel may be increased when docetaxel is given in
combination with other chemotherapeutic agents.
For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are displayed. There
was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the
trastuzumab combination arm compared to docetaxel monotherapy.
For combination with capecitabine, the most frequent treatment-related undesirable effects (≥ 5%)
reported in a phase III study in breast cancer patients failing anthracycline treatment are presented (see
capecitabine summary of product characteristics).
The following adverse reactions are frequently observed with docetaxel:
48
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 extravasations and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion,
pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower
extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is
cumulative in incidence and severity (see section 4.4).
Docetaxel 100 mg/m² single agent
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infections (G3/4: 5.7%;
including sepsis and
pneumonia, fatal in
1.7%)
Infection associated
with G4 neutropenia
(G3/4: 4.6%)
Blood and lymphatic
system disorders
Neutropenia (G4:
76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia
(G4: 0.2%)
Immune system
disorders
Hypersensitivity (G3/4:
5.3%)
Metabolism and
nutrition disorders
Anorexia
Nerveus system
disorders
Peripheral sensory
neuropathy (G3: 4.1%);
Peripheral motor
49
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
neuropathy (G3/4: 4%)
Dysgeusia (severe
0.07%)
Cardiac disorders
Arrhythmia (G3/4:
0.7%)
Cardiac failure
Hypotension;
Hypertension;
Haemorrhage
Vascular disorders
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea (severe 2.7%)
Stomatitis (G3/4: 5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe
0.2%);
Abdominal pain
(severe 1%);
Gastrointestinal
Haemorrhage (severe
0.3%)
Oesophagitis (severe:
0.4%)
Gastrointestinal
disorders
Alopecia;
Skin reaction (G3/4:
5.9%);
Nail disorders (severe
2.6%)
Skin and subcutaneous
tissue disorders
Musculoskeletal,
connective tissue
disorders
Myalgia (severe 1.4%)
Arthralgia
Fluid retention (severe:
6.5%)
Asthenia (severe
11.2%);
Pain
General disorders and
administration site
conditions
Infusion site reaction;
Non-cardiac chest
pain (severe 0.4%)
G3/4 Blood bilirubin
increased (< 5%);
G3/4 Blood alkaline
phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)
Investigations
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
50
The median cumulative dose to treatment discontinuation was more than 1,000 mg/m
2
and the median
time to fluid retention reversibility was 16.4 weeks (range 0
to 42 weeks). The onset of moderate and
severe retention is delayed (median cumulative dose: 818.9 mg/m
2
) in patients with premedication
compared with patients without premedication (median cumulative dose: 489.7 mg/m
2
); however, it
has been reported in some patients during the early courses of therapy.
Docetaxel 75 mg/m² single agent
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infections (G3/4: 5%)
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4:
1.7%)
Blood and lymphatic system
disorders
Febrile neutropenia
Immune system disorders
Hypersensitivity (no severe)
Metabolism and nutrition
disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders
Arrhythmia (no severe)
Vascular disorders
Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue
disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe 0.8%)
Musculoskeletal and connective
tissue disorders
Myalgia
Asthenia (severe 12.4%);
Fluid retention (severe 0.8%);
Pain
General disorders and
administration site conditions
G3/4 Blood bilirubin increased
(< 2%)
Investigations
51
Docetaxel 75 mg/m² in combination with doxorubicin
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 7.8%)
Blood and lymphatic
system disorders
Neutropenia (G4:
91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia
(G4:0.8%)
Immune system
disorders
Hypersensitivity (G3/4:
1.2%)
Metabolism and
nutrition disorders
Anorexia
Nervous system
disorders
Peripheral sensory
neuropathy (G3: 0.4%)
Peripheral motor
neuropathy (G3/4:
0.4%)
Cardiac failure;
Arrhythmia (no severe)
Cardiac disorders
Vascular disorders
Hypotension
Nausea (G3/4: 5%);
Stomatitis (G3/4:
7.8%);
Diarrhoea (G3/4:
6.2%);
Vomiting (G3/4: 5%);
Constipation
Gastrointestinal
disorders
Alopecia;
Nail disorders (severe
0.4%);
Skin reaction (no
severe)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Myalgia
Asthenia (severe
8.1%);
Fluid retention (severe
1.2%);
Pain
General disorders and
administration site
conditions
Infusion site reaction
Investigations
G3/4 Blood bilirubin
increased (< 2.5%);
G3/4 Blood alkaline
phosphatase increased
(< 2.5%)
G3/4 AST increased
(< 1%);
G3/4 ALT increased
(< 1%
52
Docetaxel 75 mg/m² in combination with cisplatin
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 5.7%)
Blood and lymphatic
system disorders
Neutropenia (G4:
51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia
(G4:0.5%)
Febrile neutropenia
Immune system
disorders
Hypersensitivity (G3/4:
2.5%)
Metabolism and
nutrition disorders
Anorexia
Peripheral sensory
neuropathy (G3: 3.7%);
Peripheral motor
neuropathy (G3/4: 2%)
Nervous system
disorders
Arrhythmia (G3/4:
0.7%)
Cardiac disorders
Cardiac failure
Hypotension (G3/4:
0.7%)
Vascular disorders
Gastrointestinal
disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%);
Constipation
Skin and
subcutaneous tissue
disorders
Alopecia;
Nail disorders (severe
0.7%);
Skin reaction (G3/4:
0.2%)
Musculoskeletal and
connective tissue
disorders
Myalgia (severe: 0.5%)
Asthenia (severe 9.9%);
Fluid retention (severe
0.7%);
Fever (G3/4: 1.2%)
General disorders
and administration
site conditions
Infusion site reaction;
pain
G3/4 AST increased
(0.5%);
G3/4 Blood alkaline
phosphatase increased
(0.3%)
Investigations
G3/4 Blood bilirubin
increased (2.1%);
G3/4 ALT increased
(1.3%)
53
Docetaxel 100 mg/m² in combination with trastuzumab
MedDRA system organ classes
Very common adverse reactions
Common adverse
reactions
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Febrile neutropenia (includes
neutropenia associated with fever
and antibiotic use) or neutropenic
sepsis
Metabolism and nutrition
disorders
Anorexia
Psychiatric disorders
Insomnia
Nervous system disorders
Paresthesia; Headache; Dysgeusia;
Hypoaesthesia
Eye disorders
Lacrimation increased;
Conjunctivitis
Cardiac disorders
Cardiac failure
Vascular disorders
Lymphoedema
Respiratory, thoracic and
mediastinal disorders
Epistaxis; Pharyngolaryngeal pain;
Nasopharyngitis ; Dyspnoea;
Cough; Rhinorrhoea
Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain
Skin and subcutaneous tissue
disorders
Alopecia; Erythema; Rash; Nail
disorders
Musculoskeletal and connective
tissue disorders
Myalgia; Arthralgia; Pain in
extremity; Bone pain; Back pain
General disorders and
administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal
inflammation; Pain; Influenza like
illness; Chest pain; Chills
Lethargy
Investigations
Weight increased
Cardiac disorders
Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus
trastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm,
64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm
alone.
Blood and lymphatic system disorders
Very common: Haematological toxicity was increased in patients receiving trastuzumab and
docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC
criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m
2
is
known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The
incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with
Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).
54
Docetaxel 75 mg/m² in combination with capecitabine
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Oral candidiasis (G3/4: < 1%)
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Blood and lymphatic system
disorders
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Dizziness;
Headache (G3/4: <1%);
Neuropathy peripheral
Nervous system disorders
Dysgeusia (G3/4: <1%);
Paresthesia (G3/4: <1%)
Eye disorders
Lacrimation increased
Dyspnoea (G3/4: 1%);
Cough (G3/4: <1%);
Epistaxis (G3/4: <1%)
Respiratory, thoracic and
mediastinal disorders
Pharyngolaryngeal pain (G3/4:
2%)
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Gastrointestinal disorders
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue
disorders
Hand-foot syndrome (G3/4:
24%)
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4:
<1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective
tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: <1%);
Back pain (G3/4: 1%);
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/ weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%);
General disorders and
administration site conditions
Lethargy;
Pain
Investigations
Weight decreased;
G3/4 Blood bilirubin increased
(9%)
55
Docetaxel 75 mg/m² in combination with prednisone or prednisolone
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infection (G3/4: 3.3%)
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia (G3/4:
0.6%)
Febrile neutropenia
Immune system disorders
Hypersensivity (G3/4: 0.6%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 0.6%)
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Nervous system disorders
Peripheral motor neuropathy
(G3/4: 0%)
Lacrimation increased (G 3/4;
0.6%)
Eye disorders
Cardiac disorders
Cardiac left ventricular function
decrease (G3/4: 0.3%)
Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Respiratory, thoracic and
mediastinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4:
0.9%);
Vomiting (G3/4: 1.2%)
Gastrointestinal disorders
Skin and subcutaneous tissue
disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective
tissue disorders
Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and
administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe 0.6%)
56
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
Common adverse
reactions
Uncommon adverse
reactions
Infection (G3/4: 2.4%);
Neutropenic infection.
(G3/4: 2.7%).
Infections and
infestations
Anaemia (G3/4: 3%);
Neutropenia (G3/4:
59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4: NA)
Blood and lymphatic
system disorders
Immune system
disorders
Hypersensitivity (G3/4:
0.6%)
Metabolism and
nutrition disorders
Anorexia (G3/4: 1.5%)
Dysgeusia (G3/4:
0.6%);
Peripheral sensory
neuropathy (G3/4:
<0.1%)
Nervous system
disorders
Peripheral motor
neuropathy
(G3/4: 0%);
Syncope (G3/4: 0%)
Neurotoxicity (G3/4:
0%)
Somnolence (G3/4:
0%)
Eye disorders
Conjunctivitis (G3/4:
<0.1%)
Lacrimation increased
(G3/4: <0.1%);
Cardiac disorders
Arrhythmia (G3/4:
0.2%);
Vascular disorders
Hot flush (G3/4: 0.5%)
Hypotension (G3/4:
0%)
Phlebitits (G3/4: 0%)
Lymphoedema (G3/4:
0%)
Respiratory, thoracic
and mediastinal
disorders
Cough (G3/4: 0%)
Nausea (G3/4: 5.0%);
Stomatitis (G3/4:
6.0%);
Vomiting (G3/4:
4.2%);
Diarrhoea (G3/4:
3.4%);
Constipation (G3/4:
0.5%)
Gastrointestinal
disorders
Abdominal pain (G3/4:
0.4%)
Alopecia (G3/4:
<0.1%);
Skin toxicity (G3/4:
0.6%);
Nail disorders (G3/4:
0.4%)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4:
0.2%)
Reproductive system
Amenorrhoea (G3/4:
57
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
and breast disorders
NA)
General disorders and
administration site
conditions
Asthenia (G3/4:
10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral
(G3/4: 0.2%)
Weight increased
(G3/4: 0%)
Investigations
Weight decreased
(G3/4: 0.2%)
Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in 12 patients out of the
83 patients with peripheral sensory neuropathy at the end of the chemotherapy.
Cardiac disorders
Congestive Heart Failure (CHF) has been reported in 18 of 1276 patients during the follow-up period.
In the node positive study (TAX316) one patient in each treatment arm died due to cardiac failure.
Skin and subcutaneous tissue disorders
Alopecia was observed to be ongoing during follow-up time in 25 patients out of the 736 patients with
alopecia at the end of the chemotherapy.
Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing during follow-up 140 patients out of the 251 patients with
amenorrhoea at the end of the chemotherapy.
General disorders and administration site conditions
Peripheral oedema was observed to be ongoing during follow-up time in 18 patients out of the
112 patients with peripheral oedema at the end of the chemotherapy in study TAX 316, whereas
lymphoedema was observed to be ongoing in 4 of the 5 patients with lymphoedema at the end of the
chemotherapy in the study GEICAM 9805.
Acute leukaemia / Myelodysplastic syndrome.
At a median follow-up time of 77 months, acute leukaemia occurred in 1 of 532 (0.2%) patients who
received docetaxel, doxorubicin, and cyclophosphamide in the GEICAM 9805 study. No cases were
reported in patients who received fluorouracil, doxorubicin and cyclophosphamide. No patient was
diagnosed with myelodysplastic syndrome in either treatment groups
Table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic
infection was decreased in patients who received primary G-CSF prophylaxis after it was made
mandatory in the TAC arm. – GEICAM study.
Neutropenic complications in patients receiving TAC with or without primary G-CSF prophylaxis
(GEICAM 9805)
Without primary
G-CSF prophylaxis
(n = 111)
n (%)
With primary
G-CSF prophylaxis
(n = 421)
n (%)
Neutropenia (Grade 4)
104 (93.7)
135 (32.1)
Febrile neutropenia
28 (25.2)
23 (5.5)
58
Neutropenic infection
14 (12.6)
21 (5.0)
Neutropenic infection
(Grade 3-4)
2 (1.8)
5 (1.2)
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for gastric adenocarcinoma
cancer:
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Neutropenic infection;
Infection (G3/4: 11.7%)
Blood and lymphatic system
disorders
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4:
8.8%);
Febrile neutropenia.
Immune system disorders
Hypersensitivity (G3/4: 1.7%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 11.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%).
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%).
Lacrimation increased (G3/4:
0%).
Eye disorders
Ear and labyrinth disorders
Hearing impaired (G3/4: 0%).
Cardiac disorders
Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%).
Constipation (G3/4: 1.0 %);
Gastrointestinal pain (G3/4:
1.0%);
Oesophagitis / dysphagia /
odynophagia (G3/4: 0.7%).
Skin and subcutaneous tissue
disorders
Alopecia (G3/4: 4.0%).
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%).
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention (severe/life
threatening: 1%).
General disorders and
administration site conditions
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).
59
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for Head and Neck cancer
•
Induction chemotherapy followed by radiotherapy (TAX 323)
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 6.3%);
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Cancer pain (G3/4:
0.6%)
Neutropenia (G3/4:
76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Blood and lymphatic
system
disorders
Febrile neutropenia
Immune system
disorders
Hypersensitivity (no
severe)
Metabolism and
nutrition disorders
Anorexia (G3/4: 0.6%)
Dysgeusia/Parosmia;
Peripheral sensory
neuropathy
(G3/4: 0.6%)
Nervous system
disorders
Dizziness
Lacrimation increased;
Conjunctivitis
Eye disorders
Ear and labyrinth
disorders
Hearing impaired
Cardiac disorders
Myocardial ischemia
(G3/4: 1.7%)
Arrhythmia (G3/4:
0.6%)
Venous disorder (G3/4:
0.6%)
Vascular disorders
Constipation;
Oesophagitis/dysphagia/
Odynophagia (G3/4:
0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal
haemorrhage (G3/4:
0.6%)
Gastrointestinal
disorders
Nausea (G3/4: 0.6%)
Stomatitis (G3/4:
4.0%)
Diarrhoea (G3/4:
2.9%)
Vomiting (G3/4: 0.6%)
Rash pruritic;
Dry skin;
Skin exfoliative (G3/4:
0.6%)
Skin and subcutaneous
tissue disorders
Alopecia (G3/4:
10.9%)
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.6%)
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema
General disorders and
administration site
conditions
Investigations
Weight increased
60
•
Induction chemotherapy followed by chemoradiotherapy (TAX 324)
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestation
Infection (G3/4: 3.6%)
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl
cysts and polyps)
Cancer pain (G3/4:
1.2%)
Neutropenia (G3/4:
83.5%);
Anaemia (G3/4:
12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia
Blood and the
lymphatic system
disorders
Immune system
disorders
Hypersensitivity
Metabolism and
nutrition disorders
Anorexia (G3/4: 12.0%)
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory
neuropathy
(G3/4: 1.2%)
Nervous system
disorders
Dizziness (G3/4: 2.0%);
Peripheral motor
neuropathy (G3/4: 0.4%)
Eye disorders
Lacrimation increased
Conjunctivitis
Ear and labyrinth
disorders
Hearing impaired
(G3/4: 1.2%)
Arrhythmia (G3/4:
2.0%)
Ischemia myocardial
Cardiac disorders
Vascular disorders
Venous disorder
Nausea (G3/4:13.9%);
Stomatitis (G3/4:
20.7%);
Vomiting (G3/4: 8.4%);
Diarrhoea (G3/4: 6.8%);
Oesophagitis/dysphagia/
Odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Gastrointestinal
disorders
Dyspepsia (G3/4: 0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal
haemorrhage (G3/4:
0.4%)
Skin and subcutaneous
tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritic;
Dry skin;
Desquamation
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.4%)
General disorders and
administration site
conditions
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)
Investigations
Weight decreased
Weight increased
61
Post-marketing experience
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Very rare cases of acute myeloid leukaemia
and myelodysplastic syndrome
have been reported in
association with docetaxel when used in combination with other chemotherapy agents and/or
radiotherapy.
Blood and lymphatic system disorders
Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated
intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been
reported.
Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel
administration. These reactions sometimes appear during the infusion of the medicinal product.
Eye Disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring
during infusion of the medicinal product and in association with hypersensitivity reactions have been
reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or
without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been
rarely reported.
Ear and labyrinth disorders
Rare cases of ototoxicity, hearing impaired and/or hearing loss have been reported.
Cardiac disorders
Rare cases of myocardial infarction have been reported.
Vascular disorders
Venous thromboembolic events have rarely been reported.
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome, interstitial pneumonia and pulmonary fibrosis have rarely been
reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant
radiotherapy.
Gastrointestinal disorders
Rare occurrences of dehydration as a consequence of gastrointestinal events, gastrointestinal
perforation, colitis ischaemic, colitis and neutropenic enterocolitis have been reported. Rare cases of
ileus and intestinal obstruction have been reported.
Hepatobiliary disorders
Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders,
have been reported.
Skin and subcutaneous tissue disorders
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some
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.
62
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.
There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of
overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In
cases of overdose, exacerbation of adverse events may be expected. The primary anticipated
complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and
mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose.
Other appropriate symptomatic measures should be taken, as needed.
5.1 Pharmacodynamicproperties
Pharmacotherapeutic group: Taxanes, ATC Code: L01CD 02
Preclinical data
Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable
microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The
binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown
in vitro
to disrupt the microtubular network in cells which is essential for
vital mitotic and interphase cellular functions.
Docetaxel was found to be cytotoxic
in vitro
against various murine and human tumour cell lines and
against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular
concentrations with a long cell residence time. In addition, docetaxel was found to be active on some
but not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistance
gene.
In vivo
, docetaxel is schedule independent and has a broad spectrum of experimental antitumour
activity against advanced murine and human grafted tumours.
Clinical data
Breast cancer
Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy
Patients with operable node-positive breast cancer (TAX 316)
Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant
treatment of patients with operable node-positive breast cancer and KPS ≥ 80%, between 18 and
70
years of age. After stratification according to the number of positive lymph nodes (1-3, 4+),
1491 patients were randomized to receive either docetaxel 75 mg/m
2
administered 1-hour after
doxorubicin 50 mg/m
2
and cyclophosphamide 500 mg/m
2
(TAC arm), or doxorubicin 50 mg/m
2
followed by fluorouracil 500 mg/m
2
and cyclophosphamide 500 mg/m
2
(FAC arm). Both regimens
were administered once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion;
all other medicinal products were given as intravenous bolus on day one. G-CSF was administered as
secondary prophylaxis to patients who experienced complicated neutropenia (febrile neutropenia,
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
63
according to guidelines in place at participating institutions and was given to 69% of patients who
received TAC and 72% of patients who received FAC.
An interim analysis was performed with a median follow up of 55 months. Significantly longer
disease-free survival for the TAC arm compared to the FAC arm was demonstrated. Incidence of
relapses at 5 years was reduced in patients receiving TAC compared to those who received FAC (25%
versus 32%, respectively) i.e. an absolute risk reduction by 7% (p=0.001). Overall survival at 5 years
was also significantly increased with TAC compared to FAC (87% versus 81%, respectively) i.e. an
absolute reduction of the risk of death by 6% (p=0.008). TAC-treated patient subsets according to
prospectively defined major prognostic factors were analyzed:
Disease free furvival
Overall furvival
Patient subset
Number
of
patients
Hazard
ratio*
95% CI
P=
Hazard
ratio*
95% CI
P=
No of positive
nodes
Overall 745 0.72 0.59-0.88 0.001 0.70 0.53-0.91 0.008
1-3 467 0.61 0.46-0.82 0.0009 0.45 0.29-0.70 0.0002
4+ 278 0.83 0.63-1.08 0.17 0.94 0.66-1.33 0.72
*a hazard ratio of less than 1 indicates that TAC is associated with a longer disease-free survival and
overall survival compared to FAC
The beneficial effect of TAC was not proven in patients with 4 and more positive nodes (37% of the
population) at the interim analysis stage. The effect appears to be less pronounced than in patients with
1-3 positive nodes. The benefit/risk ratio was not defined fully in patients with 4 and more positive
nodes at this analysis stage.
Patients with operable node
-
negative breast cancer eligible to receive chemotherapy (GEICAM 9805)
Data from a multicenter open label randomized trial support the use of Docetaxel 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/m
2
administered 1-hour after
doxorubicin 50 mg/m
2
and cyclophosphamide 500 mg/m
2
(539 patients in TAC arm), or doxorubicin
50 mg/m
2
followed by fluorouracil 500 mg/m
2
and cyclosphosphamide 500 mg/m
2
(521 patients in AC
arm), as adjuvant treatment of operable node-negative breast cancer patients with high risk of relapse
according to 1998 St. Gallen criteria (tumour size >2 cm and/or negative ER and PR and/or high
histological/nuclear grade (grade 2 to 3) and /or age <35 years). Both regimens were administered
once every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion, all other drugs
were given as intraveinously on day 1 every three weeks. Primary prophylactic G-CSF was made
mandatory in TAC arm after 230 patients were randomized. The incidence of Grade 4 neutropenia,
febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF
prophylaxis (see section 4.8). In both arms, after the last cycle of chemotherapy, patients with ER+
and/or PgR+ tumours received tamoxifen 20 mg once a day for up to 5 years. Adjuvant radiation
therapy was administered according to guidelines in place at participating institutions and was given to
57.3% of patients who received TAC and 51.2% of patients who received FAC.
Median duration of follow-up was 77 months. Significantly longer disease-free survival for the TAC
arm compared to the FAC arm was demonstrated. TAC-treated patients had a 32% reduction in the
risk of relapse compared to those treated with FAC (hazard ratio = 0.68, 95% CI (0.49-0.93), p=0.01).
Overall survival (OS) was also longer in the TAC arm with TAC-treated patients having a 24%
reduction in the risk of death compared to FAC (hazard ratio = 0.76, 95% CI (0.46-1.26, p=0.29).
However, the distribution of OS was not significantly different between the 2 groups.
TAC-treated patient subsets according to prospectively defined major prognostic factors were
analyzed (see table below):
64
Subset Analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study (Intent-to-
Treat Analysis)
Patient subset
Number of patients
in TAC group
Disease Free Survival
Hazard ratio*
95% CI
Overall
539
0.68
0.49-0.93
Age category 1
<50 years
>
50 years
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
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
216
259
0.79
0.77
0.59
0.24-2.6
0.46-1.3
0.39-0.9
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.
285
254
0.64
0.72
Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallen
chemotherapy criteria – (ITT population) were performed and presented here below
TAC
FAC
Hazard ratio
(TAC/FAC)
Subgroups
(n=539)
(n=521)
(95% CI)
p-value
Meeting relative indication
for chemotherapy
a
No
18/214
(8.4%)
26/227
(11.5%)
0.796
(0.434 - 1.459)
0.4593
Yes
48/325
(14.8%)
69/294
(23.5%)
0.606
(0.42 - 0.877)
0.0072
TAC = docetaxel, doxorubicin and cyclophosphamide
FAC = 5-fluorouracil, doxorubicin and cyclophospamide
CI = confidence interval
ER = estrogen receptor
PR = progesterone receptor
a
ER/PR-negative or Grade 3 or tumor size >5 cm
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.
65
Menopausal status
Pre-Menopausal
Post-Menopausal
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
66
(100 mg/m
2
) with or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant
chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had
received prior adjuvant anthracyclines. The main test method used to determine HER2 positivity in
this pivotal study was immunohistochemistry (IHC). A minority of patients were tested using
fluorescence in-situ hybridization (FISH). In this study, 87% of patients had disease that was IHC 3+,
and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are
summarized in the following table:
Parameter
Docetaxel plus trastuzumab
1
n=92
Docetaxel
1
n=94
Response rate
(95% CI)
61%
(50-71)
34%
(25-45)
Median duration of response
(months)
(95% CI)
11.4
(9.2-15.0)
5.1
(4.4-6.2)
Median TTP (months)
(95% CI)
10.6
(7.6-12.9)
5.7
(5.0-6.5)
22.1
2
(17.6-28.9)
TTP=time to progression; “ne” indicates that it could not be estimated or it was not yet reached.
1
Full analysis set (intent-to-treat)
2
Estimated median survival
30.5
2
(26.8-ne)
Docetaxel in combination with capecitabine
Data from one multicenter, randomised, controlled phase III clinical study support the use of docetaxel
in combination with capecitabine for treatment of patients with locally advanced or metastatic breast
cancer after failure of cytotoxic chemotherapy, including an anthracycline. In this study, 255 patients
were randomised to treatment with docetaxel (75 mg/m
2
as a 1 hour intravenous infusion every
3 weeks) and capecitabine (1250 mg/m
2
twice daily for 2 weeks followed by 1-week rest period).
256 patients were randomised to treatment with docetaxel alone (100 mg/ m
2
as a 1 hour intravenous
infusion every 3 weeks). Survival was superior in the docetaxel +capecitabine combination arm
(p=0.0126). Median survival was 442 days (docetaxel + capecitabine) vs. 352 days (docetaxel alone).
The overall objective response rates in the all-randomised population (investigator assessment) were
41.6% (docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive
disease was superior in the docetaxel + capecitabine combination arm (p<0.0001). The median time to
progression was 186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks)
and overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive
Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).
There was less use of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease
related medications (p=0.06) and radiotherapy (p<0.01) in patients treated with docetaxel at 75 mg/m²
compared to those with BSC.
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/m
2
as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m
2
over
30-60 minutes every 3 weeks (TCis), Docetaxel 75 mg/m
2
as a 1 hour infusion in combination with
67
Median survival (months)
(95% CI)
carboplatin (AUC 6 mg/ml. min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m
2
administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m
2
administered on
day 1 of cycles repeated every 4 weeks (VCis).
Survival data, median time to progression and response rates for two arms of the study are illustrated
in the following table:
TCis
n=408
VCis
n=404
Statistical analysis
Overall survival
(Primary end-point):
Median survival (months)
11.3
10.1
Hazard ratio: 1.122
[97.2% CI: 0.937; 1.342]*
1-year Survival (%)
46
41
Treatment difference: 5.4%
[95% CI: -1.1; 12.0]
2-year Survival (%)
21
14
Treatment difference: 6.2%
[95% CI: 0.2; 12.3]
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/m
2
every 3 weeks for 10 cycles.
•
Docetaxel 30 mg/m
2
administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.
•
Mitoxantrone 12 mg/m
2
every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone or prednisolone 5 mg twice daily,
continuously.
Patients who received docetaxel every three weeks demonstrated significantly longer overall survival
compared to those treated with mitoxantrone. The increase in survival seen in the docetaxel weekly
arm was not statistically significant compared to the mitoxantrone control arm. Efficacy endpoints for
the docetaxel arms versus the control arm are summarized in the following table:
Endpoint
Docetaxel
every 3 weeks
Docetaxel
every week
Mitoxantrone
every 3 weeks
Number of patients
Median survival (months)
95% CI
335
18.9
(17.0-21.2)
334
17.4
(15.7-19.0)
337
16.5
(14.4-18.6)
68
Hazard ratio
95% CI
p-value
†
*
0.761
(0.619-0.936)
0.0094
0.912
(0.747-1.113)
0.3624
--
--
--
Number of patients
PSA** response rate (%)
95% CI
p-value*
291
45.4
(39.5-51.3)
0.0005
282
47.9
(41.9-53.9)
<0.0001
300
31.7
(26.4-37.3)
--
Number of patients
Pain response rate (%)
95% CI
p-value*
153
34.6
(27.1-42.7)
0.0107
154
31.2
(24.0-39.1)
0.0798
157
21.7
(15.5-28.9)
--
Number of patients
Tumour response rate
(%)
95% CI
p-value*
141
12.1
(7.2-18.6)
0.1112
134
8.2
(4.2-14.2)
0.5853
137
6.6
(3.0-12.1)
--
†
Stratified log rank test
*Threshold for statistical significance=0.0175
**PSA: Prostate-Specific Antigen
Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every
3 weeks, it is possible that certain patients may benefit from docetaxel every week.
No statistical differences were observed between treatment groups for Global Quality of Life.
Gastric adenocarcinoma
A multicenter, open-label, randomized study, was conducted to evaluate the safety and efficacy of
docetaxel for the treatment of patients with metastatic gastric adenocarcinoma, including
adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for
metastatic disease. A total of 445 patients with KPS>70 were treated with either docetaxel (T)
(75 mg/m
2
on day 1) in combination with cisplatin (C) (75 mg/m
2
on day 1) and 5-fluorouracil (F)
(750 mg/m
2
per day for 5 days) or cisplatin (100 mg/m
2
on day 1) and 5-fluorouracil (1000 mg/m
2
per
day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF
arm.
The median number of cycles administered per patient was 6 (with a range of 1-16) for the TCF arm
compared to 4 (with a range of 1-12) for the CF arm. Time to progression (TTP) was the primary
endpoint. The risk reduction of progression was 32.1% and was associated with a significantly longer
TTP (p=0.0004) in favour of the TCF arm. Overall survival was also significantly longer (p=0.0201)
in favour of the TCF arm with a risk reduction of mortality of 22.7%. Efficacy results are summarized
in the following table:
Efficacy of docetaxel in the treatment of patients with gastric adenocarcinoma
Endpoint
TCF
n=221
CF
n=224
Median TTP (months)
(95%CI)
5.6
(4.86-5.91)
3.7
(3.45-4.47)
Hazard ratio
(95% CI)
*p-value
1.473
(1.189-1.825)
0.0004
Median survival (months)
(95% CI)
2-year estimate (%)
9.2
(8.38-10.58)
18.4
8.6
(7.16-9.46)
8.8
Hazard ratio
(95% CI)
*p-value
1.293
(1.041-1.606)
0.0201
69
Overall response rate (CR+PR) (%)
36.7
25.4
p-value
0.0106
Progressive disease as best overall
Response (%)
16.7
25.9
*Unstratified log rank test
Subgroup analyses across age, gender and race consistently favoured the TCF arm compared to the CF
arm.
A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed
a statistically significant difference although always in favour of the TCF regimen and showed that the
benefit of TCF over CF is clearly observed between 18 and 30 months of follow up.
Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favour
of the TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global
health status on the QLQ-C30 questionnaire (p=0.0121) and a longer time to definitive worsening of
Karnofsky performance status (p=0.0088) compared to patients treated with CF.
Head and neck cancer
•
Induction chemotherapy followed by radiotherapy (TAX323)
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell
carcinoma of the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label,
randomized study (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN,
and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the
docetaxel arm received docetaxel (T) 75 mg/m
2
followed by cisplatin (P) 75 mg/m
2
followed by
5-fluorouracil (F) 750 mg/m
2
per day as a continuous infusion for 5 days. This regimen was
administered every three weeks for 4 cycles in case at least a minor response (≥ 25% reduction in
bidimensionally measured tumour size) was observed after 2 cycles. At the end of chemotherapy, with
a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not
progress received radiotherapy (RT) according to institutional guidelines for 7 weeks (TPF/RT).
Patients on the comparator arm received cisplatin (P) 100 mg/m
2
followed by 5-fluorouracil (F)
1000 mg/m
2
per day for 5 days. This regimen was administered every three weeks for 4 cycles in case
at least a minor response (≥ 25% reduction in bidimensionally measured tumour size) was observed
after 2 cycles. At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval
of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to
institutional guidelines for 7 weeks (PF/RT). Locoregional therapy with radiation was delivered either
with a conventional fraction (1.8 Gy - 2.0 Gy once a day, 5 days per week for a total dose of
66 to 70 Gy), or accelerated/hyperfractionated regimens of radiation therapy (twice a day, with a
minimum interfraction interval of 6 hours, 5 days per week). A total of 70 Gy was recommended for
accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed
following chemotherapy, before or after radiotherapy. Patients on the TPF arm received antibiotic
prophylaxis 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 favour of the TPF arm compared to the PF arm (median OS: 18.6 vs.
14.5 months respectively) with a 28% risk reduction of mortality, p = 0.0128. Efficacy results are
presented in the table below:
Efficacy of docetaxel in the induction treatment of patients
with inoperable locally advanced SCCHN (Intent-to-Treat Analysis)
Endpoint
Docetaxel +
Cis+5-FU
n=177
Cis+5-FU
n=181
Median progression free survival (months)
11.4
8.3
70
(95%CI)
(10.1-14.0)
(7.4-9.1)
Adjusted hazard ratio
(95% CI)
*p-value
0.70
(0.55-0.89)
0.0042
Median survival (months)
(95% CI)
18.6
(15.7-24.0)
14.5
(11.6-18.7)
Hazard ratio
(95% CI)
**p-value
0.72
(0.56-0.93)
0.0128
Best overall response to chemotherapy (%)
(95%CI)
67.8
(60.4-74.6)
53.6
(46.0-61.0)
***p-value
0.006
Best overall response to study treatment
[chemotherapy +/- radiotherapy] (%)
(95%CI)
72.3
(65.1-78.8)
58.6
(51.0-65.8)
***p-value
0.006
Median duration of response to
chemotherapy ± radiotherapy (months)
(95% CI)
n=128
15.7
(13.4-24.6)
n=106
11.7
(10.2-17.4)
Hazard ratio
(95% CI)
**p-value
0.72
(0.52-0.99)
0.0457
A hazard ratio of less than 1 favours docetaxel + cisplatin + 5-FU
*Cox model (adjustment for Primary tumour site, T and N clinical stages and PSWHO)
**Log rank test
*** Chi-square test
Quality of life parameters
Patients treated with TPF experienced significantly less deterioration of their Global health score
compared to those treated with PF (p=0.01, using the EORTC QLQ-C30 scale).
Clinical benefit parameters
The performance status scale, for head and neck (PSS-HN) subscales designed to measure
understandability of speech, ability to eat in public, and normalcy of diet, was significantly in favour
of TPF as compared to PF.
Median time to first deterioration of WHO performance status was significantly longer in the TPF arm
compared to PF. Pain intensity score improved during treatment in both groups indicating adequate
pain management
•
Induction chemotherapy followed by chemoradiotherapy (TAX324)
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced
squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a 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).
71
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
n=255
Cis+5-FU
n=246
Median overall survival (months)
(95%CI)
70.6
(49.0-NA)
30.1
(20.9-51.5)
Hazard ratio
(95% CI)
*p-value
0.70
(0.54-0.90)
0.0058
Median PFS (months)
(95% CI)
35.5
(19.3-NA)
13.1
(10.6-20.2)
Hazard ratio
(95% CI)
**p-value
0.71
(0.56-0.90)
0.004
Best overall response (CR + PR) to
chemotherapy (%)
(95%CI)
71.8
(65.8-77.2)
64.2
(57.9-70.2)
***p-value
0.070
Best overall response (CR + PR) to study
treatment [chemotherapy +/- radiotherapy]
(%)
(95%CI)
76.5
(70.8-81.5)
71.5
(65.5-77.1)
***p-value 0.209
A hazard ratio of less than 1 favours docetaxel + cisplatin + fluorouracil
* Un-adjusted log-rank test
** Un-adjusted log-rank test, not adjusted for multiple comparisons
*** Chi-square test, not adjusted for multiple comparisons
NA-not applicable
5.2
Pharmacokinetic properties
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of
20-115 mg/m
2
in Phase I studies. The kinetic profile of docetaxel is dose independent and consistent
with a three-compartment pharmacokinetic model with half lives for the α, β and γ phases of 4 min,
36 min and 11.1 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel
from the peripheral compartment. Following the administration of a 100 mg/m
2
dose given as a one
hour infusion a mean peak plasma level of 3.7 μg/ml was obtained with a corresponding AUC of
4.6 h.μg/ml. Mean values for total body clearance and steady-state volume of distribution were
21 l/h/m
2
and 113 l, respectively. Inter individual variation in total body clearance was approximately
50%. Docetaxel is more than 95% bound to plasma proteins.
72
A study of
14
C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in
both the urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl
ester group, within seven days, the urinary and faecal excretion accounted for about 6% and 75% of
the administered radioactivity, respectively. About 80% of the radioactivity recovered in faeces is
excreted during the first 48 hours as one major inactive metabolite and 3 minor inactive metabolites
and very low amounts of unchanged medicinal product.
A population pharmacokinetic analysis has been performed with docetaxel in 577 patients.
Pharmacokinetic parameters estimated by the model were very close to those estimated from Phase I
studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient. In a small
number of patients (n=23) with clinical chemistry data suggestive of mild to moderate liver function
impairment (ALT, AST ≥1.5 times the ULN associated with alkaline phosphatase ≥2.5 times the
ULN), total clearance was lowered by 27% on average (see section 4.2). Docetaxel clearance was not
modified in patients with mild to moderate fluid retention and there are no data available in patients
with severe fluid retention.
When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma
levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin
and cyclophosphamide were not influenced by their coadministration.
Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice
versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (C
max
and AUC) and no
effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5’-DFUR.
Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following
monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is
similar to that observed with cisplatin alone.
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid
tumours had no influence on the pharmacokinetics of each individual medicinal product.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard
dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the
pharmacokinetics of docetaxel was observed.
5.3 Preclinical safety data
The carcinogenic potential of docetaxel has not been studied.
Docetaxel has been shown to be mutagenic in the
in vitro
micronucleus and chromosome aberration
test in CHO-K1 cells and in the
in vivo
micronucleus test in the mouse. However, it did not induce
mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent
with the pharmacological activity of docetaxel.
Adverse effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair
male fertility.
6.1 List of excipients
Concentrate
Polysorbate 80
Ethanol, anhydrous
Solvent
73
Water for injections.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
6.6.
6.3 Shelf-life
•
18 months.
•
Premix solution: Chemical and physical in-use stability has been demonstrated for 8 hours when
stored either between 2°C and 8°C or at room temperature (below 25°C). From a
microbiological point of view, the product should be used immediately. If not used immediately,
in-use storage times and conditions prior to use are the responsibility of the user and would
normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled
and validated aseptic conditions.
•
Infusion solution: Chemical and physical in-use stability has been demonstrated for 4 hours at
room temperature (below 25°C). From a microbiological point of view, the product should be
used immediately. If not used immediately, in-use storage times and conditions prior to use are
the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless
dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage and other handling
Do not store above 25°C.
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Each carton contains:
•
One vial of concentrate and,
•
One vial of solvent
•
Docetaxel Teva 80 mg vial
15 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
This vial contains 2.88 ml of a 27.73 mg/ml solution of docetaxel in polysorbate 80 (fill volume:
94.4 mg/3.40 ml). This fill volume has been established during the development of docetaxel to
compensate for liquid loss during preparation of the premix due to foaming, adhesion to the
walls of the vial and "dead-volume". This overfill ensures that after dilution with the entire
contents of the accompanying solvent for docetaxel vial, there is a minimal extractable premix
volume of 8 ml containing 10 mg/ml docetaxel which corresponds to the labelled amount of
80 mg per vial.
Solvent for Docetaxel Teva 80 mg vial
15 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
Solvent vial contains 5.12 ml of water for injections (fill volume: 6.29 ml). The addition of the
entire contents of the solvent vial to the contents of the Docetaxel Teva 80 mg concentrate for
solution for infusion vial ensures a premix concentration of 10 mg/ml docetaxel.
6.6 Special precautions for disposal and other handling
74
Docetaxel Teva 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 Teva concentrate, premix solution or infusion solution should come into contact with
skin, wash immediately and thoroughly with soap and water. If Docetaxel concentrate, premix solution
or infusion solution should come into contact with mucous membranes, wash immediately and
thoroughly with water.
Preparation for the intravenous administration
a)
Preparation of the Docetaxel Teva premix solution (10 mg docetaxel/ml)
If the vials are stored under refrigeration, allow the required number of Docetaxel Teva boxes to stand
at room temperature (below 25°C) for 5 minutes.
Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Teva vial by partially inverting the vial.
Inject the entire contents of the syringe into the corresponding Docetaxel Teva vial.
Remove the syringe and needle and mix manually by repeated inversions for at least 45 seconds. Do
not shake.
Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then check that
the solution is homogenous and clear (foaming is normal even after 5 minutes due to the presence of
polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after preparation.
However the chemical and physical stability of the premix solution has been demonstrated for 8 hours
when stored either between 2°C and 8°C or at room temperature (below 25°C).
b)
Preparation of the infusion solution
More than one premix vial may be necessary to obtain the required dose for the patient. Based on the
required dose for the patient expressed in mg, aseptically withdraw the corresponding premix volume
containing 10 mg/ml docetaxel from the appropriate number of premix vials using graduated syringes
fitted with a needle. For example, a dose of 140 mg docetaxel would require 14 ml docetaxel premix
solution.
Inject the required premix volume into a non-PVC 250 ml infusion bag containing either 5% glucose
solution or sodium chloride 9 mg/ml (0.9%) solution for infusion.
If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so
that a concentration of 0.74 mg/ml docetaxel is not exceeded.
Mix the infusion bag or bottle manually using a rocking motion.
The Docetaxel Teva infusion solution should be used within 4 hours and should be aseptically
administered as a 1-hour infusion under room temperature (below 25°C) and normal lighting
conditions.
As with all parenteral products, Docetaxel Teva premix solution and infusion solution should be
visually inspected prior to use, solutions containing a precipitate should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
75
8. MARKETING AUTHORISATION NUMBER
EU/1/09/611/002
26 January 2010
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
76
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
77
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
Name and address of the manufacturer(s) responsible for batch release
Pharmachemie BV.
Swensweg 5, Postbus 552, 2003 RN Haarlem
The Netherlands
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllő, Táncsics Mihály út 82
Hungary
Teva Kutno SA
Sienkiewicza 25;
99-300 Kutno
Poland
Teva Czech Industries s.r.o
Ostravská 29
Č.p. 305
747 70 Opava-Komárov
Czech Republic
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the
Marketing Authorisation is in place and functioning before and whilst the product is on the market.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
78
ANNEX III
LABELLING AND PACKAGE LEAFLET
79
A. LABELLING
80
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON – 20 mg
1.
Docetaxel Teva 20 mg concentrate and solvent for solution for infusion
docetaxel
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each single-dose vial of Docetaxel Teva concentrate contains 20 mg docetaxel (anhydrous). Each ml
of concentrate contains 27.73 mg docetaxel.
3.
LIST OF EXCIPIENTS
Docetaxel concentrate vial:
polysorbate 80, anhydrous ethanol.
Solvent vial:
water for injections.
See leaflet for further information.
4.
Concentrate and solvent for solution for infusion.
Each carton contains:
•
one vial of 0.72 ml concentrate (20 mg of docetaxel),
•
one vial of 1.28 ml solvent (water for injections).
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
CAUTION: Dilution of concentrate required using the entire contents of the solvent vial.
Reconstituted solution must be further diluted in the infusion diluent before administration.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
KEEP OUT OF THE REACH AND SIGHT OF CHILDREN.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
CYTOTOXIC. To be administered under the supervision of a physician experienced in the use of
cytotoxic agents
81
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C .
Do not freeze
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Single-use vials.
Discard unused contents appropriately
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
12. MARKETINGAUTHORISATIONNUMBER(S)
EU/1/09/611/001
13.
BATCH NUMBER
Batch:
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATIONINBRAILLE
Justification for not including Braille accepted.
82
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL – CONCENTRATE 20 mg
Docetaxel Teva 20 mg concentrate for solution for infusion
docetaxel
2. METHOD OF ADMINISTRATION
Intravenous use.
3. EXPIRY DATE
EXP:
4. BATCH NUMBER
Batch:
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
0.72 ml (Fill: 0.88 ml)
6. OTHER
83
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL – SOLVENT FOR 20 mg
Solvent for Docetaxel Teva 20 mg
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP:
4. BATCH NUMBER
Batch:
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
water for injections
1.28 ml (Fill: 1.71 ml)
6. OTHER
84
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON – 80 mg
1.
Docetaxel Teva 80 mg concentrate and solvent for solution for infusion
docetaxel
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each single dose vial of of Docetaxel Teva concentrate contains 80 mg docetaxel (anhydrous). Each
ml of concentrate contains 27.73 mg docetaxel.
3.
LIST OF EXCIPIENTS
Docetaxel concentrate vial:
polysorbate 80, anhydrous ethanol
Solvent vial:
water for injections.
See leaflet for further information.
4.
Concentrate and solvent for solution for infusion.
Each carton contains:
•
one vial (2.88 ml) of concentrate (80 mg of docetaxel),
•
one vial (5.12 ml) of solvent (water for injections).
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
CAUTION: Dilution of concentrate required using the entire contents of the solvent vial.
Reconstituted solution must be further diluted in the infusion diluent before administration.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
KEEP OUT OF THE REACH AND SIGHT OF CHILDREN.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
85
CYTOTOXIC. To be administered under the supervision of a physician experienced in the use of
cytotoxic agents
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
Do not freeze
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Single-use vials.
Discard unused contents appropriately
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
12. MARKETINGAUTHORISATIONNUMBER(S)
EU/1/09/611/002
13. BATCHNUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATIONINBRAILLE
Justification for not including Braille accepted.
86
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL – CONCENTRATE 80 mg
Docetaxel Teva 80 mg concentrate for solution for infusion
docetaxel
2. METHOD OF ADMINISTRATION
Intravenous use
3. EXPIRY DATE
EXP:
4. BATCH NUMBER
Batch:
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
2.88 ml (Fill: 3.40 ml)
6. OTHER
87
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL – SOLVENT FOR 80 mg
Solvent for Docetaxel Teva 80 mg
2. METHOD OF ADMINISTRATION
3. EXPIRY DATE
EXP:
4. BATCH NUMBER
Batch:
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
water for injections
5.12 ml (Fill: 6.29 ml)
6. OTHER
88
B. PACKAGE LEAFLET
89
PACKAGE LEAFLET: INFORMATION FOR THE USER
Docetaxel Teva 20 mg concentrate and solvent for solution for infusion
docetaxel
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet,
please tell your doctor or hospital pharmacist.
In this leaflet
1.
What Docetaxel Teva is and what it is used for
2.
Before you use Docetaxel Teva
3.
How to use Docetaxel Teva
4.
Possible side effects
5.
How to store Docetaxel Teva
6.
Further information
1. WHAT DOCETAXEL TEVA IS AND WHAT IT IS USED FOR
The name of this medicine is Docetaxel Teva. Docetaxel is a substance derived from the needles of
yew trees.
Docetaxel belongs to the group of anti-cancer medicines called taxoids.
Docetaxel Teva has been prescribed by your doctor for the treatment of breast cancer, special forms of
lung cancer (non-small cell lung cancer), prostate cancer, gastric cancer or head and neck cancer:
-
For the treatment of advanced breast cancer, Docetaxel Teva could be administered either alone
or in combination with doxorubicin, or trastuzumab, or capecitabine.
-
For the treatment of early breast cancer with or without lymph node involvement, Docetaxel
Teva could be administered in combination with doxorubicin and cyclophosphamide.
-
For the treatment of lung cancer, Docetaxel Teva could be administered either alone or in
combination with cisplatin.
-
For the treatment of prostate cancer, Docetaxel Teva is administered in combination with
prednisone or prednisolone.
-
For the treatment of metastatic gastric cancer, Docetaxel Teva is administered in combination
with cisplatin and 5-fluorouracil.
-
For the treatment of head and neck cancer, Docetaxel Teva is administered in combination with
cisplatin and 5-fluorouracil.
2. BEFORE YOU USE DOCETAXEL TEVA
You must NOT be given Docetaxel Teva if
•
you are allergic (hypersensitive) to docetaxel or any of the other ingredients of Docetaxel Teva
•
the number of white blood cells is too low
•
you have a severe liver disease
Take special care with Docetaxel Teva
Before each treatment with Docetaxel Teva, you will have blood tests to check that you have enough
blood cells and sufficient liver function to receive Docetaxel Teva. In case of white blood cell
disturbances, you may experience associated fever or infections.
90
-
If you have any further questions, ask your doctor or your hospital pharmacist.
You will be asked to take premedication consisting of an oral corticosteroid such as dexamethasone,
one day prior to Docetaxel Teva administration and to continue for one or two days after it in order to
minimise certain undesirable effects which may occur after the infusion of Docetaxel Teva in
particular allergic reactions and fluid retention (swelling of the hands, feet, legs or weight gain).
During treatment, you may be given other medicines to maintain the number of your blood cells.
Taking other medicines
Please tell your doctor or hospital pharmacist if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription. This is because Docetaxel Teva or
other medicines may not work as well as expected and you may be more likely to get a side effect.
Pregnancy
Ask your doctor for advice before being given any medicine.
Docetaxel Teva must
NOT
be administered if you are pregnant unless clearly indicated by your
doctor.
You must not become pregnant during treatment with this medicine and must use an effective method
of contraception during therapy because Docetaxel Teva may be harmful for the unborn baby. If
pregnancy occurs during your treatment, you must immediately inform your doctor.
If you are a man being treated with Docetaxel Teva you 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 because
docetaxel may alter male fertility.
Breast-feeding
You must not breast-feed while you are treated with Docetaxel Teva.
Driving and using machines
There is no reason why you cannot drive between courses of Docetaxel Teva except if you feel dizzy
or are unsure of yourself.
3. HOW TO USE DOCETAXEL TEVA
Docetaxel Teva will be administered to you by a healthcare professional.
Usual dose
The dose will depend on your weight and your general condition. Your doctor will calculate your body
surface area in square meters (m²) and will determine the dose you should receive.
Method and route of administration
Docetaxel Teva will be given by infusion into one of your veins (intravenous use). The infusion will
last approximately one hour during which you will be in the hospital.
Frequency of administration
You should usually receive your infusion once every 3 weeks.
Your doctor may change the dose and frequency of dosing depending on your blood tests, your
general condition and your response to Docetaxel Teva. In particular, please inform your doctor in
case of diarrhoea, sores in the mouth, feeling of numbness or pins and needles, fever and give her/him
91
results of your blood tests. Such information will allow her/him to decide whether a dose reduction is
needed. If you have any further questions on the use of this medicine, ask your doctor or hospital
pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Docetaxel Teva can cause side effects, although not everybody gets them.
Your doctor will discuss these with you and will explain the potential risks and benefits of your
treatment.
The frequency of possible side effects listed below is defined using the following convention: very
common (affects more than 1 user in 10); common (affects 1 to 10 users in 100); uncommon (affects 1
to 10 users in 1,000); rare (affects 1 to 10 users in 10,000); very rare (affects less than 1 user in
10,000); not known (frequency cannot be estimated from the available data).
The most commonly reported adverse reactions of Docetaxel Teva alone are: decrease in the number
of red blood cells or white blood cells, hair loss, nausea, vomiting, sores in the mouth, diarrhoea and
tiredness.
The severity of adverse events of Docetaxel Teva may be increased when Docetaxel Teva is given in
combination with other chemotherapeutic agents.
During the infusion at the hospital the following allergic reactions
(experienced in more than 1
person in 10)
may occur:
•
flushing, skin reactions, itching,
•
chest tightness; difficulty in breathing,
•
fever or chills,
•
back pain
•
low blood pressure
More severe reactions may occur.
The hospital staff will monitor your condition closely during treatment. Tell them immediately if you
notice any of these effects.
Between infusions of Docetaxel Teva the following may occur, and the frequency may vary with the
combinations of medicines that are received:
Very common (experienced in more than 1 in 10 patients)
•
infections, decrease in the number of red (anaemia), or white blood cells (which are important in
fighting infection) and platelets,
•
fever: if this happens you must tell your doctor immediately
•
allergic reactions as described above
•
loss of appetite (anorexia)
•
insomnia
•
feeling of numbness or pins and needles or pain in the joints or muscles
•
headache
•
alteration in sense of taste
•
inflammation of the eye or increased tearing of the eyes
•
swelling caused by faulty lymphatic drainage
•
shortness of breath
•
nasal drainage; inflammation of the throat and nose; cough
•
bleeding from the nose
•
sores in the mouth
•
stomach upsets including nausea, vomiting and diarrhoea, constipation
92
•
abdominal pain
•
indigestion
•
short term hair loss (in most cases normal hair growth should return)
•
redness and swelling of the palms of your hands or soles of your feet which may cause your skin
to peel (this may also occur on the arms, face, or body)
•
change in the colour of your nails, which may detach
•
muscle aches and pains; back pain or bone pain
•
change or absence of menstrual period
•
swelling of the hands, feet, legs
•
tiredness; or flu-like symptoms
•
weight gain or loss.
Common (experienced in less than 1 in 10 but more than 1 in 100 patients)
•
oral candidiasis
•
dehydration
•
dizziness
•
hearing impaired
•
decrease in blood pressure; irregular or rapid heart beat
•
heart failure
•
oesophagatis
•
dry mouth
•
difficulty or painful swallowing
•
haemorrhage
•
raised liver enzymes (hence the need for regular blood tests).
Uncommon
(experienced in more than 1 in 1,000 but less than 1 in 100 patients)
•
fainting
•
at the injection site, skin reactions, phlebitis (inflammation of the vein) or swelling
•
inflammation of the colon, small intestine; intestinal perforation
•
blood clots.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or hospital pharmacist.
5. HOW TO STORE DOCETAXEL TEVA
Keep out of the reach and sight of children.
Docetaxel Teva should not be used after the expiry date which is stated on the carton and vials.
Do not store above 25°C.
Do not freeze.
Store in the original package in order to protect from light.
The premix solution should be used immediately after preparation. However the chemical and physical
stability of the premix solution has been demonstrated for 8 hours when stored either between 2°C
and 8°C or at room temperature (below 25°C).
The infusion solution should be used within 4 hours at room temperature (below 25°C).
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
93
6. FURTHER INFORMATION
What Docetaxel Teva concentrate vial contains:
-
The active substance is docetaxel. Each vial of Docetaxel Teva concentrate contains 20 mg of
docetaxel. Each ml of concentrate contains 27.73 mg docetaxel.
-
The other ingredients are polysorbate 80 and 25.1% (w/w) anhydrous ethanol.
What the solvent vial contains:
Water for injections.
What Docetaxel Teva looks like and contents of the pack:
Docetaxel Teva concentrate for solution for infusion is a clear viscous, yellow to brown-yellow
solution.
Each carton contains:
•
one 6 ml clear glass vial with a flip-off cap containing 0.72 ml concentrate and,
•
one 6 ml clear glass vial with a flip-off cap containing 1.28 ml of solvent.
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturer:
Pharmachemie B.V.
Swensweg 5
PO Box 552
2003 RN Haarlem, The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
H-2100 Gödöllő,
Hungary
Teva Kutno SA
Sienkiewicza 25;
99-300 Kutno
Poland
Teva Czech Industries s.r.o
Ostravská 29
Č.p. 305
747 70 Opava-Komárov
Czech Republic
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél: +32 3 820 73 73
94
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
95
This leaflet was last approved in
{
MM/YYYY
}
.
Detailed information on this medicine is available on the website of the European Medicines Agency
96
The following information is intended for medical or healthcare professional only:
PREPARATION GUIDE FOR USE WITH DOCETAXEL TEVA 20 mg CONCENTRATE
AND SOLVENT FOR SOLUTION FOR INFUSION
__________________________________________________________________________
It is important that you read the entire contents of this procedure prior to the preparation of either the
Docetaxel Teva premix solution or the Docetaxel Teva infusion solution
1. FORMULATION
Docetaxel Teva 20 mg concentrate for solution for infusion is a clear viscous, yellow to brown-yellow
solution containing 27.73 mg/ml docetaxel (anhydrous) in polysorbate 80. The solvent for Docetaxel
Teva is water for injections.
2. PRESENTATION
Docetaxel Teva is supplied as single-dose vials.
Each box contains one Docetaxel Teva vial (20 mg) and one corresponding solvent for Docetaxel
Teva vial in a carton.
Docetaxel Teva vials should not be stored above 25°C and should be protected from light.
Docetaxel Teva should not be used after the expiry date shown on the carton and vials.
2.1 Docetaxel 20 mg vial:
•
The Docetaxel 20 mg vial is a 6 ml clear glass vial with a bromobutyl rubber stopper and a
flip-off cap.
•
The Docetaxel 20 mg vial contains a solution of docetaxel in polysorbate 80 at a concentration
of 27.73 mg/ml.
•
Each vial contains 20 mg/0.72 ml of a 27.73 mg/ml solution of docetaxel in polysorbate 80 (fill
volume: 24.4 mg/0.88 ml). This fill volume has been established during the development of
docetaxel to compensate for liquid loss during preparation of the premix due to foaming,
adhesion to the walls of the vial and "dead-volume". This overfill ensures that after dilution with
the entire contents of the accompanying solvent for docetaxel vial, there is a minimal extractable
premix volume of 2 ml containing 10 mg/ml docetaxel which corresponds to the labelled
amount of 20 mg per vial.
2.2 Solvent for Docetaxel 20 mg vial:
•
The solvent for Docetaxel 20 mg vial is a 6 ml clear glass vial with a bromobutyl rubber stopper
and a flip-off cap.
•
The solvent for Docetaxel composition is water for injections.
•
Each solvent vial contains 1.28 ml of water for injections (fill volume: 1.71 ml). The addition of
the entire contents of the solvent vial to the contents of the Docetaxel concentrate for solution
for infusion vial ensures a premix concentration of 10 mg/ml docetaxel.
3. RECOMMENDATIONS FOR THE SAFE HANDLING
97
Docetaxel Teva is an antineoplastic agent and, as with other potentially toxic compounds, caution
should be exercised when handling it and preparing Docetaxel Teva solutions. The use of gloves is
recommended.
If Docetaxel Teva concentrate, premix solution or infusion solution should come into contact with
skin, wash immediately and thoroughly with soap and water. If Docetaxel Teva concentrate, premix
solution or infusion solution should come into contact with mucous membranes, wash immediately
and thoroughly with water.
4. PREPARATION FOR THE INTRAVENOUS ADMINISTRATION
4.1 Preparation of the Docetaxel Teva premix solution (10 mg docetaxel/ml)
4.1.1
If the vials are stored under refrigeration, allow the required number of Docetaxel Teva boxes
to stand at room temperature (below 25°C) for 5 minutes.
4.1.2
Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Teva vial by partially inverting the vial.
4.1.3
Inject the entire contents of the syringe into the corresponding Docetaxel Teva vial.
4.1.4
Remove the syringe and needle and mix manually by repeated inversions for at least 45
seconds. Do not shake.
4.1.5
Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then
check that the solution is homogenous and clear (foaming is normal even after 5 minutes due
to the presence of polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after
preparation. However the chemical and physical stability of the premix solution has been
demonstrated for 8 hours when stored either between +2°C and +8°C or at room temperature
(below 25°C).
4.2 Preparation of the infusion solution
4.2.1
More than one premix vial may be necessary to obtain the required dose for the patient. Based
on the required dose for the patient expressed in mg, aseptically withdraw the corresponding
premix volume containing 10 mg/ml docetaxel from the appropriate number of premix vials
using graduated syringes fitted with a needle. For example, a dose of 140 mg docetaxel would
require 14 ml docetaxel premix solution.
4.2.2
Inject the required premix volume into a 250 ml non-PVC infusion bag containing either 5%
glucose solution or sodium chloride 9 mg/ml (0.9%) solution for infusion. If a dose greater
than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a
concentration of 0.74 mg/ml docetaxel is not exceeded.
4.2.3
Mix the infusion bag or bottle manually using a rocking motion.
4.2.4
The Docetaxel Teva infusion solution should be used within 4 hours and should be aseptically
administered as a 1-hour infusion under room temperature (below 25°C) and normal lighting
conditions.
4.2.5
As with all parenteral products, Docetaxel Teva premix solution and infusion solution should
be visually inspected prior to use, solutions containing a precipitate should be discarded.
98
5. DISPOSAL
All materials that have been utilised for dilution and administration should be disposed of according to
standard procedures.
99
PACKAGE LEAFLET: INFORMATION FOR THE USER
Docetaxel Teva 80 mg concentrate and solvent for solution for infusion
docetaxel
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet,
please tell your doctor or hospital pharmacist.
In this leaflet
1.
What Docetaxel Teva is and what it is used for
2.
Before you use Docetaxel Teva
3.
How to use Docetaxel Teva
4.
Possible side effects
5.
How to store Docetaxel Teva
6.
Further information
1. WHAT DOCETAXEL TEVA IS AND WHAT IT IS USED FOR
The name of this medicine is Docetaxel Teva. Docetaxel is a substance derived from the needles of
yew trees.
Docetaxel belongs to the group of anti-cancer medicines called taxoids.
Docetaxel Teva has been prescribed by your doctor for the treatment of breast cancer, special forms of
lung cancer (non-small cell lung cancer), prostate cancer, gastric cancer or head and neck cancer:
-
For the treatment of advanced breast cancer, Docetaxel Teva could be administered either alone
or in combination with doxorubicin, or trastuzumab, or capecitabine.
-
For the treatment of early breast cancer with or without lymph node involvement, Docetaxel
Teva could be administered in combination with doxorubicin and cyclophosphamide.
-
For the treatment of lung cancer, Docetaxel Teva could be administered either alone or in
combination with cisplatin.
-
For the treatment of prostate cancer, Docetaxel Teva is administered in combination with
prednisone or prednisolone.
-
For the treatment of metastatic gastric cancer, Docetaxel Teva is administered in combination
with cisplatin and 5-fluorouracil.
-
For the treatment of head and neck cancer, Docetaxel Teva is administered in combination with
cisplatin and 5-fluorouracil.
2. BEFORE YOU USE DOCETAXEL TEVA
You must NOT be given Docetaxel Teva if
•
you are allergic (hypersensitive) to docetaxel or any of the other ingredients of Docetaxel Teva
•
the number of white blood cells is too low
•
you have a severe liver disease
Take special care with Docetaxel Teva
Before each treatment with Docetaxel Teva, you will have blood tests to check that you have enough
blood cells and sufficient liver function to receive Docetaxel Teva. In case of white blood cell
disturbances, you may experience associated fever or infections.
100
-
If you have any further questions, ask your doctor or your hospital pharmacist.
You will be asked to take premedication consisting of an oral corticosteroid such as dexamethasone,
one day prior to Docetaxel Teva administration and to continue for one or two days after it in order to
minimise certain undesirable effects which may occur after the infusion of Docetaxel Teva in
particular allergic reactions and fluid retention (swelling of the hands, feet, legs or weight gain).
During treatment, you may be given other medicines to maintain the number of your blood cells.
Taking other medicines
Please tell your doctor or hospital pharmacist if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription. This is because Docetaxel Teva or
other medicines may not work as well as expected and you may be more likely to get a side effect.
Pregnancy
Ask your doctor for advice before being given any medicine.
Docetaxel Teva must
NOT
be administered if you are pregnant unless clearly indicated by your
doctor.
You must not become pregnant during treatment with this medicine and you must use an effective
contraception during therapy because Docetaxel Teva may be harmful for the unborn baby. If
pregnancy occurs during your treatment, you must immediately inform your doctor.
If you are a man being treated with Docetaxel Teva you 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 because
docetaxel may alter male fertility.
Breast-feeding
You must not breast-feed while you are treated with Docetaxel Teva.
Driving and using machines
There is no reason why you cannot drive between courses of Docetaxel Teva except if you feel dizzy
or are unsure of yourself.
3. HOW TO USE DOCETAXEL TEVA
Docetaxel Teva will be administered to you by a healthcare professional.
Usual dose
The dose will depend on your weight and your general condition. Your doctor will calculate your body
surface area in square meters (m²) and will determine the dose you should receive.
Method and route of administration
Docetaxel Teva will be given by infusion into one of your veins (intravenous use). The infusion will
last approximately one hour during which you will be in the hospital.
Frequency of administration
You should usually receive your infusion once every 3 weeks.
101
Your doctor may change the dose and frequency of dosing depending on your blood tests, your
general condition and your response to Docetaxel Teva. In particular, please inform your doctor in
case of diarrhoea, sores in the mouth, feeling of numbness or pins and needles, fever and give her/him
results of your blood tests. Such information will allow her/him to decide whether a dose reduction is
needed. If you have any further questions on the use of this medicine, ask your doctor or hospital
pharmacist.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Docetaxel Teva can cause side effects, although not everybody gets them.
Your doctor will discuss these with you and will explain the potential risks and benefits of your
treatment.
The frequency of possible side effects listed below is defined using the following convention: very
common (affects more than 1 user in 10); common (affects 1 to 10 users in 100); uncommon (affects 1
to 10 users in 1,000); rare (affects 1 to 10 users in 10,000); very rare (affects less than 1 user in
10,000); not known (frequency cannot be estimated from the available data).
The most commonly reported adverse reactions of Docetaxel Teva alone are: decrease in the number
of red blood cells or white blood cells, hair loss, nausea, vomiting, sores in the mouth, diarrhoea and
tiredness.
The severity of adverse events of Docetaxel Teva may be increased when Docetaxel Teva is given in
combination with other chemotherapeutic agents.
During the infusion at the hospital the following allergic reactions
(experienced in more than 1
person in 10)
may occur:
•
flushing, skin reactions, itching,
•
chest tightness; difficulty in breathing,
•
fever or chills,
•
back pain
•
low blood pressure
More severe reactions may occur.
The hospital staff will monitor your condition closely during treatment. Tell them immediately if you
notice any of these effects.
Between infusions of Docetaxel Teva the following may occur, and the frequency may vary with the
combinations of medicines that are received:
Very common (experienced in more than 1 in 10 patients)
•
infections, decrease in the number of red (anaemia), or white blood cells (which are important in
fighting infection) and platelets,
•
fever: if this happens you must tell your doctor immediately
•
allergic reactions as described above
•
loss of appetite (anorexia)
•
insomnia
•
feeling of numbness or pins and needles or pain in the joints or muscles
•
headache
•
alteration in sense of taste
•
inflammation of the eye or increased tearing of the eyes
•
swelling caused by faulty lymphatic drainage
•
shortness of breath
•
nasal drainage; inflammation of the throat and nose; cough
102
•
bleeding from the nose
•
sores in the mouth
•
stomach upsets including nausea, vomiting and diarrhoea, constipation
•
abdominal pain
•
indigestion
•
short term hair loss (in most cases normal hair growth should return)
•
redness and swelling of the palms of your hands or soles of your feet which may cause your skin
to peel (this may also occur on the arms, face, or body)
•
change in the colour of your nails, which may detach
•
muscle aches and pains; back pain or bone pain
•
change or absence of menstrual period
•
swelling of the hands, feet, legs
•
tiredness; or flu-like symptoms
•
weight gain or loss.
Common (experienced in less than 1 in 10 but more than 1 in 100 patients)
•
oral candidiasis
•
dehydration
•
dizziness
•
hearing impaired
•
decrease in blood pressure; irregular or rapid heart beat
•
heart failure
•
oesophagatis
•
dry mouth
•
difficulty or painful swallowing
•
haemorrhage
•
raised liver enzymes (hence the need for regular blood tests).
Uncommon
(experienced in more than 1 in 1,000 but less than 1 in 100 patients)
•
fainting
•
at the injection site, skin reactions, phlebitis (inflammation of the vein) or swelling
•
inflammation of the colon, small intestine; intestinal perforation
•
blood clots.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or hospital pharmacist.
5. HOW TO STORE DOCETAXEL TEVA
Keep out of the reach and sight of children.
Docetaxel Teva should not be used after the expiry date which is stated on the carton and vials.
Do not store above 25°C.
Do not freeze.
Store in the original package in order to protect from light.
The premix solution should be used immediately after preparation. However the chemical and physical
stability of the premix solution has been demonstrated for 8 hours when stored either between 2°C
and 8°C or at room temperature (below 25°C).
The infusion solution should be used within 4 hours at room temperature (below 25°C).
103
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What Docetaxel Teva concentrate vial contains:
-
The active substance is docetaxel. Each vial of Docetaxel Teva concentrate contains 80 mg of
docetaxel. Each ml of concentrate contains 27.73 mg docetaxel.
-
The other ingredients are polysorbate 80 and 25.1% (w/w) anhydrous ethanol.
What the solvent vial contains:
Water for injections.
What Docetaxel Teva looks like and contents of the pack:
Docetaxel Teva concentrate for solution for infusion is a clear viscous, yellow to brown-yellow
solution.
Each carton contains:
•
one 15 ml clear glass vial with a flip-off cap containing 2.88 ml concentrate and,
•
one 15 ml clear glass vial with a flip-off cap containing 5.12 ml of solvent.
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturer:
Pharmachemie B.V.
Swensweg 5
PO Box 552
2003 RN Haarlem, The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
H-2100 Gödöllő,
Hungary
Teva Kutno SA
Sienkiewicza 25;
99-300 Kutno
Poland
Teva Czech Industries s.r.o
Ostravská 29
Č.p. 305
747 70 Opava-Komárov
Czech Republic
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
104
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
105
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{
MM/YYYY
}
Detailed information on this medicine is available on the website of the European Medicines Agency
106
The following information is intended for medical or healthcare professional only:
PREPARATION GUIDE FOR USE WITH DOCETAXEL TEVA 80 mg CONCENTRATE
AND SOLVENT FOR SOLUTION FOR INFUSION
__________________________________________________________________________
It is important that you read the entire contents of this procedure prior to the preparation of either the
Docetaxel Teva premix solution or the Docetaxel Teva infusion solution
1. FORMULATION
Docetaxel Teva 80 mg concentrate for solution for infusion is a clear viscous, yellow to brown-yellow
solution containing 27.73 mg/ml docetaxel (anhydrous) in polysorbate 80. The solvent for Docetaxel
Teva is water for injections.
2. PRESENTATION
Docetaxel Teva is supplied as single-dose vials.
Each box contains one Docetaxel Teva vial (80 mg) and one corresponding solvent for Docetaxel
Teva vial in a carton.
Docetaxel Teva vials should not be stored above 25°C and should be protected from light.
Docetaxel Teva should not be used after the expiry date shown on the carton and vials.
2.1 Docetaxel 80 mg vial:
•
The Docetaxel 80 mg vial is a 15 ml clear glass vial with a bromobutyl rubber stopper and a
flip-off cap.
•
The Docetaxel 80 mg vial contains a solution of docetaxel in polysorbate 80 at a concentration
of 27.73 mg/ml.
Each vial contains 80 mg/2.88 ml of a 27.73 mg/ml solution of docetaxel in polysorbate 80 (fill
volume: 94.4 mg/3.40 ml). This fill volume has been established during the development of
docetaxel to compensate for liquid loss during preparation of the premix due to foaming,
adhesion to the walls of the vial and "dead-volume". This overfill ensures that after dilution with
the entire contents of the accompanying solvent for docetaxel vial, there is a minimal extractable
premix volume of 8 ml containing 10 mg/ml docetaxel which corresponds to the labelled
amount of 80 mg per vial.
2.2 Solvent for Docetaxel 80 mg vial:
•
The solvent for Docetaxel 80 mg vial is a 15 ml clear glass vial with a bromobutyl rubber
stopper and a flip-off cap.
•
The solvent for Docetaxel composition is water for injections.
Each solvent vial contains 5.12 ml of water for injections (fill volume: 6.29 ml). The addition of
the entire contents of the solvent vial to the contents of the docetaxel 80 mg concentrate for
solution for infusion vial ensures a premix concentration of 10 mg/ml docetaxel.
3. RECOMMENDATIONS FOR THE SAFE HANDLING
107
Docetaxel Teva is an antineoplastic agent and, as with other potentially toxic compounds, caution
should be exercised when handling it and preparing Docetaxel Teva solutions. The use of gloves is
recommended.
If Docetaxel Teva concentrate, premix solution or infusion solution should come into contact with
skin, wash immediately and thoroughly with soap and water. If Docetaxel Teva concentrate, premix
solution or infusion solution should come into contact with mucous membranes, wash immediately
and thoroughly with water.
4. PREPARATION FOR THE INTRAVENOUS ADMINISTRATION
4.1 Preparation of the Docetaxel Teva premix solution (10 mg docetaxel/ml)
4.1.1 If the vials are stored under refrigeration, allow the required number of Docetaxel Teva boxes
to stand at room temperature (below 25°C) for 5 minutes.
4.1.2 Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Teva vial by partially inverting the vial.
4.1.3 Inject the entire contents of the syringe into the corresponding Docetaxel Teva vial.
4.1.4 Remove the syringe and needle and mix manually by repeated inversions for at least 45
seconds. Do not shake.
4.1.5 Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then
check that the solution is homogenous and clear (foaming is normal even after 5 minutes due
to the presence of polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after
preparation. However the chemical and physical stability of the premix solution has been
demonstrated for 8 hours when stored either between +2°C and +8°C or at room temperature
(below 25°C).
4.2 Preparation of the infusion solution
4.2.1 More than one premix vial may be necessary to obtain the required dose for the patient. Based
on the required dose for the patient expressed in mg, aseptically withdraw the corresponding
premix volume containing 10 mg/ml docetaxel from the appropriate number of premix vials
using graduated syringes fitted with a needle. For example, a dose of 140 mg docetaxel would
require 14 ml docetaxel premix solution.
4.2.2 Inject the required premix volume into a 250 ml non-PVC infusion bag containing either 5%
glucose solution or sodium chloride 9 mg/ml (0.9%) solution for infusion. If a dose greater
than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a
concentration of 0.74 mg/ml docetaxel is not exceeded.
4.2.3
Mix the infusion bag or bottle manually using a rocking motion.
4.2.4
The Docetaxel Teva infusion solution should be used within 4 hours and should be aseptically
administered as a 1-hour infusion under room temperature (below 25°C) and normal lighting
conditions.
4.2.5
As with all parenteral products, Docetaxel Teva premix solution and infusion solution should
be visually inspected prior to use, solutions containing a precipitate should be discarded.
108
5. DISPOSAL
All materials that have been utilised for dilution and administration should be disposed of according to
standard procedures.
109
Source: European Medicines Agency
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