ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Docefrez 20 mg powder and solvent for concentrate for solution for infusion
2.
Each single-dose vial of powder contains 20 mg docetaxel (anhydrous).
After reconstitution, 1 ml of concentrate contains 24 mg docetaxel.
Excipients: the solvent contains 35.4% (w/w) ethanol.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for concentrate for solution for infusion.
White lyophilised powder.
The solvent is a viscous, clear and colourless solution.
4.
Breast cancer
Docetaxel 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 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 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 in combination with trastuzumab is indicated for the treatment of patients with metastatic breast
cancer whose tumours over express HER2 and who previously have not received chemotherapy for
metastatic disease.
Docetaxel in combination with capecitabine is indicated for the treatment of patients with locally advanced
or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included
an anthracycline.
Non-small cell lung cancer
Docetaxel is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung
cancer after failure of prior chemotherapy.
2
Docetaxel 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 in combination with prednisone or prednisolone is indicated for the treatment of patients with
hormone refractory metastatic prostate cancer.
Gastric adenocarcinoma
Docetaxel 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 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.
In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m
2
every three weeks,
combined with capecitabine at 1250 mg/m
2
twice daily (within 30 minutes after a meal) for 2 weeks
3
followed by a 1-week rest period. For capecitabine dose calculation according to body surface area, see
capecitabine summary of product characteristics.
Non-small cell lung cancer
In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen is
docetaxel 75 mg/m
2
immediately followed by cisplatin 75 mg/m
2
over 30-60 minutes. For treatment after
failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m
2
as a single agent.
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).
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
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/m
2
. If the patient
continues to experience these reactions at 60 mg/m
2
, the treatment should be discontinued.
Adjuvant therapy for breast cancer
4
Prostate cancer
Gastric adenocarcinoma
General
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/m
2
.
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/m
2
.
• For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the docetaxel dose.
For trastuzumab dose modifications, see trastuzumab summary of product characteristics.
In combination with cisplatin and 5-fluorouracil
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF
use, the docetaxel dose should be reduced from 75 to 60 mg/m
2
. If subsequent episodes of complicated
neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m
2
. In case of Grade 4
thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m
2
. Patients should not be
retreated with subsequent cycles of docetaxel until neutrophils recover to a level > 1,500 cells/mm
3
and
platelets recover to a level > 100,000 cells/mm
3
. Discontinue treatment if these toxicities persist (see section
4.4).
Recommended dose modifications for toxicities in patients treated with docetaxel in combination with
cisplatin and 5-fluorouracil (5-FU):
Toxicity Dose adjustment
Diarrhoea grade 3 First episode: reduce 5-FU dose by 20%.
Second episode: then reduce docetaxel dose by 20%.
Diarrhoea grade 4 First episode: reduce docetaxel and 5-FU doses by 20%.
Second episode: discontinue treatment.
Stomatitis/mucositis grade 3 First episode: reduce 5-FU dose by 20%.
Second episode: stop 5-FU only, at all subsequent cycles.
Third episode: reduce docetaxel dose by 20%.
Stomatitis/mucositis grade 4 First episode: stop 5-FU only, at all subsequent cycles.
Second episode: reduce docetaxel dose by 20%.
For cisplatin and 5-fluorouracil dose adjustments, see the corresponding summary of product characteristics.
In the pivotal SCCHN studies, patients who experienced complicated neutropenia (including prolonged
neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide prophylactic
coverage (e.g. day 6-15) in all subsequent cycles.
Special populations:
5
In combination with cisplatin
Based on pharmacokinetic data with docetaxel at 100 mg/ m
2
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 in nasopharyngeal carcinoma in children aged 1 month to less than 18
years have not yet been established.
There is no relevant use of docetaxel in the paediatric population in the indications breast cancer, non-small
cell lung cancer, prostate cancer, gastric carcinoma and head and neck cancer, not including type II and III
less differentiated nasopharyngeal carcinoma.
Elderly
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).
In the case of severe neutropenia (<500 cells/mm
3
for seven days or more) during a course of docetaxel
therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic
measures are recommended (see section 4.2).
6
Patients with hepatic impairment
In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile
neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic G-CSF.
Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated
neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF
should be closely monitored, (see sections 4.2 and 4.8).
In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile
neutropenia and/or neutropenic infection occurred at lower rates when patients received primary G-CSF
prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy
with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged
neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored (see sections 4.2
and 4.8).
Hypersensitivity reactions
Patients should be observed closely for hypersensitivity reactions especially during the first and second
infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion
of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. If
hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not
require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or
generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients
who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel.
Cutaneous reactions
Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema followed
by desquamation has been observed. Severe symptoms such as eruptions followed by desquamation which
lead to interruption or discontinuation of docetaxel treatment were reported (see section 4.2).
Fluid retention
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be
monitored closely.
Patients with liver impairment
In patients treated with docetaxel at 100 mg/m
2
as single agent who have serum transaminase levels (ALT
and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than
2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths
including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections,
thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in those patients
with elevated liver function test (LFTs) is 75 mg/m
2
and LFTs should be measured at baseline and before
each cycle (see section 4.2).
For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent with
serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended and docetaxel
should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma,
the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN associated with alkaline
phosphatase > 2.5 × ULN, and bilirubin> 1 x ULN; for these patients, no dose-reductions can be
recommended and docetaxel should not be used unless strictly indicated. No data are available in patients
with hepatic impairment treated by docetaxel in combination in the other indications.
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).
7
Cardiac toxicity
Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab,
particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be
moderate to severe and has been associated with death (see section 4.8).
When patients are candidates for treatment with docetaxel in combination with trastuzumab, they should
undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g.
every three months) to help identify patients who may develop cardiac dysfunction. For more details see
summary of product characteristics of trastuzumab.
Others
Contraceptive measures must be taken by both men and women during treatment and for men at least 6-
months after cessation of therapy (see section 4.6).
Additional cautions for use in adjuvant treatment of breast cancer
Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or
infection), G-CSF and dose reduction should be considered (see section 4.2).
Gastrointestinal reactions
Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia, may
be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.
Congestive heart failure
Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow
up period.
Leukaemia
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed
myelodysplasia or myeloid leukaemia requires haematological follow-up.
Patients with 4+ nodes
The benefit/risk ratio for TAC in patients with 4+ nodes was not defined fully at the interim analysis (see
section 5.1).
Elderly
There are limited data available in patients >70 years of age on docetaxel use in combination with
doxorubicin and cyclophosphamide.
Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study, 209 patients were 65
years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every
three weeks, the incidence of related nail changes occurred at a rate ≥ 10% higher in patients who were 65
years of age or greater compared to younger patients. The incidence of related fever, diarrhoea, anorexia,
and peripheral oedema occurred at rates ≥ 10% higher in patients who were 75 years of age or greater versus
less than 65 years.
Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part) patients
treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were
65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse
events was higher in the elderly patients compared to younger patients. The incidence 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.
Ethanol
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
8
In vitro
studies have shown that the metabolism of docetaxel may be modified by the concomitant
administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the enzyme
competitively) cytochrome P450-3A such as ciclosporine, terfenadine, ketoconazole, erythromycin and
troleandomycin. As a result, caution should be exercised when treating patients with these medicinal
products as concomitant therapy since there is a potential for a significant interaction.
Docetaxel is highly protein bound (>95%). Although the possible
in vivo
interaction of docetaxel with
concomitantly administered medicinal product has not been investigated formally,
in vitro
interactions with
tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin,
salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition,
dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of
digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co-
administration. Limited data from a single uncontrolled study were suggestive of an interaction between
docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was about 50% higher
than values previously reported for carboplatin monotherapy.
Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic prostate
cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4. No statistically
significant effect of prednisone on the pharmacokinetics of docetaxel was observed.
Docetaxel should be administered with caution in patients concomitantly receiving potent CYP3A4
inhibitors (e.g. protease inhibitors like ritonavir, azole antifungals like ketoconazole or itraconazole). A drug
interaction study performed in patients receiving ketoconazole and docetaxel showed that the clearance of
docetaxel was reduced by half by ketoconazole, probably because the metabolism of docetaxel involves
CYP3A4 as a major (single) metabolic pathway. Reduced tolerance of docetaxel may occur, even at lower
doses.
There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be both
embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other cytotoxic
medicinal products, docetaxel may cause foetal harm when administered to pregnant women.
Therefore,docetaxel must not be used during pregnancy unless clearly indicated.
Women of childbearing potential /contraception:
Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to
inform the treating physician immediately should this occur.
An effective method of contraception should be used during treatment.
In non clinical studies, docetaxel has genotoxic effects and may alter male fertility (see section 5.3).
Therefore, men being treated with docetaxel are advised not to father a child during and up to 6 months after
treatment and to seek advice on conservation of sperm prior to treatment.
Lactation:
Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk.
Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be
discontinued for the duration of docetaxel therapy.
No studies on the effects on the ability to drive and use machines have been performed.
9
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/m
2
and 75 mg/m
2
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) and the COSTART terms 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:
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.
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.
10
Severe reactions were characterised by hypotension and/or bronchospasm or generalized rash/erythema (see
section 4.4).
Skin and subcutaneous tissue disorders
Reversible cutaneous reactions have been observed and were generally considered as mild to moderate.
Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including
severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with
pruritus. Eruptions generally occurred within one week after the docetaxel infusion. Less frequently, severe
symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation
of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by
hypo- or hyperpigmentation and sometimes pain and onycholysis.
General disorders and administration site conditions
Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or
dryness of the skin, phlebitis or extravasation and swelling of the vein. Fluid retention includes events such
as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The
peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of
3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).
Docetaxel 100 mg/m² single agent
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infections (G3/4;5.7%;
including sepsis and
pneumonia, fatal in
1.7%)
Infection associated with
G4 neutropenia
(G3/4:4.6%)
Blood and lymphatic
system disorders
Neutropenia (G4:76.4%)
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia (G4:
0.2%)
Immune system
disorders
Hypersensitivity (G3/4:
5.3%)
Metabolism and
nutrition disorders
Anorexia
Nervous system
disorders
Peripheral sensory
neuropathy
(G3: 4.1%);
Peripheral motor
neuropathy (G3/4: 4%);
Dysgeusia (severe
0.07%)
Cardiac disorders
Arrhythmia (G3/4:0.7%)
Cardiac failure
Vascular disorders
Hypotension;
Hypertension;
Haemorrhage
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea (severe 2.7%)
Gastrointestinal
disorders
Stomatitis (G3/4: 5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation (severe
0.2%);
Abdominal pain (severe
1%);
Gastrointestinal
haemorrhage (severe
0.3%)
Oesophagitis (severe:
0.4%)
11
Skin and subcutaneous
tissue disorders
Alopecia;
Skin reaction (G3/4:
5.9%);
Nail disorders (severe
2.6%)
Musculoskeletal and
connective tissue
disorders
Myalgia (severe: 1.4%) Arthralgia
General disorders and
administration site
conditions
Fluid retention (severe:
6.5%);
Asthenia (severe
11.2%);
Pain
Infusion site reaction;
Non-cardiac chest pain
(severe: 0.4%)
Investigations
G3/4 Blood bilirubin
increased (< 5%);
G3/4 Blood alkaline
phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)
Blood and lymphatic system disorders
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia
Nervous system disorders
Reversibility data are available among 35.3% of patients who developed neurotoxicity following docetaxel
treatment at 100 mg/m² as single agent. The events were spontaneously reversible within 3 months.
Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions were
reversible within 21 days.
General disorders and administration site conditions
The median cumulative dose to treatment discontinuation was more than 1,000 mg/m2 and the median time
to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset of moderate and severe
retention is delayed (median cumulative dose: 818.9 mg/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%)
Blood and lymphatic system
disorders
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Febrile neutropenia
Immune system disorders
Hypersensitivity (no severe)
Metabolism and nutrition
disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders
Arrhythmia (no severe)
12
Skin and subcutaneous tissue disorders
Vascular disorders
Hypotension
Gastrointestinal disorders
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Constipation
Skin and subcutaneous tissue
disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe 0.8%)
Musculoskeletal and connective
tissue disorders
Myalgia
General disorders and
administration site conditions
Asthenia (severe 12.4%);
Fluid retention (severe 0.8%);
Pain
Investigations
G3/4 Blood bilirubin increased
(<2%)
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 disorders
Cardiac failure;
Arrhythmia (no severe)
Vascular disorders
Hypotension
Gastrointestinal
disorders
Nausea (G3/4: 5%);
Stomatitis (G3/4: 7.8%);
Diarrhoea (G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation
Skin and subcutaneous
tissue disorders
Alopecia;
Nail disorders (severe:
0.4%);
Skin reaction (no severe)
Musculoskeletal and
connective tissue
disorders
Myalgia
General disorders and
administration site
conditions
Asthenia (severe: 8.1%);
Fluid retention (severe:
1.2%);
Pain
Infusion site reaction
Investigations
G3/4 Blood bilirubin
G3/4 AST increased
13
increased (<2.5%);
G3/4 Blood alkaline
phosphatase increased
(<2.5%)
(<1%);
G3/4 ALT increased
(<1%)
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
Nervous system
disorders
Peripheral sensory
neuropathy (G3: 3.7%)
Peripheral motor
neuropathy (G3/4: 2%)
Cardiac disorders
Arrhythmia (G3/4:
0.7%)
Cardiac failure
Vascular disorders
Hypotension (G3/4:
0.7%)
Gastrointestinal
disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%)
Constipation
Skin and subcutaneous
tissue disorders
Alopecia;
Nail disorders (severe:
0.7%);
Skin reaction (G3/4:
0.2%)
Musculoskeletal and
connective tissue
disorders
Myalgia (severe: 0.5%)
General disorders and
administration site
conditions
Asthenia (severe: 9.9%)
Fluid retention (severe:
0.7%)
Fever (G3/4: 1.2%)
Infusion site reaction;
Pain
Investigations
G3/4 Blood bilirubin
increased (2.1%);
G3/4 ALT increased
(1.3%)
G3/4 AST increased
(0.5%);
G3/4 Blood alkaline
phosphatase increased
(0.3%)
Docetaxel 100 mg/m² in combination with trastuzumab:
MedDRA system organ
classes
Very common adverse
reactions
Common adverse
reactions
14
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).
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%)
Blood and lymphatic system
disorders
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition
Anorexia (G3/4: 1%);
Dehydration (G3/4: 2%);
15
disorders
Decreased appetite
Nervous system disorders
Dysgeusia (G3/4: <1%);
Paraesthesia (G3/4: <1%)
Dizziness;
Headache (G3/4: <1%);
Neuropathy peripheral
Eye disorders
Lacrimation increased
Respiratory, thoracic and
mediastinal disorders
Pharyngolaryngeal pain
(G3/4: 2%)
Dyspnoea (G3/4: 1%);
Cough (G3/4: <1%);
Epistaxis (G3/4: <1%)
Gastrointestinal disorders
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue
disorders
Hand-foot syndrome (G3/4:
24%)
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous (G3/4:
<1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective
tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: <1%);
Back pain (G3/4: 1%);
General disorders and
administration site conditions
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%)
Lethargy;
Pain
Investigations
Weight decreased;
G3/4 Blood bilirubin increased
(9%)
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%)
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Peripheral motor neuropathy
(G3/4: 0%)
Eye disorders
Lacrimation increased (G3/4:
0.6%)
Cardiac disorders
Cardiac left ventricular function
decrease (G3/4: 0.3%)
Respiratory, thoracic and
mediastinal disorders
Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Gastrointestinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis (G3/4:
0.9%);
Vomiting (G3/4: 1.2%)
16
Skin and subcutaneous tissue
disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective
bone disorders
Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and
administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe 0.6%)
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%).
Blood and lymphatic
system disorders
Anaemia (G3/4: 3%);
Neutropenia (G3/4:
59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia (G3/4:
NA)
Immune system
disorders
Hypersensitivity (G3/4:
0.6%)
Metabolism and
nutrition disorders
Anorexia (G3/4: 1.5%)
Nervous system
disorders
Dysgeusia (G3/4: 0.6%);
Peripheral sensory
neuropathy (G3/4: 0.1%)
Peripheral motor
neuropathy (G3/4: 0%);
Syncope (G3/4: 0%);
Neurotoxicity (G3/4:
0%);
Somnolence (G3/4: 0%)
Eye disorders
Conjunctivitis (G3/4:
<0.1%)
Lacrimation increased
(G3/4: 0.1%);
Cardiac disorders
Arrhythmia (G3/4:
0.2%);
Vascular disorders
Hot flush (G3/4: 0.5%)
Hypotension (G3/4: 0%);
Phlebitis (G3/4: 0%)
Lymphoedema (G3/4:
0%)
Respiratory, thoracic
and mediastinal
disorders
Cough (G3/4: 0%)
Gastrointestinal
disorders
Nausea (G3/4: 5.0%);
Stomatitis (G3/4: 6.0%);
Vomiting (G3/4: 4.2%);
Diarrhoea (G3/4: 3.4%);
Constipation (G3/4: 0.5%)
Abdominal pain (G3/4:
0.4%)
Skin and subcutaneous
tissue disorders
Alopecia (G3/4:
<0.1%);
Skin disorder (G3/4:
0.6%);
Nail disorders (G3/4:
0.4%)
17
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4: 0.2%)
Reproductive system
and breast disorders
Amenorrhoea (G3/4:
NA)
General disorders and
administration site
conditions
Asthenia (G3/4: 10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral (G3/4:
0.2%)
Investigations
Weight increased (G3/4:
0%);
Weight decreased
(G3/4: 0.2%)
Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in 12 patients out of the 83
patients with peripheral sensory neuropathy at the end of the chemotherapy.
Cardiac disorders
Congestive Heart Failure (CHF) has been reported in 18 of 1276 patiens during the follow-up period.
In the node positive study (TAX316) one patient in each treatment arm died because of cardiac failure.
Skin and subcutaneous tissue disorders
Alopecia was observed to be ongoing during follow-up in 25 patients out of the 736 patients with alopecia at
the end of the chemotherapy.
Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing during follow-up in 140 patients out of the 251 patients with
amenorrhoea at the end of the chemotherapy.
General disorders and administration site conditions
Peripheral oedema was observed to be ongoing during follow-up time in 18 patients out of the 112 patients
with peripheral oedema at the end of the chemotherapy in study TAX 316, whereas lymphoedema was
observed to be ongoing in 4 of the 5 patients with lymphoedema at the end of the chemotherapy in the study
GEICAM 9805.
Acute leukaemia / Myelodysplastic syndrome
At a median follow-up time of 77 months, acute leukaemia occurred in 1 of 532 (0.2%) patients who
received docetaxel, doxorubicin, and cyclophosphamide in the GEICAM 9805 study. No cases were
reported in patients who received fluorouracil, doxorubicin and cyclophosphamide. No patient was
diagnosed with myelodysplastic syndrome in either treatment groups.
Table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection
was decreased in patients who received primary G-CSF prophylaxis after it was made mandatory in the TAC
arm - GEICAM study.
Neutropenic complications in patients receiving TAC with or without primary G-CSF prophylaxis
(GEICAM 9805)
Without primary
G-CSF prophylaxis
(n = 111)
n (%)
With primary
G-CSF prophylaxis
(n = 421)
n (%)
Neutropenia (Grade 4)
104 (93.7)
135 (32.1)
Febrile neutropenia
28 (25.2)
23 (5.5)
Neutropenic infection
14 (12.6)
21 (5.0)
18
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%)
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%).
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%).
Eye disorders
Lacrimation increased (G3/4:
0%).
Ear and labyrinth disorders
Hearing impaired (G3/4: 0%).
Cardiac disorders
Arrhythmia (G3/4: 1.0%).
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%).
Constipation (G3/4: 1.0%);
Gastrointestinal pain (G3/4:
1.0%);
Oesophagitis/dysphagia/odynop
hagia (G3/4: 0.7%).
Skin and subcutaneous tissue
disorders
Alopecia (G3/4: 4.0%)
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%).
General disorders and
administration site conditions
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention (severe/life-
threatening: 1%).
Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively,
regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of the
cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of patients
when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without prophylactic G-CSF,
(see section 4.2).
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
Cancer pain (G3/4:
0.6%)
19
(incl cysts and
polyps)
Blood and
lymphatic system
disorders
Neutropenia G3/4:
76.3%)
Anaemia (G3/4: 9.2%)
Thrombocytopenia
(G3/4: 5.2%)
Febrile neutropenia
Immune system
disorders
Hypersensitivity (no
severe)
Metabolism and
nutrition disorders
Anorexia (G3/4:0.6%)
Nervous system
disorders
Dysgeusia/Parosmia;
Peripheral sensory
neuropathy
(G3/4: 0.6%)
Dizziness
Eye disorders
Lacrimation increased
Conjunctivitis
Ear and labyrinth
disorders
Hearing impaired
Cardiac disorders
Myocardial ischemia
(G3/4: 1.7%)
Arrhythmia (G3/4:
0.6%)
Vascular disorders
Venous disorder (G3/4:
0.6%)
Gastrointestinal
disorders
Nausea (G3/4: 0.6%);
Stomatitis (G3/4: 4.0%);
Diarrhoea (G3/4: 2.9%);
Vomiting (G3/4: 0.6%)
Constipation
Esophagitis/dysphagia/
odynophagia (G3/4:
0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal
haemorrhage (G3/4:
0.6%)
Skin and
subcutaneous tissue
disorders
Alopecia (G3/4:
10.9%).
Rash pruritic;
Dry skin;
Skin exfoliative (G3/4:
0.6%)
Musculoskeletal
and connective
tissue disorders
Myalgia (G3/4: 0.6%)
General disorders
and administration
site conditions
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema
Investigations
Weight increased
•
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
Cancer pain (G3/4:
1.2%)
20
(incl cysts and
polyps)
Blood and lymphatic
system disorders
Neutropenia G3/4:
83.5%)
Anaemia (G3/4:
12.4%)
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia
Immune system
disorders
Hypersensitivity
Metabolism and
nutrition disorders
Anorexia (G3/4:
12.0%)
Nervous system
disorders
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory
neuropathy
(G3/4: 1.2%)
Dizziness (G3/4:
2.0%);
Peripheral motor
neuropathy
(G3/4: 0.4%)
Eye disorders
Lacrimation increased Conjunctivitis
Ear and labyrinth
disorders
Hearing impaired
(G3/4: 1.2%)
Cardiac disorders
Arrhythmia (G3/4:
2.0%)
Ischemia myocardial
Vascular disorders
Venous disorder
Gastrointestinal
disorders
Nausea (G3/4: 13.9%);
Stomatitis (G3/4:
20.7%);
Vomiting (G3/4:
8.4%);
Diarrhoea (G3/4:
6.8%);
Esophagitis/dysphagia/
odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Dyspepsia (G3/4:
0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal
haemorrhage (G3/4:
0.4%)
Skin and
subcutaneous tissue
disorders
Alopecia (G3/4:
4.0%);
Rash pruritic
Dry skin;
Desquamation
Musculoskeletal 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
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.
21
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.
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.
22
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Taxanes, ATC Code: L01CD02
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
Data from a multicenter open label randomized study support the use of docetaxel for the adjuvant treatment
of patients with operable node-positive breast cancer and KPS ≥ 80%, between 18 and 70 years of age. After
stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to
receive either docetaxel 75 mg/m
2
administered 1-hour after doxorubicin 50 mg/m
2
and cyclophosphamide
500 mg/m
2
(TAC arm), or doxorubicin 50 mg/m
2
followed by fluorouracil 500 mg/m
2
and
cyclosphosphamide 500 mg/m
2
(FAC arm). Both regimens were administered once every 3 weeks for 6
cycles. Docetaxel was administered as a 1-hour infusion, all other medicinal products were given as
intravenous bolus on day one. G-CSF was administered as secondary prophylaxis to patients who
experienced complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection). Patients on
the TAC arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days
starting on day 5 of each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients
with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years.
Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and
was given to 69% of patients who received TAC and 72% of patients who received FAC.
(TAX 316)
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
23
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
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
745
0.72
0.59-0.88
0.001
0.70
0.53-0.91
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 intravenously 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):
Subset Analyses-Adjuvant Therapy in Patients with Node-negative Breast Cancer Study
(Intent-to-Treat Analysis)
Disease Free Survival
Patient subset
Number of patients
in TAC group
Hazard ratio*
95% CI
Overall
539
0.68
0.49-0.93
24
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
Menopausal status
Pre-Menopausal
Post-Menopausal
285
254
0.64
0.72
0.40-1
0.47-1.12
* a hazard ratio (TAC/FAC) of less than 1 indicates that TAC is associated with a longer disease free
survival compared to FAC.
Exploratory subgroup analyses for disease-free survival for patients who meet the 2009 St. Gallen
chemotherapy criteria – (ITT population) were performed and presented here
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.
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
25
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 anemia (15.8% versus 8.5%) than AT arm, and, in addition, a higher incidence of severe
cardiac toxicity: congestive heart failure (3.8% versus 2.8%), absolute LVEF decrease ≥ 20% (13.1 %
versus 6.1%), absolute LVEF decrease ≥ 30% (6.2% versus 1.1%). Toxic deaths occurred in 1 patient in the
AT arm (congestive heart failure) and in 4 patients in the AC arm (1 due to septic shock and 3 due to
congestive heart failure).
In both arms, quality of life measured by the EORTC questionnaire was comparable and stable during
treatment and follow-up.
Docetaxel in combination with trastuzumab
Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic breast
cancer whose tumours over express HER2, and who previously had not received chemotherapy for
metastatic disease. One hundred eighty six patients were randomized to receive docetaxel (100 mg/m2) with
or without trastuzumab; 60% of patients received prior anthracycline-based adjuvant chemotherapy.
Docetaxel plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant
anthracyclines. The main test method used to determine HER2 positivity in this pivotal study was
immunohistochemistry (IHC). A minority of patients were tested using fluorescence in-situ hybridization
26
(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.
1Full 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/m2 as a 1 hour intravenous infusion every 3 weeks) and
capecitabine (1250 mg/m2 twice daily for 2 weeks followed by 1-week rest period). 256 patients were
randomised to treatment with docetaxel alone (100 mg/ m2 as a 1 hour intravenous infusion every 3 weeks).
Survival was superior in the docetaxel +capecitabine combination arm (p=0.0126). Median survival was
442 days (docetaxel + capecitabine) vs. 352 days (docetaxel alone).
The overall objective response rates in the all-randomised population (investigator assessment) were 41.6%
(docetaxel + capecitabine) vs. 29.7% (docetaxel alone); p = 0.0058. Time to progressive disease was
superior in the docetaxel + capecitabine combination arm (p<0.0001). The median time to progression was
186 days (docetaxel + capecitabine) vs. 128 days (docetaxel alone).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks) and
overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive Care. The
1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%). There was less use
of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease-related 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/m2 as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/ m
2
over 30-60 minutes every
3 weeks (TCis), docetaxel 75 mg/ m
2
as a 1 hour infusion in combination with carboplatin (AUC
6 mg/ml.min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/ m
2
administered over 6-10
minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated
every 4 weeks (VCis).
27
Median survival (months)
(95% CI)
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 endpoint)
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]
Medium 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
Hazard ratio
95% CI
p-value†*
335
18.9
(17.0-21.2)
0.761
(0.619-0.936)
0.0094
334
17.4
(15.7-19.0)
0.912
(0.747-1.113)
0.3624
337
16.5
(14.4-18.6)
--
--
--
Number of patients
PSA** response rate (%)
291
45.4
282
47.9
300
31.7
28
95% CI
p-value*
(39.5-51.3)
0.0005
(41.9-53.9)
<0.0001
(26.4-37.3)
--
Number of patients
Pain response rate (%)
95% CI
p-value*
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/m2 on day 1) and 5-fluorouracil (1000 mg/m
2
per day for 5 days). The length of a treatment cycle
was 3 weeks for the TCF arm and 4 weeks for the CF arm. The median number of cycles administered per
patient was 6 (with a range of 1-16) for the TCF arm compared to 4 (with a range of 1-12) for the CF arm.
Time to progression (TTP) was the primary endpoint. The risk reduction of progression was 32.1% and was
associated with a significantly longer TTP (p=0.0004) in favor of the TCF arm. Overall survival was also
significantly longer (p=0.0201) in favor of the TCF arm with a risk reduction of mortality of 22.7%.
Efficacy results are summarized in the following table:
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) 9.2 8.6
(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
Overall response rate (CR+PR) (%)
36.7
25.4
p-value
0.0106
Progressive disease as best overall
response (%)
16.7
25.9
*Unstratified logrank test
29
Subgroup analyses across age, gender and race consistently favored the TCF arm compared to the CF arm.
A survival update analysis conducted with a median follow-up time of 41.6 months no longer showed a
statistically significant difference although always in favour of the TCF regimen and showed that the benefit
of TCF over CF is clearly observed between 18 and 30 months of follow up.
Overall, quality of life (QoL) and clinical benefit results consistently indicated improvement in favor of the
TCF arm. Patients treated with TCF had a longer time to 5% definitive deterioration of global health status
on the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive worsening of Karnofsky
performance status (p = 0.0088) compared to patients treated with CF.
Head and neck cancer
•
Induction chemotherapy followed by radiotherapy (TAX323)
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of
the head and neck (SCCHN) was evaluated in a phase III, multicenter, open-label, randomized study
(TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO perfomance
status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received
docetaxel 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 favor of the TPF arm compared to the PF arm (median
OS: 18.6 vs. 14.5 months respectively) with a 28% risk reduction of mortality, p=0.0128.
Efficacy results are presented in the table below:
30
Efficacy of docetaxel in the induction treatment of patients with inoperable locally advanced
SCCHN (Intent-to-Treat Analysis)
Endpoint
Docetaxel+Cis+5-FU
n=177
Cis+5-FU
n=181
Median progression free survival (months)
(95%CI)
11.4
(10.1-14.0)
8.3
(7.4-9.1)
Adjusted hazard ratio
(95%CI)
*p-value
0.70
(0.55-0.89)
0.0042
Median progression free survival (months)
(95%CI)
18.6
(15.7-24.0)
14.5
(11.6-18.7)
Adjusted Hazard ratio
(95%CI)
*p-value
0.72
(0.56-0.93)
0.0128
Best overall response to chemotherapy (%)
(95%CI)
***p-value
67.8
(60.4-74.6)
53.6
(46.0-61.0)
0.006
Best overall response to study treatment
[chemotherapy +/- radiotherapy] (%)
(95%CI)
***p-value
72.3
(65.1-78.8)
58.6
(51.0-65.8)
0.006
Median duration of response to chemotherapy ±
radiotherapy (months)
(95%CI)
n=128
15.7
(13.4-24.6)
n=106
11.7
(10.2-17.4)
Hazard ratio
(95%CI)
**p-value
0.72
(0.52-0.99)
0.0457
A hazard ratio of less than 1 favors Docetaxel +Cisplatin+5-FU
*Cox model (adjustment for Primary tumour site, T and N clinical stages and PSWHO)
**Logrank test
*** Chi-square test
Quality of life parameters
Patients treated with TPF experienced significantly less deterioration of their Global health score compared
to those treated with PF (p=0.01, using the EORTC QLQ-C30 scale).
Clinical benefit parameters
The performance status scale, for head and neck (PSS-HN) subscales designed to measure understandability
of speech, ability to eat in public, and normalcy of diet, was significantly in favor of TPF as compared to PF.
Median time to first deterioration of WHO performance status was significantly longer in the TPF arm
compared to PF. Pain intensity score improved during treatment in both groups indicating adequate pain
management.
31
•
Induction chemotherapy followed by chemoradiotherapy (TAX324)
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced squamous
cell carcinoma of the head and neck (SCCHN) was evaluated in a randomized, multicenter open-label,
phase III, study (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO
performance status of 0 or 1, were randomized to one of two arms. The study population comprised patients
with technically unresectable disease, patients with low probability of surgical cure and patients aiming at
organ preservation. The efficacy and safety evaluation solely addressed survival endpoints and the success
of organ preservation was not formally addressed. Patients on the docetaxel arm received docetaxel (T)
75 mg/m² by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m² administered as a 30-minute
to three-hour intravenous infusion, followed by the continuous intravenous infusion of 5-fluorouracil (F)
1000 mg/m²/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. All patients who
did not have progressive disease were to receive chemoradiotherapy (CRT) as per protocol (TPF/CRT).
Patients on the comparator arm received cisplatin (P) 100 mg/m² as a 30-minute to three-hour intravenous
infusion on day 1 followed by the continuous intravenous infusion of 5-fluorouracil (F) 1000 mg/m²/day
from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients who did not have
progressive disease were to receive CRT as per protocol (PF/CRT).
Patients in both treatment arms were to receive 7 weeks of CRT following induction chemotherapy with a
minimum interval of 3 weeks and no later than 8 weeks after start of the last cycle (day 22 to day 56 of last
cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for
a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation
(2 Gy per day, 5 days per week for 7 weeks, for a total dose of 70-72 Gy). Surgery on the primary site of
disease and/or neck could be considered at anytime following completion of CRT. All patients on the
docetaxel-containing arm of the study received prophylactic antibiotics. The primary efficacy endpoint in
this study, overall survival (OS) was significantly longer (log-rank test, p = 0.0058) with the docetaxel-
containing regimen compared to PF (median OS: 70.6 versus 30.1 months respectively), with a 30% risk
reduction in mortality compared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54-0.90)
with an overall median follow up time of 41.9 months. The secondary endpoint, PFS, demonstrated a 29%
risk reduction of progression or death and a 22 month improvement in median PFS (35.5 months for TPF
and 13.1 for PF). This was also statistically significant with an HR of 0.71; 95% CI 0.56-0.90; log-rank test
p = 0.004.
Efficacy results are presented in the table below:
32
Efficacy of docetaxel in the induction treatment of patients
with locally advanced SCCHN (Intent-to-Treat Analysis)
Endpoint
Docetaxel + Cis + 5-FU
n = 255
Cis + 5-FU
n = 246
Median overall survival (months)
(95% CI)
70.6
(49.0-NA)
30.1
(20.9-51.5)
Hazard ratio:
(95% CI)
*p-value
0.70
(0.54-0.90)
0.0058
Median PFS (months)
(95% CI)
35.5
(19.3-NA)
13.1
(10.6 - 20.2)
Hazard ratio:
(95% CI)
**p-value
0.71
(0.56 - 0.90)
0.004
Best overall response (CR + PR) to chemotherapy
(%)
(95% CI)
71.8
(65.8-77.2)
64.2
(57.9-70.2)
***p-value
0.070
Best overall response (CR + PR) to study treatment
[chemotherapy +/- chemoradiotherapy] (%)
(95%CI)
76.5
(70.8-81.5)
71.5
(65.5-77.1)
***p-value
0.209
A hazard ratio of less than 1 favors docetaxel + cisplatin + fluorouracil
*un-adjusted log-rank test
**un-adjusted log-rank test, not adjusted for multiple comparisons
***Chi square test, not adjusted for multiple comparisons
NA-not applicable
5.2 Pharmacokinetic properties
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of
20-115 mg/m
2
in phase I studies. The kinetic profile of docetaxel is dose independent and consistent with a
three-compartment pharmacokinetic model with half lives for the α, β and γ phases of 4 min, 36 min and
11.1 h, respectively. The late phase is due, in part, to a relatively slow efflux of docetaxel from the
peripheral compartment. Following the administration of a 100 mg/m
2
dose given as a one-hour infusion a
mean peak plasma level of 3.7 μg/ml was obtained with a corresponding AUC of 4.6 h μg/ml. Mean values
for total body clearance and steady-state volume of distribution were 21 l/h/m
2
and 113 l, respectively. Inter
individual variation in total body clearance was approximately 50%. Docetaxel is more than 95% bound to
plasma proteins.
A study of
14
C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in both the
urine and faeces following cytochrome P450-mediated oxidative metabolism of the tert-butyl ester group,
within seven days, the urinary and faecal excretion accounted for about 6% and 75% of the administered
radioactivity, respectively. About 80% of the radioactivity recovered in faeces is excreted during the first 48
hours as one major inactive metabolite and 3 minor inactive metabolites and very low amounts of unchanged
medicinal product.
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
33
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 (Cmax 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.
6.1 List of excipients
Solvent
Ethanol, anhydrous
Polysorbate 80
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section
6.6.
Do not use any PVC equipment or device. Docefrez is incompatible with PVC equipment or devices.
6.3 Shelf life
Vial
24 months
34
Reconstituted solution
The reconstituted solution contains 24 mg/ml docetaxel and should be used immediately after preparation.
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 8 hours when
stored either between 2°C and 8°C or below 25°C and for the final solution for infusion for 4 hours below
25°C .
From a microbiological point of view, the reconstituted solution 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 hrs at 2 to 8°C, unless reconstitution and further dilution has taken place in
controlled and validated aseptic conditions.
6.4
Special precautions for storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.
6.5
Nature and contents of container
Docefrez 20 mg powder and solvent for concentrate for solution for infusion
Powder vial:
5 ml colourless type 1 glass vial with grey bromobutyl rubber stopper and sealed with a dark green colour
flip-off aluminium seal.
Solvent vial
1 ml colourless type 1 glass vial with grey bromobutyl rubber stopper sealed with dark blue flip-off with
aluminium seal.
Each carton contains:
• one single-dose powder vial with 20 mg docetaxel (plus 22% overfill: 24.4 mg), and
• one single-dose solvent vial with 1 ml solvent for Docefrez
The overfills are included to ensure that, after dilution with the entire volume of the accompanying solvent
vial, the minimum extractable volume of reconstituted concentrate containing 20 mg or 80 mg docetaxel,
respectively, may be withdrawn from the vial.
6.6 Special precautions for disposal and other handling
Docetaxel is an antineosplastic agent and, as with other potentially cytotoxic compounds, caution should be
exercised when preparing docetaxel solutions. An appropriate aseptic technique should be used for all steps.
If docetaxel powder, reconstituted concentrate or solution for infusion should come into contact with skin,
wash immediately and thoroughly with soap and water. If docetaxel powder, reconstituted concentrate, or
solution for infusion should come into contact with mucous membranes, wash immediately and thoroughly
with water.
Both the reconstituted concentrate and the solution for infusion should be visually inspected prior to use.
Any solution containing a precipitate should be discarded.
Do not use any PVC equipment or device. Docefrez is incompatible with PVC equipment or devices.
Docefrez powder and solvent for concentrate for solution for infusion is for single use only.
35
:
Instructions for reconstitution
More than one vial may be necessary to obtain the required dose for the patient. For example, a dose of
140 mg docetaxel would require one 80 mg pack and three 20 mg packs. The required number of Docefrez
powder vials should be allowed to reach room temperature (between 15°C - 25°C) for 5 minutes.
Using a syringe with a needle, the entire contents of the correct vial of solvent for Docefrez is to be
withdrawn and injected into the respective Docefrez powder vials.
Shake well for complete solubilisation of powder (the powder will be dissolved in less than 90 seconds).
The reconstituted solution contains approximately 24 mg/ml docetaxel and should be used immediately after
preparation.
Preparation of the infusion solution
After reconstitution, each vial contains an extractable volume of approx 0.84 ml concentrate, corresponding
to approximately 20 mg docetaxel.
The volume of concentrate (24 mg/ml docetaxel) corresponding to the required dose (mg) for the patient
should be withdrawn (from the appropriate number of vials) using graduated syringes fitted with a needle.
This volume of concentrate should be injected into a 250 ml infusion bag or bottle containing either glucose
50 mg/ml (5%) solution or sodium chloride 9 mg/ml (0.9%) solution for infusion.
If a dose greater than 200 mg docetaxel is required, a larger volume of the infusion vehicle should be used,
so that a concentration of 0.74 mg/ml docetaxel is not exceeded in the final solution for infusion.
The solution in the infusion bag or bottle should be allowed to mix manually using a rocking motion.
Method of administration
The docetaxel infusion solution should be used within 4 hours and should be aseptically administered as a
1 hour infusion under room temperature and normal lighting conditions.
Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Sun Pharmaceutical Industries Europe B.V.
Polarisavenue 87
2132 JH Hoofddorp
The Netherlands
tel: +31-23-5685501
fax: +31-23-5685505
8.
EU/1/10/630/001
9.
Date of first authorisation: 10 May 2010
36
Detailed information on this product is available on the website of the European Medicines Agency (EMA):
http://www.ema.europa.eu.
37
1.
Source: European Medicines Agency
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