ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Docetaxel Teva Pharma 20 mg concentrate and solvent for solution for infusion
Each single-dose vial of Docetaxel Teva Pharma concentrate contains 20 mg docetaxel (anhydrous).
Each ml of concentrate contains 27.73 mg docetaxel.
Excipients
:
Each vial of concentrate contains 25.1% (w/w) anhydrous ethanol.
For a full list of excipients, see section 6.1.
Concentrate and solvent for solution for infusion.
The concentrate is a clear viscous, yellow to brown-yellow solution.
The solvent is a colourless solution.
4.1 Therapeuticindications
Breast cancer
Docetaxel Teva Pharma 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.
Non-small cell lung cancer
Docetaxel Teva Pharma is indicated for the treatment of patients with locally advanced or metastatic
non-small cell lung cancer after failure of prior chemotherapy.
Docetaxel Teva Pharma in combination with cisplatin is indicated for the treatment of patients with
unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not
previously received chemotherapy for this condition.
Prostate cancer
Docetaxel Teva Pharma in combination with prednisone or prednisolone is indicated for the treatment
of patients with hormone refractory metastatic prostate cancer.
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 and non-small cell lung cancer, 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
2
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
For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose
of docetaxel is 100 mg/m
2
in monotherapy.
Non-small cell lung cancer
In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen
is docetaxel 75 mg/m
2
immediately followed by cisplatin 75 mg/m
2
over 30-60 minutes. For treatment
after failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m² as a single
agent.
Prostate cancer
The recommended dose of docetaxel is 75 mg/m
2
. Prednisone or prednisolone 5 mg orally twice daily
is administered continuously (see section 5.1).
Dose adjustments during treatment
General
Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm
3
.
In patients who experienced either febrile neutropenia, neutrophil count <500 cells/mm
3
for more than
one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel
therapy, the dose of docetaxel should be reduced from 100 mg/m
2
to 75 mg/m
2
and/or from
75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment
should be discontinued.
In combination with cisplatin
For patients who are dosed initially at docetaxel 75 mg/m
2
in combination with cisplatin and whose
nadir of platelet count during the previous course of therapy is < 25,000 cells/mm
3
, or in patients who
experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxel
dose in subsequent cycles should be reduced to 65 mg/m
2
. For cisplatin dose adjustments, see the
corresponding summary of product characeteristics.
Special populations
Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who have both
elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal
range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of
docetaxel is 75 mg/m
2
(see sections 4.4 and 5.2). For those patients with serum bilirubin >ULN and/or
ALT and AST >3.5 times the ULN associated with alkaline phosphatase >6 times the ULN, no
dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
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 and prostate cancer.
3
Elderly
Based on a population pharmacokinetic analysis, there are no special instructions for use in the
elderly.
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).
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.
4
Cutaneous reactions
Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema
followed by desquamation has been observed. Severe symptoms such as eruptions followed by
desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see
section 4.2).
Fluid retention
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be
monitored closely.
Patients with liver impairment
In patients treated with docetaxel at 100 mg/m
2
as single agent who have serum transaminase levels
(ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels
greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as
toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia,
infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel
in those patients with elevated liver function test (LFTs) is 75 mg/m
2
and LFTs should be measured at
baseline and before each cycle (see section 4.2).
For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent
with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended
and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric
adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN
associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x UNL; for these patients, no
dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No
data are available in patients with hepatic impairment treated by docetaxel in combination in the other
indications.
Patients with renal impairment
There are no data available in patients with severely impaired renal function treated with docetaxel.
Nervous system
The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).
Cardiac toxicity
Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab,
particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may
be moderate to severe and has been associated with death (see section 4.8).
When patients are candidates for treatment with docetaxel in combination with trastuzumab, they
should undergo baseline cardiac assessment. Cardiac function should be further monitored during
treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For
more details see Summary of Product Characteristics of trastuzumab.
Others
Contraceptive measures must be taken by both men and women during treatment and for men at least
6 months after cessation of therapy (see section 4.6).
5
Additional cautions for use in adjuvant treatment of breast cancer
Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or
infection), G-CSF and dose reduction should be considered (see section 4.2).
Gastrointestinal reactions
Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia,
may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated
promptly.
Congestive heart failure
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.
In vitro
studies have shown that the metabolism of docetaxel may be modified by the concomitant
administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the
enzyme competitively) cytochrome P450-3A such as cyclosporine, terfenadine, ketoconazole,
erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with
these medicinal products as concomitant therapy since there is a potential for a significant interaction.
Docetaxel is highly protein bound (>95%). Although the possible
in vivo
interaction of docetaxel with
concomitantly administered medicinal products has not been investigated formally,
in vitro
interactions with tightly protein-bound drugs such as erythromycin, diphenhydramine, propranolol,
propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein
binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel.
Docetaxel did not influence the binding of digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their
coadministration. Limited data from a single uncontrolled study were suggestive of an interaction
6
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.
4.8 Undesirableeffects
The adverse reactions considered to be possibly or probably related to the administration of docetaxel
have been obtained in:
•
1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent
respectively.
•
258 patients who received docetaxel in combination with doxorubicin.
•
406 patients who received docetaxel in combination with cisplatin.
•
92 patients treated with docetaxel in combination with trastuzumab.
•
255 patients who received docetaxel in combination with capecitabine.
•
332 patients who received docetaxel in combination with prednisone or prednisolone (clinically
important treatment related adverse events are presented).
•
1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively)who received
docetaxel in combination with doxorubicin and cyclophosphamide (clinically important
treatment related adverse events are presented).
7
•
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 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.
Severe reactions were characterised by hypotension and/or bronchospasm or generalized
rash/erythema (see section 4.4).
Nervous system disorders
The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2
and 4.4). Mild to moderate neuro-sensory signs are characterised by paresthesia, dysesthesia or pain
including burning. Neuro-motor events are mainly characterised by weakness.
Skin and subcutaneous tissue disorders
Reversible cutaneous reactions have been observed and were generally considered as mild to
moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and
hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently
associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.
Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to
interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe
nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.
8
General disorders and administration site conditions
Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation,
redness or dryness of the skin, phlebitis or extravasations and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion,
pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower
extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is
cumulative in incidence and severity (see section 4.4).
9
Docetaxel 100 mg/m² single agent
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infections (G3/4: 5.7%;
including sepsis and
pneumonia, fatal in
1.7%)
Infection associated
with G4 neutropenia
(G3/4: 4.6%)
Blood and lymphatic
system disorders
Neutropenia
(G4: 76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia
(G4: 0.2%)
Immune system
disorders
Hypersensitivity
(G3/4: 5.3%)
Metabolism and
nutrition disorders
Anorexia
Nerveus system
disorders
Peripheral sensory
neuropathy (G3: 4.1%);
Peripheral motor
neuropathy (G3/4: 4%)
Dysgeusia (severe
0.07%)
Cardiac disorders
Arrhythmia
(G3/4: 0.7%)
Cardiac failure
Hypotension;
Hypertension;
Haemorrhage
Vascular disorders
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea (severe 2.7%)
Stomatitis (G3/4: 5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation
(severe 0.2%);
Abdominal pain
(severe 1%);
Gastrointestinal
Haemorrhage
(severe 0.3%)
Oesophagitis
(severe: 0.4%)
Gastrointestinal
disorders
Skin and subcutaneous
tissue disorders
Alopecia;
Skin reaction
(G3/4: 5.9%);
Nail disorders
(severe 2.6%)
Musculoskeletal,
connective tissue
disorders
Myalgia (severe 1.4%)
Arthralgia
Fluid retention
(severe: 6.5%)
Asthenia
(severe 11.2%);
Pain
General disorders and
administration site
conditions
Infusion site reaction;
Non-cardiac chest
pain (severe 0.4%)
Investigations
G3/4 Blood bilirubin
increased (< 5%);
10
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
G3/4 Blood alkaline
phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)
Blood and lymphatic system disorders
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia.
Nervous system disorders
Reversibility data are available among 35.3% of patients who developed neurotoxicity following
docetaxel treatment at 100 mg/m² as single agent. The events were spontaneously reversible within
3 months.
Skin and subcutaneous tissue disorders
Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions
were reversible within 21 days.
General disorders and administration site conditions
The median cumulative dose to treatment discontinuation was more than 1,000 mg/m
2
and the median
time to fluid retention reversibility was 16.4 weeks (range 0
to 42 weeks). The onset of moderate and
severe retention is delayed (median cumulative dose: 818.9 mg/m
2
) in patients with premedication
compared with patients without premedication (median cumulative dose: 489.7 mg/m
2
); however, it
has been reported in some patients during the early courses of therapy.
11
Docetaxel 75 mg/m² single agent
MedDRA system srgan classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infections (G3/4: 5%)
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)
Blood and lymphatic system
disorders
Febrile neutropenia
Immune system disorders
Hypersensitivity (no severe)
Metabolism and nutrition
disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders
Arrhythmia (no severe)
Vascular disorders
Hypotension
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Gastrointestinal disorders
Constipation
Skin and subcutaneous tissue
disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe 0.8%)
Musculoskeletal and connective
tissue disorders
Myalgia
Asthenia (severe 12.4%);
Fluid retention (severe 0.8%);
Pain
General disorders and
administration site conditions
Investigations
G3/4 Blood bilirubin increased
(< 2%)
12
Docetaxel 75 mg/m² in combination with doxorubicin
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 7.8%)
Blood and lymphatic
system disorders
Neutropenia
(G4: 91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia
(G4: 0.8%)
Immune system
disorders
Hypersensitivity
(G3/4: 1.2%)
Metabolism and
nutrition disorders
Anorexia
Nervous system
disorders
Peripheral sensory
neuropathy (G3: 0.4%)
Peripheral motor
neuropathy
(G3/4: 0.4%)
Cardiac failure;
Arrhythmia (no severe)
Cardiac disorders
Vascular disorders
Hypotension
Nausea (G3/4: 5%);
Stomatitis
(G3/4: 7.8%);
Diarrhoea
(G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation
Gastrointestinal
disorders
Alopecia;
Nail disorders
(severe 0.4%);
Skin reaction
(no severe)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Myalgia
Asthenia
(severe 8.1%);
Fluid retention
(severe 1.2%);
Pain
General disorders and
administration site
conditions
Infusion site reaction
Investigations
G3/4 Blood bilirubin
increased (< 2.5%);
G3/4 Blood alkaline
phosphatase increased
(< 2.5%)
G3/4 AST increased
(< 1%);
G3/4 ALT increased
(< 1%)
13
Docetaxel 75 mg/m² in combination with cisplatin
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 5.7%)
Blood and lymphatic
system disorders
Neutropenia
(G4: 51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia
(G4:0.5%)
Febrile neutropenia
Immune system
disorders
Hypersensitivity
(G3/4: 2.5%)
Metabolism and
nutrition disorders
Anorexia
Peripheral sensory
neuropathy (G3: 3.7%);
Peripheral motor
neuropathy (G3/4: 2%)
Nervous system
disorders
Arrhythmia
(G3/4: 0.7%)
Cardiac disorders
Cardiac failure
Hypotension
(G3/4: 0.7%)
Vascular disorders
Gastrointestinal
disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%);
Constipation
Skin and
subcutaneous tissue
disorders
Alopecia;
Nail disorders
(severe 0.7%);
Skin reaction
(G3/4: 0.2%)
Musculoskeletal and
connective tissue
disorders
Myalgia (severe: 0.5%)
Asthenia (severe 9.9%);
Fluid retention
(severe 0.7%);
Fever (G3/4: 1.2%)
General disorders
and administration
site conditions
Infusion site reaction;
pain
Investigations
G3/4 Blood bilirubin
increased (2.1%);
G3/4 ALT increased
(1.3%)
G3/4 AST increased
(0.5%);
G3/4 Blood alkaline
phosphatase increased
(0.3%)
14
Docetaxel 100 mg/m² in combination with trastuzumab
MedDRA system organ classes
Very common adverse reactions
Common adverse
reactions
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Febrile neutropenia (includes
neutropenia associated with fever
and antibiotic use) or neutropenic
sepsis
Metabolism and nutrition
disorders
Anorexia
Psychiatric disorders
Insomnia
Nervous system disorders
Paresthesia; Headache; Dysgeusia;
Hypoaesthesia
Eye disorders
Lacrimation increased;
Conjunctivitis
Cardiac disorders
Cardiac failure
Vascular disorders
Lymphoedema
Respiratory, thoracic and
mediastinal disorders
Epistaxis; Pharyngolaryngeal pain;
Nasopharyngitis ; Dyspnoea;
Cough; Rhinorrhoea
Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain
Skin and subcutaneous tissue
disorders
Alopecia; Erythema; Rash; Nail
disorders
Musculoskeletal and connective
tissue disorders
Myalgia; Arthralgia; Pain in
extremity; Bone pain; Back pain
General disorders and
administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal
inflammation; Pain; Influenza like
illness; Chest pain; Chills
lethargy
Investigations
Weight increased
Cardiac disorders
Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus
trastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm,
64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm
alone.
Blood and lymphatic system disorders
Very common: Haematological toxicity was increased in patients receiving trastuzumab and
docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC
criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m
2
is
known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The
incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with
Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).
15
Docetaxel 75 mg/m² in combination with capecitabine
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Oral candidiasis (G3/4: < 1%)
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Blood and lymphatic system
disorders
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Dizziness;
Headache (G3/4: <1%);
Neuropathy peripheral
Nervous system disorders
Dysgeusia (G3/4: <1%);
Paresthesia (G3/4: <1%)
Eye disorders
Lacrimation increased
Dyspnoea (G3/4: 1%);
Cough (G3/4: <1%);
Epistaxis (G3/4: <1%)
Respiratory, thoracic and
mediastinal disorders
Pharyngolaryngeal pain
(G3/4: 2%)
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Gastrointestinal disorders
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue
disorders
Hand-foot syndrome
(G3/4: 24%)
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous
(G3/4: <1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective
tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: <1%);
Back pain (G3/4: 1%);
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/ weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%);
General disorders and
administration site conditions
Lethargy;
Pain
Investigations
Weight decreased;
G3/4 Blood bilirubin increased
(9%)
16
Docetaxel 75 mg/m² in combination with prednisone or prednisolone
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infection (G3/4: 3.3%)
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia
(G3/4: 0.6%)
Febrile neutropenia
Immune system disorders
Hypersensitivity (G3/4: 0.6%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 0.6%)
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Nervous system disorders
Peripheral motor neuropathy
(G3/4: 0%)
Lacrimation increased
(G3/4: 0.6%)
Eye disorders
Cardiac disorders
Cardiac left ventricular function
decrease (G3/4: 0.3%)
Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Respiratory, thoracic and
mediastinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis
(G3/4: 0.9%);
Vomiting (G3/4: 1.2%)
Gastrointestinal disorders
Skin and subcutaneous tissue
disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective
tissue disorders
Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and
administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe 0.6%)
17
Adjuvant therapy with Docetaxel 75 mg/m² in combination with doxorubicin and cyclophosphamide
in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer - pooled
data
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 2.4%);
Neutropenic infection
(G3/4: 2.7%).
.
Anaemia (G3/4: 3%);
Neutropenia
(G3/4: 59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4: NA)
Blood and lymphatic
system disorders
Immune system
disorders
Hypersensitivity
(G3/4: 0.6%)
Metabolism and
nutrition disorders
Anorexia (G3/4: 1.5%)
Dysgeusia
(G3/4: 0.6%);
Peripheral sensory
neuropathy
(G3/4: <0.1%)
Nervous system
disorders
Peripheral motor
neuropathy
(G3/4: 0%);
Syncope (G3/4: 0%)
Neurotoxicity
(G3/4: 0%);
Somnolence
(G3/4: 0%)
Eye disorders
Conjunctivitis
(G3/4: <0.1%)
Lacrimation disorder
(G3/4: <0.1%);
Cardiac disorders
Arrhythmia
(G3/4: 0.2%);
Vascular disorders
Hot Flush (G3/4: 0.5%)
Hypotension
(G3/4: 0%)
Phlebitis (G3/4: 0%)
Lymphoedema
(G3/4: 0%)
Respiratory, thoracic
and mediastinal
disorders
Cough (G3/4: 0%)
Nausea (G3/4: 5.0%);
Stomatitis
(G3/4: 6.0%);
Vomiting (G3/4: 4.2%);
Diarrhoea
(G3/4: 3.4%);
Constipation
(G3/4: 0.5%)
Gastrointestinal
disorders
Abdominal pain
(G3/4: 0.4%)
Alopecia(G3/4: <0.1%);
Skin disorder
(G3/4: 0.6%);
Nail disorders
(G3/4: 0.4%)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.7%);
Arthralgia (G3/4: 0.2%)
Reproductive system
Amenorrhoea
18
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
and breast disorders
(G3/4: NA)
General disorders and
administration site
conditions
Asthenia
(G3/4: 10.0%);
Pyrexia (G3/4: NA);
Oedema peripheral
(G3/4: 0.2%)
Weight increased
(G3/4: 0%)
Weight decreased
(G3/4: 0.2%)
Investigations
Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in 12 patients out of the
83 patients with peripheral sensory neuropathy at the end of the chemotherapy.
Cardiac disorders
Congestive Heart Failure (CHF) has been reported in 18 of 1276 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.
19
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)
Neutropenic infection
(Grade 3-4)
2 (1.8)
5 (1.2)
20
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for gastric adenocarcinoma
cancer:
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Neutropenic infection;
Infection (G3/4: 11.7%)
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia
(G3/4: 8.8%);
Febrile neutropenia.
Blood and lymphatic system
disorders
Immune system disorders
Hypersensitivity (G3/4: 1.7%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 11.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%).
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%).
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 /
odynophagia (G3/4: 0.7%).
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%).
Skin and subcutaneous tissue
disorders
Alopecia (G3/4: 4.0%).
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention (severe/life
threatening:
1%).
General disorders and
administration site conditions
Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively,
regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of
the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of
patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without
prophylactic G-CSF, (see section 4.2).
21
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for Head and Neck cancer
•
Induction chemotherapy followed by radiotherapy (TAX 323)
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 6.3%);
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Cancer pain (G3/4: 0.6%)
Neutropenia
(G3/4: 76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Blood and lymphatic
system disorders
Febrile neutropenia
Immune system
disorders
Hypersensitivity
(no severe)
Metabolism and
nutrition disorders
Anorexia (G3/4: 0.6%)
Dysgeusia/Parosmia;
Peripheral sensory
neuropathy
(G3/4: 0.6%)
Nervous system
disorders
Dizziness
Lacrimation increased;
Conjunctivitis
Eye disorders
Ear and labyrinth
disorders
Hearing impaired
Cardiac disorders
Myocardial ischemia
(G3/4: 1.7%)
Arrhythmia
(G3/4: 0.6%)
Venous disorder
(G3/4: 0.6%)
Vascular disorders
Constipation;
Oesophagitis/dysphagia/
Odynophagia
(G3/4: 0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal
haemorrhage(G3/4: 0.6%)
Gastrointestinal
disorders
Nausea (G3/4:0.6%)
Stomatitis
(G3/4: 4.0%)
Diarrhoea
(G3/4: 2.9%)
Vomiting (G3/4: 0.6%)
Rash pruritics;
Dry skin;
Skin exfoliative
(G3/4: 0.6%)
Skin and subcutaneous
tissue disorders
Alopecia
(G3/4: 10.9%)
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.6%)
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema
General disorders and
administration site
conditions
Investigations
Weight increased
22
•
Induction chemotherapy followed by chemoradiotherapy (TAX 324)
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 3.6%)
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl
cysts and polyps)
Cancer pain
(G3/4: 1.2%)
Neutropenia
(G3/4: 83.5%);
Anaemia
(G3/4: 12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia
Blood and lymphatic
system disorders
Immune system
disorders
Hypersensitivity
Metabolism and
nutrition disorders
Anorexia (G3/4: 12.0%)
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory
neuropathy
(G3/4: 1.2%)
Nervous system
disorders
Dizziness (G3/4: 2.0%);
Peripheral motor
neuropathy (G3/4: 0.4%)
Eye disorders
Lacrimation increased
Conjunctivitis
Ear and labyrinth
disorders
Hearing impaired
(G3/4: 1.2%)
Arrhythmia
(G3/4: 2.0%)
Ischemia myocardial
Cardiac disorders
Vascular disorders
Venous disorder
Nausea (G3/4: 13.9%);
Stomatitis
(G3/4: 20.7%);
Vomiting (G3/4: 8.4%);
Diarrhoea (G3/4: 6.8%);
Oesophagitis/dysphagia/
Odynophagia
(G3/4: 12.0%);
Constipation
(G3/4: 0.4%)
Gastrointestinal
disorders
Dyspepsia (G3/4: 0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal
haemorrhage
(G3/4: 0.4%)
Skin and subcutaneous
tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritus;
Dry skin;
Desquamation
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.4%)
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention
(G3/4: 1.2%);
Oedema (G3/4: 1.2%)
General disorders and
administration site
conditions
Investigations
Weight decreased
Weight increased
23
Post-marketing experience
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Very rare cases of acute myeloid leukaemia
and myelodysplastic syndrome
have been reported in
association with docetaxel when used in combination with other chemotherapy agents and/or
radiotherapy.
Blood and lymphatic system disorders
Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated
intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been
reported.
Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel
administration. These reactions sometimes appear during the infusion of the medicinal product.
Eye Disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring
during infusion of the medicinal product and in association with hypersensitivity reactions have been
reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or
without conjunctivitis, as cases of lachrymal 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 erythematous and bullous eruptions such as erythema multiform,
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 lymphedema have been reported with docetaxel.
24
General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration
and pulmonary oedema have rarely been reported.
There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of
overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In
cases of overdose, exacerbation of adverse events may be expected. The primary anticipated
complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and
mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose.
Other appropriate symptomatic measures should be taken, as needed.
5.1 Pharmacodynamicproperties
Pharmacotherapeutic group: Taxanes, ATC Code: L01CD 02
Preclinical data
Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable
microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The
binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown
in vitro
to disrupt the microtubular network in cells which is essential for
vital mitotic and interphase cellular functions.
Docetaxel was found to be cytotoxic
in vitro
against various murine and human tumour cell lines and
against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular
concentrations with a long cell residence time. In addition, docetaxel was found to be active on some
but not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistance
gene.
In vivo
, docetaxel is schedule independent and has a broad spectrum of experimental antitumour
activity against advanced murine and human grafted tumours.
Clinical data
Breast cancer
Two randomised phase III comparative studies, involving a total of 326 alkylating or
392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the
recommended dose and regimen of 100 mg/m² every 3 weeks.
In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m² every 3 weeks).
Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p=0.38) or
time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p=0.54), docetaxel increased
response rate (52% vs. 37%, p=0.01) and shortened time to response (12 weeks vs. 23 weeks,
p=0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15
doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart
failure).
In anthracycline-failure patients, docetaxel was compared to the combination of mitomycin C and
vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel increased response rate
(33% vs. 12%, p<0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p=0.0004) and
prolonged overall survival (11 months vs. 9 months, p=0.01).
25
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%).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks)
and overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive
Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).
There was less use of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease
related medications (p=0.06) and radiotherapy (p<0.01) in patients treated with docetaxel at 75 mg/m²
compared to those with BSC.
The overall response rate was 6.8% in the evaluable patients, and the median duration of response was
26.1 weeks.
Docetaxel in combination with platinum agents in chemotherapy-naïve patients
In a phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or
greater, and who did not receive previous chemotherapy for this condition, were randomised to either
Docetaxel (T) 75 mg/m
2
as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m
2
over
30-60 minutes every 3 weeks (TCis), Docetaxel 75 mg/m
2
as a 1 hour infusion in combination with
carboplatin (AUC 6 mg/ml. min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m
2
administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m
2
administered on
day 1 of cycles repeated every 4 weeks (VCis).
Survival data, median time to progression and response rates for two arms of the study are illustrated
in the following table:
TCis
n=408
VCis
n=404
Statistical Analysis
Overall survival
(Primary end-point):
Median survival (months)
11.3
10.1
Hazard ratio: 1.122
[97.2% CI: 0.937; 1.342]*
1-year Survival (%)
46
41
Treatment difference: 5.4%
[95% CI: -1.1; 12.0]
2-year Survival (%)
21
14
Treatment difference: 6.2%
[95% CI: 0.2; 12.3]
Median time to progression
(weeks)
22.0
23.0
Hazard ratio: 1.032
[95% CI: 0.876; 1.216]
Overall response rate (%):
31.6
24.5
Treatment difference: 7.1%
[95% CI: 0.7; 13.5]
26
*: 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 (%)
95% CI
p-value*
291
45.4
(39.5-51.3)
0.0005
282
47.9
(41.9-53.9)
<0.0001
300
31.7
(26.4-37.3)
--
Number of patients
Pain response rate (%)
95% CI
p-value*
153
34.6
(27.1-42.7)
0.0107
154
31.2
(24.0-39.1)
0.0798
157
21.7
(15.5-28.9)
--
Number of patients
Tumour response rate
(%)
95% CI
p-value*
141
12.1
(7.2-18.6)
0.1112
134
8.2
(4.2-14.2)
0.5853
137
6.6
(3.0-12.1)
--
†
Stratified log rank test
*Threshold for statistical significance=0.0175
**PSA: Prostate-Specific Antigen
Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every
3 weeks, it is possible that certain patients may benefit from docetaxel every week.
No statistical differences were observed between treatment groups for Global Quality of Life.
27
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 lowered by 27% on average (see section 4.2). Docetaxel clearance was not
modified in patients with mild to moderate fluid retention and there are no data available in patients
with severe fluid retention.
When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma
levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin
and cyclophosphamide were not influenced by their coadministration.
Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice
versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (C
max
and AUC) and no
effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5’-DFUR.
Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following
monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is
similar to that observed with cisplatin alone.
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid
tumours had no influence on the pharmacokinetics of each individual medicinal product.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard
dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the
pharmacokinetics of docetaxel was observed.
5.3 Preclinical safety data
The carcinogenic potential of docetaxel has not been studied.
Docetaxel has been shown to be mutagenic in the
in vitro
micronucleus and chromosome aberration
test in CHO-K1 cells and in the
in vivo
micronucleus test in the mouse. However, it did not induce
mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent
with the pharmacological activity of docetaxel.
28
Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair
male fertility.
6.1 List of excipients
Concentrate
Polysorbate 80
Ethanol, anhydrous
Solvent
Water for injections.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
Section 6.6.
6.3 Shelf-life
•
18 months.
•
Premix solution: Chemical and physical in-use stability has been demonstrated for 8 hours when
stored either between 2°C and 8°C or at room temperature (below 25°C). From a
microbiological point of view, the product should be used immediately. If not used immediately,
in-use storage times and conditions prior to use are the responsibility of the user and would
normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled
and validated aseptic conditions.
•
Infusion solution: Chemical and physical in-use stability has been demonstrated for 4 hours at
room temperature (below 25°C). From a microbiological point of view, the product should be
used immediately. If not used immediately, in-use storage times and conditions prior to use are
the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless
dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage and other handling
Do not store above 25°C.
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Each carton contains:
•
One vial of concentrate and,
•
One vial of solvent
•
Docetaxel Teva Pharma 20 mg vial
6 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
This vial contains 0.72 ml of a 27.73 mg/ml solution of docetaxel in polysorbate 80 (fill volume:
24.4 mg/0.88 ml). This fill volume has been established during the development of docetaxel to
compensate for liquid loss during preparation of the premix due to foaming, adhesion to the
walls of the vial and "dead-volume". This overfill ensures that after dilution with the entire
contents of the accompanying solvent for docetaxel vial, there is a minimal extractable premix
29
volume of 2 ml containing 10 mg/ml docetaxel which corresponds to the labelled amount of
20 mg per vial.
Solvent for Docetaxel Teva Pharma 20
mg vial
6 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
Solvent vial contains 1.28 ml of water for injections (fill volume: 1.71 ml). The addition of the
entire contents of the solvent vial to the contents of the Docetaxel Teva Pharma 20 mg
concentrate for solution for infusion vial ensures a premix concentration of 10 mg/ml docetaxel.
6.6 Special precautions for disposal and other handling
Docetaxel Teva Pharma is an antineoplastic agent and, as with other potentially toxic compounds,
caution should be exercised when handling it and preparing Docetaxel solutions. The use of gloves is
recommended.
If Docetaxel Teva Pharma concentrate, premix solution or infusion solution should come into contact
with skin, wash immediately and thoroughly with soap and water. If Docetaxel concentrate, premix
solution or infusion solution should come into contact with mucous membranes, wash immediately
and thoroughly with water.
Preparation for the intravenous administration
a)
Preparation of the Docetaxel Teva Pharma premix solution (10 mg docetaxel/ml)
If the vials are stored under refrigeration, allow the required number of Docetaxel Teva Pharma boxes
to stand at room temperature (below 25°C) for 5 minutes.
Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Teva Pharma vial by partially inverting the vial.
Inject the entire contents of the syringe into the corresponding Docetaxel Teva Pharma vial.
Remove the syringe and needle and mix manually by repeated inversions for at least 45 seconds. Do
not shake.
Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then check that
the solution is homogenous and clear (foaming is normal even after 5 minutes due to the presence of
polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after preparation.
However the chemical and physical stability of the premix solution has been demonstrated for 8 hours
when stored either between 2°C and 8°C or at room temperature (below 25°C).
b)
Preparation of the infusion solution
More than one premix vial may be necessary to obtain the required dose for the patient. Based on the
required dose for the patient expressed in mg, aseptically withdraw the corresponding premix volume
containing 10 mg/ml docetaxel from the appropriate number of premix vials using graduated syringes
fitted with a needle. For example, a dose of 140 mg docetaxel would require 14 ml docetaxel premix
solution.
Inject the required premix volume into a non-PVC 250 ml infusion bag containing either 5% glucose
solution or sodium chloride 9 mg/ml (0.9%) solution for infusion.
If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so
that a concentration of 0.74 mg/ml docetaxel is not exceeded.
30
Mix the infusion bag or bottle manually using a rocking motion.
The Docetaxel Teva Pharma infusion solution should be used within 4 hours and should be aseptically
administered as a 1-hour infusion under room temperature (below 25°C) and normal lighting
conditions.
As with all parenteral products, Docetaxel Teva Pharma premix solution and infusion solution should
be visually inspected prior to use, solutions containing a precipitate should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
8. MARKETING AUTHORISATION NUMBER
Detailed information on this product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
31
1.
Docetaxel Teva Pharma 80 mg concentrate and solvent for solution for infusion
Each single dose vial of Docetaxel Teva Pharma concentrate contains 80 mg docetaxel (anhydrous).
Each ml of concentrate contains 27.73 mg docetaxel.
Excipients
:
Each vial of concentrate contains 25.1% (w/w) anhydrous ethanol.
For a full list of excipients, see section 6.1.
Concentrate and solvent for solution for infusion.
The concentrate is a clear viscous, yellow to brown-yellow solution.
The solvent is a colourless solution.
4.1 Therapeuticindications
Breast cancer
Docetaxel Teva Pharma 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.
Non-small cell lung cancer
Docetaxel Teva Pharma is indicated for the treatment of patients with locally advanced or metastatic
non-small cell lung cancer after failure of prior chemotherapy.
Docetaxel Teva Pharma in combination with cisplatin is indicated for the treatment of patients with
unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not
previously received chemotherapy for this condition.
Prostate cancer
Docetaxel Teva Pharma in combination with prednisone or prednisolone is indicated for the treatment
of patients with hormone refractory metastatic prostate cancer.
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 and non-small cell lung cancer, 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
32
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
For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose
of docetaxel is 100 mg/m
2
in monotherapy.
Non-small cell lung cancer
In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen
is docetaxel 75 mg/m
2
immediately followed by cisplatin 75 mg/m
2
over 30-60 minutes. For treatment
after failure of prior platinum-based chemotherapy, the recommended dose is 75 mg/m² as a single
agent.
Prostate cancer
The recommended dose of docetaxel is 75 mg/m
2
. Prednisone or prednisolone 5 mg orally twice daily
is administered continuously (see section 5.1).
Dose adjustments during treatment
General
Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm
3
.
In patients who experienced either febrile neutropenia, neutrophil count <500 cells/mm
3
for more than
one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel
therapy, the dose of docetaxel should be reduced from 100 mg/m
2
to 75 mg/m
2
and/or from
75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment
should be discontinued.
In combination with cisplatin
For patients who are dosed initially at docetaxel 75 mg/m
2
in combination with cisplatin and whose
nadir of platelet count during the previous course of therapy is < 25,000 cells/mm
3
, or in patients who
experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the docetaxel
dose in subsequent cycles should be reduced to 65 mg/m
2
. For cisplatin dose adjustments, see the
corresponding summary of product characeteristics.
Special populations
Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who have both
elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal
range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of
docetaxel is 75 mg/m
2
(see sections 4.4 and 5.2). For those patients with serum bilirubin >ULN and/or
ALT and AST >3.5 times the ULN associated with alkaline phosphatase >6 times the ULN, no
dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
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 and prostate cancer.
33
Elderly
Based on a population pharmacokinetic analysis, there are no special instructions for use in the
elderly.
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).
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.
34
Cutaneous reactions
Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema
followed by desquamation has been observed. Severe symptoms such as eruptions followed by
desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see
section 4.2).
Fluid retention
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be
monitored closely.
Patients with liver impairment
In patients treated with docetaxel at 100 mg/m
2
as single agent who have serum transaminase levels
(ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels
greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as
toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia,
infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel
in those patients with elevated liver function test (LFTs) is 75 mg/m
2
and LFTs should be measured at
baseline and before each cycle (see section 4.2).
For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent
with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended
and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric
adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN
associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x UNL; for these patients, no
dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No
data are available in patients with hepatic impairment treated by docetaxel in combination in the other
indications.
Patients with renal impairment
There are no data available in patients with severely impaired renal function treated with docetaxel.
Nervous system
The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).
Cardiac toxicity
Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab,
particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may
be moderate to severe and has been associated with death (see section 4.8).
When patients are candidates for treatment with docetaxel in combination with trastuzumab, they
should undergo baseline cardiac assessment. Cardiac function should be further monitored during
treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For
more details see Summary of Product Characteristics of trastuzumab.
Others
Contraceptive measures must be taken by both men and women during treatment and for men at least
6 months after cessation of therapy (see section 4.6).
35
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.
In vitro
studies have shown that the metabolism of docetaxel may be modified by the concomitant
administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the
enzyme competitively) cytochrome P450-3A such as cyclosporine, terfenadine, ketoconazole,
erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with
these medicinal products as concomitant therapy since there is a potential for a significant interaction.
Docetaxel is highly protein bound (>95%). Although the possible
in vivo
interaction of docetaxel with
concomitantly administered medicinal products has not been investigated formally,
in vitro
interactions with tightly protein-bound drugs such as erythromycin, diphenhydramine, propranolol,
propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein
binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel.
Docetaxel did not influence the binding of digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their
coadministration. 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.
36
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.
4.8 Undesirableeffects
The adverse reactions considered to be possibly or probably related to the administration of docetaxel
have been obtained in:
•
1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent
respectively.
•
258 patients who received docetaxel in combination with doxorubicin.
•
406 patients who received docetaxel in combination with cisplatin.
•
92 patients treated with docetaxel in combination with trastuzumab.
•
255 patients who received docetaxel in combination with capecitabine.
•
332 patients who received docetaxel in combination with prednisone or prednisolone (clinically
important treatment related adverse events are presented).
•
1276 patients (744 and 532 in TAX 316 and GEICAM 9805 respectively) who received
docetaxel in combination with doxorubicin and cyclophosphamide (clinically important
treatment related adverse events are presented).
•
300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and
79 patients in the phase II part) who received docetaxel in combination with cisplatin and
5-fluorouracil (clinically important treatment related adverse events are presented).
37
•
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 and the MedRA 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.
Severe reactions were characterised by hypotension and/or bronchospasm or generalized
rash/erythema (see section 4.4).
Nervous system disorders
The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2
and 4.4). Mild to moderate neuro-sensory signs are characterised by paresthesia, dysesthesia or pain
including burning. Neuro-motor events are mainly characterised by weakness.
Skin and subcutaneous tissue disorders
Reversible cutaneous reactions have been observed and were generally considered as mild to
moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and
hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently
associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion.
Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to
interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe
nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.
General disorders and administration site conditions
Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation,
redness or dryness of the skin, phlebitis or extravasations and swelling of the vein.
Fluid retention includes events such as peripheral oedema and less frequently pleural effusion,
pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower
38
extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is
cumulative in incidence and severity (see section 4.4).
Docetaxel 100 mg/m² single agent
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infections (G3/4: 5.7%;
including sepsis and
pneumonia, fatal in
1.7%)
Infection associated
with G4 neutropenia
(G3/4: 4.6%)
Blood and lymphatic
system disorders
Neutropenia
(G4: 76.4%);
Anaemia (G3/4: 8.9%);
Febrile neutropenia
Thrombocytopenia
(G4: 0.2%)
Immune system
disorders
Hypersensitivity (G3/4:
5.3%)
Metabolism and
nutrition disorders
Anorexia
Nerveus system
disorders
Peripheral sensory
neuropathy (G3: 4.1%);
Peripheral motor
neuropathy (G3/4: 4%)
Dysgeusia
(severe 0.07%)
Cardiac disorders
Arrhythmia
(G3/4: 0.7%)
Cardiac failure
Hypotension;
Hypertension;
Haemorrhage
Vascular disorders
Respiratory, thoracic
and mediastinal
disorders
Dyspnoea (severe 2.7%)
Stomatitis (G3/4: 5.3%);
Diarrhoea (G3/4: 4%);
Nausea (G3/4: 4%);
Vomiting (G3/4: 3%)
Constipation
(severe 0.2%);
Abdominal pain
(severe 1%);
Gastrointestinal
Haemorrhage
(severe 0.3%)
Oesophagitis
(severe: 0.4%)
Gastrointestinal
disorders
Alopecia;
Skin reaction
(G3/4: 5.9%);
Nail disorders
(severe 2.6%)
Skin and subcutaneous
tissue disorders
Musculoskeletal,
connective tissue
disorders
Myalgia (severe 1.4%)
Arthralgia
General disorders and
Fluid retention
Infusion site reaction;
39
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
administration site
conditions
(severe: 6.5%)
Asthenia
(severe 11.2%);
Pain
Non-cardiac chest
pain (severe 0.4%)
G3/4 Blood bilirubin
increased (< 5%);
G3/4 Blood alkaline
phosphatase increased
(< 4%);
G3/4 AST increased
(<3%),
G3/4 ALT increased
(<2%)
Investigations
Blood and lymphatic system disorders
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia.
Nervous system disorders
Reversibility data are available among 35.3% of patients who developed neurotoxicity following
docetaxel treatment at 100 mg/m² as single agent. The events were spontaneously reversible within
3 months.
Skin and subcutaneous tissue disorders
Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions
were reversible within 21 days.
General disorders and administration site conditions
The median cumulative dose to treatment discontinuation was more than 1,000 mg/m
2
and the median
time to fluid retention reversibility was 16.4 weeks (range 0
to 42 weeks). The onset of moderate and
severe retention is delayed (median cumulative dose: 818.9 mg/m
2
) in patients with premedication
compared with patients without premedication (median cumulative dose: 489.7 mg/m
2
); however, it
has been reported in some patients during the early courses of therapy.
40
Docetaxel 75 mg/m² single agent
MedDRA system srgan classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infections (G3/4: 5%)
Neutropenia (G4: 54.2%);
Anaemia (G3/4: 10.8%);
Thrombocytopenia
(G4: 1.7%)
Blood and lymphatic system
disorders
Febrile neutropenia
Immune system disorders
Hypersensitivity (no severe)
Metabolism and nutrition
disorders
Anorexia
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 0.8%)
Peripheral motor neuropathy
(G3/4: 2.5%)
Cardiac disorders
Arrhythmia (no severe)
Vascular disorders
Hypotension
Nausea (G3/4: 3.3%);
Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Gastrointestinal disorders
Constipation
Skin and subcutaneous tissue
disorders
Alopecia;
Skin reaction (G3/4: 0.8%)
Nail disorders (severe 0.8%)
Musculoskeletal and connective
tissue disorders
Myalgia
Asthenia (severe 12.4%);
Fluid retention (severe 0.8%);
Pain
General disorders and
administration site conditions
Investigations
G3/4 Blood bilirubin increased
(< 2%)
41
Docetaxel 75 mg/m² in combination with doxorubicin
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 7.8%)
Blood and lymphatic
system disorders
Neutropenia
(G4: 91.7%);
Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia
(G4: 0.8%)
Immune system
disorders
Hypersensitivity
(G3/4: 1.2%)
Metabolism and
nutrition disorders
Anorexia
Nervous system
disorders
Peripheral sensory
neuropathy (G3: 0.4%)
Peripheral motor
neuropathy
(G3/4: 0.4%)
Cardiac failure;
Arrhythmia (no severe)
Cardiac disorders
Vascular disorders
Hypotension
Nausea (G3/4: 5%);
Stomatitis
(G3/4: 7.8%);
Diarrhoea
(G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation
Gastrointestinal
disorders
Alopecia;
Nail disorders
(severe 0.4%);
Skin reaction (no
severe)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Myalgia
Asthenia
(severe 8.1%);
Fluid retention
(severe 1.2%);
Pain
General disorders and
administration site
conditions
Infusion site reaction
Investigations
G3/4 Blood bilirubin
increased (< 2.5%);
G3/4 Blood alkaline
phosphatase increased
(< 2.5%)
G3/4 AST increased
(< 1%);
G3/4 ALT increased
(< 1%
42
Docetaxel 75 mg/m² in combination with cisplatin
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 5.7%)
Blood and lymphatic
system disorders
Neutropenia
(G4: 51.5%);
Anaemia (G3/4: 6.9%);
Thrombocytopenia
(G4: 0.5%)
Febrile neutropenia
Immune system
disorders
Hypersensitivity
(G3/4: 2.5%)
Metabolism and
nutrition disorders
Anorexia
Peripheral sensory
neuropathy (G3: 3.7%);
Peripheral motor
neuropathy (G3/4: 2%)
Nervous system
disorders
Arrhythmia
(G3/4: 0.7%)
Cardiac disorders
Cardiac failure
Hypotension
(G3/4: 0.7%)
Vascular disorders
Gastrointestinal
disorders
Nausea (G3/4: 9.6%);
Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%);
Constipation
Skin and
subcutaneous tissue
disorders
Alopecia;
Nail disorders
(severe 0.7%);
Skin reaction
(G3/4: 0.2%)
Musculoskeletal and
connective tissue
disorders
Myalgia (severe: 0.5%)
Asthenia (severe 9.9%);
Fluid retention
(severe 0.7%);
Fever (G3/4: 1.2%)
General disorders
and administration
site conditions
Infusion site reaction;
pain
G3/4 AST increased
(0.5%);
G3/4 Blood alkaline
phosphatase increased
(0.3%)
Investigations
G3/4 Blood bilirubin
increased (2.1%);
G3/4 ALT increased
(1.3%)
43
Docetaxel 100 mg/m² in combination with trastuzumab
MedDRA system organ classes
Very common adverse reactions
Common adverse
reactions
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Febrile neutropenia (includes
neutropenia associated with fever
and antibiotic use) or neutropenic
sepsis
Metabolism and nutrition
disorders
Anorexia
Psychiatric disorders
Insomnia
Nervous system disorders
Paresthesia; Headache; Dysgeusia;
Hypoaesthesia
Eye disorders
Lacrimation increased;
Conjunctivitis
Cardiac disorders
Cardiac failure
Vascular disorders
Lymphoedema
Respiratory, thoracic and
mediastinal disorders
Epistaxis; Pharyngolaryngeal pain;
Nasopharyngitis ; Dyspnoea;
Cough; Rhinorrhoea
Gastrointestinal disorders
Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain
Skin and subcutaneous tissue
disorders
Alopecia; Erythema; Rash; Nail
disorders
Musculoskeletal and connective
tissue disorders
Myalgia; Arthralgia; Pain in
extremity; Bone pain; Back pain
General disorders and
administration site conditions
Asthenia; Oedema peripheral;
Pyrexia; Fatigue; Mucosal
inflammation; Pain; Influenza like
illness; Chest pain; Chills
lethargy
Investigations
Weight increased
Cardiac disorders
Symptomatic cardiac failure was reported in 2.2% of the patients who received docetaxel plus
trastuzumab compared to 0% of patients given docetaxel alone. In the docetaxel plus trastuzumab arm,
64% had received a prior anthracycline as adjuvant therapy compared with 55% in the docetaxel arm
alone.
Blood and lymphatic system disorders
Very common: Haematological toxicity was increased in patients receiving trastuzumab and
docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC
criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m
2
is
known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The
incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with
Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).
44
Docetaxel 75 mg/m² in combination with capecitabine
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Oral candidiasis (G3/4: < 1%)
Neutropenia (G3/4: 63%);
Anaemia (G3/4: 10%)
Blood and lymphatic system
disorders
Thrombocytopenia (G3/4: 3%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 1%);
Decreased appetite
Dehydration (G3/4: 2%)
Dizziness;
Headache (G3/4: <1%);
Neuropathy peripheral
Nervous system disorders
Dysgeusia (G3/4: <1%);
Paresthesia (G3/4: <1%)
Eye disorders
Lacrimation increased
Dyspnoea (G3/4: 1%);
Cough (G3/4: <1%);
Epistaxis (G3/4: <1%)
Respiratory, thoracic and
mediastinal disorders
Pharyngolaryngeal pain
(G3/4: 2%)
Stomatitis (G3/4: 18%);
Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Gastrointestinal disorders
Abdominal pain upper;
Dry mouth
Skin and subcutaneous tissue
disorders
Hand-foot syndrome
(G3/4: 24%)
Alopecia (G3/4: 6%);
Nail disorders (G3/4: 2%)
Dermatitis;
Rash erythematous
(G3/4: <1%);
Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective
tissue disorders
Myalgia (G3/4: 2%);
Arthralgia (G3/4: 1%)
Pain in extremity (G3/4: <1%);
Back pain (G3/4: 1%);
Asthenia (G3/4: 3%);
Pyrexia (G3/4: 1%);
Fatigue/ weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%);
General disorders and
administration site conditions
Lethargy;
Pain
Investigations
Weight decreased;
G3/4 Blood bilirubin increased
(9%)
45
Docetaxel 75 mg/m² in combination with prednisone or prednisolone
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Infection (G3/4: 3.3%)
Blood and lymphatic system
disorders
Neutropenia (G3/4: 32%);
Anaemia (G3/4: 4.9%)
Thrombocytopenia
(G3/4: 0.6%)
Febrile neutropenia
Immune system disorders
Hypersensivity (G3/4: 0.6%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 0.6%)
Peripheral sensory neuropathy
(G3/4: 1.2%);
Dysgeusia (G3/4: 0%)
Nervous system disorders
Peripheral motor neuropathy
(G3/4: 0%)
Lacrimation increased (G
3/4; 0.6%)
Eye disorders
Cardiac disorders
Cardiac left ventricular function
decrease (G3/4: 0.3%)
Epistaxis (G3/4: 0%);
Dyspnoea (G3/4: 0.6%);
Cough (G3/4: 0%)
Respiratory, thoracic and
mediastinal disorders
Nausea (G3/4: 2.4%);
Diarrhoea (G3/4: 1.2%);
Stomatitis/Pharyngitis
(G3/4: 0.9%);
Vomiting (G3/4: 1.2%)
Gastrointestinal disorders
Skin and subcutaneous tissue
disorders
Alopecia;
Nail disorders (no severe)
Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective
tissue disorders
Arthralgia (G3/4: 0.3%);
Myalgia (G3/4: 0.3%)
General disorders and
administration site conditions
Fatigue (G3/4: 3.9%);
Fluid retention (severe 0.6%)
46
Adjuvant therapy with Docetaxel 75 mg/m² in combination with doxorubicin and cyclophosphamide
in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer - pooled
data
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infection
(G3/4: 2.4%);
Neutropenic infection.
(G3/4: 2.7%)
Infections and
infestations
Anaemia (G3/4: 3%);
Neutropenia
(G3/4: 59.2%);
Thrombocytopenia
(G3/4: 1.6%);
Febrile neutropenia
(G3/4: NA)
Blood and lymphatic
system disorders
Immune system
disorders
Hypersensitivity
(G3/4: 0.6%)
Metabolism and
nutrition disorders
Anorexia (G3/4: 1.5%)
Dysgeusia
(G3/4: 0.6%);
Peripheral sensory
neuropathy
(G3/4: <0.1%)
Nervous system
disorders
Peripheral motor
neuropathy
(G3/4: 0%);
Syncope (G3/4: 0%)
Neurotoxicity(G3/4: 0%);
Somnolence (G3/4: 0%)
Eye disorders
Conjunctivitis
(G3/4: <0.1%)
Lacrimation disorder
(G3/4: <0.1%);
Cardiac disorders
Arrhythmia
(G3/4: 0.2%);
Vascular disorders
HotFlush (G3/4: 0.5%)
Hypotension
(G3/4: 0%)
Phlebitis (G3/4: 0%)
Lymphoedema
(G3/4: 0%)
Respiratory, thoracic
and mediastinal
disorders
Cough (G3/4: 0%)
Nausea (G3/4: 5.0%);
Stomatitis
(G3/4: 6.0%);
Vomiting
(G3/4: 4.2%);
Diarrhoea
(G3/4: 3.4%);
Constipation
(G3/4: 0.5%)
Gastrointestinal
disorders
Abdominal pain
(G3/4: 0.4%)
Alopecia
(G3/4: <0.1%);
Skin disorder
(G3/4: 0.6%);
Nail disorders
(G3/4: 0.4%)
Skin and subcutaneous
tissue disorders
Musculoskeletal and
Myalgia (G3/4: 0.7%);
47
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
connective tissue
disorders
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%)
Weight increased
(G3/4: 0%)
Weight decreased
(G3/4: 0.2%)
Investigations
Nervous system disorders
Peripheral sensory neuropathy was observed to be ongoing during follow-up in 12 patients out of the
83 patients with peripheral sensory neuropathy at the end of the chemotherapy.
Cardiac disorders
Congestive Heart Failure (CHF) has been reported in 18 of 1276 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 time in 25 patients out of the 736 patients with
alopecia at the end of the chemotherapy.
Reproductive system and breast disorders
Amenorrhoea was observed to be ongoing during follow-up 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.
48
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)
Neutropenic infection
(Grade 3-4)
2 (1.8)
5 (1.2)
49
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for gastric adenocarcinoma
cancer:
MedDRA system organ
classes
Very common adverse
reactions
Common adverse reactions
Infections and infestations
Neutropenic infection;
Infection (G3/4:
11.7%)
Blood and lymphatic system
disorders
Anaemia (G3/4: 20.9%);
Neutropenia (G3/4: 83.2%);
Thrombocytopenia
(G3/4: 8.8%);
Febrile neutropenia.
Immune system disorders
Hypersensitivity (G3/4: 1.7%)
Metabolism and nutrition
disorders
Anorexia (G3/4: 11.7%)
Dizziness (G3/4: 2.3%);
Peripheral motor neuropathy
(G3/4: 1.3%).
Nervous system disorders
Peripheral sensory neuropathy
(G3/4: 8.7%).
Lacrimation increased
(G3/4: 0%).
Eye disorders
Ear and labyrinth disorders
Hearing impaired (G3/4: 0%).
Cardiac disorders
Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders
Diarrhoea (G3/4: 19.7%);
Nausea (G3/4: 16%);
Stomatitis (G3/4: 23.7%);
Vomiting (G3/4: 14.3%).
Constipation (G3/4: 1.0 %);
Gastrointestinal pain
(G3/4: 1.0%);
Oesophagitis / dysphagia /
odynophagia (G3/4: 0.7%).
Skin and subcutaneous tissue
disorders
Alopecia (G3/4: 4.0%).
Rash pruritus (G3/4: 0.7%);
Nail disorders (G3/4: 0.7%);
Skin exfoliation (G3/4: 0%).
Lethargy (G3/4: 19.0%);
Fever (G3/4: 2.3%);
Fluid retention (severe/life
threatening: 1%).
General disorders and
administration site conditions
Blood and lymphatic system disorders
Febrile neutropenia and neutropenic infection occurred in 17.2% and 13.5% of patients respectively,
regardless of G-CSF use. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of
the cycles). Febrile neutropenia and neutropenic infection occurred respectively in 12.1% and 3.4% of
patients when patients received prophylactic G-CSF, in 15.6% and 12.9% of patients without
prophylactic G-CSF, (see section 4.2).
50
Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil for Head and Neck cancer
•
Induction chemotherapy followed by radiotherapy (TAX 323)
MedDRA system
organ classes
Very common
adverse reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestations
Infection (G3/4: 6.3%);
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Cancer pain (G3/4: 0.6%)
Neutropenia
(G3/4: 76.3%);
Anaemia (G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Blood and lymphatic
system disorders
Febrile neutropenia
Immune system
disorders
Hypersensitivity
(no severe)
Metabolism and
nutrition disorders
Anorexia (G3/4: 0.6%)
Dysgeusia/Parosmia;
Peripheral sensory
neuropathy
(G3/4: 0.6%)
Nervous system
disorders
Dizziness
Lacrimation increased;
Conjunctivitis
Eye disorders
Ear and labyrinth
disorders
Hearing impaired
Cardiac disorders
Myocardial ischemia
(G3/4: 1.7%)
Arrhythmia
(G3/4: 0.6%)
Venous disorder
(G3/4: 0.6%)
Vascular disorders
Constipation;
Oesophagitis/dysphagia/
Odynophagia
(G3/4: 0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal
haemorrhage(G3/4: 0.6%)
Gastrointestinal
disorders
Nausea (G3/4: 0.6%)
Stomatitis
(G3/4: 4.0%)
Diarrhoea
(G3/4: 2.9%)
Vomiting (G3/4: 0.6%)
Rash pruritus;
Dry skin;
Skin exfoliative
(G3/4:0.6%)
Skin and subcutaneous
tissue disorders
Alopecia
(G3/4: 10.9%)
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.6%)
Lethargy (G3/4: 3.4%);
Pyrexia (G3/4: 0.6%);
Fluid retention;
Oedema
General disorders and
administration site
conditions
Investigations
Weight increased
51
•
Induction chemotherapy followed by chemoradiotherapy (TAX 324)
MedDRA system
organ classes
Very common adverse
reactions
Common adverse
reactions
Uncommon adverse
reactions
Infections and
infestation
Infection (G3/4: 3.6%)
Neutropenic infection
Neoplasms benign,
malignant and
unspecified (incl
cysts and polyps)
Cancer pain
(G3/4: 1.2%)
Neutropenia
(G3/4: 83.5%);
Anaemia
(G3/4: 12.4%);
Thrombocytopenia
(G3/4: 4.0%);
Febrile neutropenia
Blood and lymphatic
system disorders
Immune system
disorders
Hypersensitivity
Metabolism and
nutrition disorders
Anorexia (G3/4: 12.0%)
Dysgeusia/Parosmia
(G3/4: 0.4%);
Peripheral sensory
neuropathy
(G3/4: 1.2%)
Nervous system
disorders
Dizziness (G3/4: 2.0%);
Peripheral motor
neuropathy (G3/4: 0.4%)
Eye disorders
Lacrimation increased
Conjunctivitis
Ear and labyrinth
disorders
Hearing impaired
(G3/4: 1.2%)
Arrhythmia
(G3/4: 2.0%)
Ischemia myocardial
Cardiac disorders
Vascular disorders
Venous disorder
Nausea (G3/4: 13.9%);
Stomatitis
(G3/4: 20.7%);
Vomiting (G3/4: 8.4%);
Diarrhoea (G3/4: 6.8%);
Oesophagitis/dysphagia/
Odynophagia
(G3/4: 12.0%);
Constipation
(G3/4: 0.4%)
Gastrointestinal
disorders
Dyspepsia (G3/4: 0.8%);
Gastrointestinal pain
(G3/4: 1.2%);
Gastrointestinal
haemorrhage
(G3/4: 0.4%)
Skin and subcutaneous
tissue disorders
Alopecia (G3/4: 4.0%);
Rash pruritic;
Dry skin;
Desquamation
Musculoskeletal and
connective tissue
disorders
Myalgia (G3/4: 0.4%)
General disorders and
administration site
conditions
Lethargy (G3/4: 4.0%);
Pyrexia (G3/4: 3.6%);
Fluid retention
(G3/4: 1.2%);
Oedema (G3/4:1.2%)
Investigations
Weight decreased
Weight increased
52
Post-marketing experience
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Very rare cases of acute myeloid leukaemia
and myelodysplastic syndrome
have been reported in
association with docetaxel when used in combination with other chemotherapy agents and/or
radiotherapy.
Blood and lymphatic system disorders
Bone marrow suppression and other haematologic adverse reactions have been reported. Disseminated
intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been
reported.
Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.
Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel
administration. These reactions sometimes appear during the infusion of the medicinal product.
Eye Disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring
during infusion of the medicinal product and in association with hypersensitivity reactions have been
reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or
without conjunctivitis, as cases of lachrymal 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 erythematous and bullous eruptions such as erythema multiform,
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 lymphedema have been reported with docetaxel.
53
General disorders and administration site conditions
Radiation recall phenomena have rarely been reported.
Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration
and pulmonary oedema have rarely been reported.
There were a few reports of overdose. There is no known antidote for docetaxel overdose. In case of
overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In
cases of overdose, exacerbation of adverse events may be expected. The primary anticipated
complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and
mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose.
Other appropriate symptomatic measures should be taken, as needed.
5.1 Pharmacodynamicproperties
Pharmacotherapeutic group: Taxanes, ATC Code: L01CD 02
Preclinical data
Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable
microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The
binding of docetaxel to microtubules does not alter the number of protofilaments.
Docetaxel has been shown
in vitro
to disrupt the microtubular network in cells which is essential for
vital mitotic and interphase cellular functions.
Docetaxel was found to be cytotoxic
in vitro
against various murine and human tumour cell lines and
against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular
concentrations with a long cell residence time. In addition, docetaxel was found to be active on some
but not all cell lines over expressing the p-glycoprotein which is encoded by the multidrug resistance
gene.
In vivo
, docetaxel is schedule independent and has a broad spectrum of experimental antitumour
activity against advanced murine and human grafted tumours.
Clinical data
Breast Cancer
Two randomised phase III comparative studies, involving a total of 326 alkylating or
392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel at the
recommended dose and regimen of 100 mg/m² every 3 weeks.
In alkylating-failure patients, docetaxel was compared to doxorubicin (75 mg/m² every 3 weeks).
Without affecting overall survival time (docetaxel 15 months vs. doxorubicin 14 months, p=0.38) or
time to progression (docetaxel 27 weeks vs. doxorubicin 23 weeks, p=0.54), docetaxel increased
response rate (52% vs. 37%, p=0.01) and shortened time to response (12 weeks vs. 23 weeks,
p=0.007). Three docetaxel patients (2%) discontinued the treatment due to fluid retention, whereas 15
doxorubicin patients (9%) discontinued due to cardiac toxicity (three cases of fatal congestive heart
failure).
In anthracycline-failure patients, docetaxel was compared to the combination of mitomycin C and
vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel increased response rate
(33% vs. 12%, p<0.0001), prolonged time to progression (19 weeks vs. 11 weeks, p=0.0004) and
prolonged overall survival (11 months vs. 9 months, p=0.01).
54
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%).
Non-small cell lung cancer
Patients previously treated with chemotherapy with or without radiotherapy
In a phase III study, in previously treated patients, time to progression (12.3 weeks versus 7 weeks)
and overall survival were significantly longer for docetaxel at 75 mg/m² compared to Best Supportive
Care. The 1-year survival rate was also significantly longer in docetaxel (40%) versus BSC (16%).
There was less use of morphinic analgesic (p<0.01), non-morphinic analgesics (p<0.01), other disease
related medications (p=0.06) and radiotherapy (p<0.01) in patients treated with docetaxel at 75 mg/m²
compared to those with BSC.
The overall response rate was 6.8% in the evaluable patients, and the median duration of response was
26.1 weeks.
Docetaxel in combination with platinum agents in chemotherapy-naïve patients
In a phase III study, 1218 patients with unresectable stage IIIB or IV NSCLC, with KPS of 70% or
greater, and who did not receive previous chemotherapy for this condition, were randomised to either
Docetaxel (T) 75 mg/m
2
as a 1 hour infusion immediately followed by cisplatin (Cis) 75 mg/m
2
over
30-60 minutes every 3 weeks (TCis), Docetaxel 75 mg/m
2
as a 1 hour infusion in combination with
carboplatin (AUC 6 mg/ml. min) over 30-60 minutes every 3 weeks, or vinorelbine (V) 25 mg/m
2
administered over 6-10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m
2
administered on
day 1 of cycles repeated every 4 weeks (VCis).
Survival data, median time to progression and response rates for two arms of the study are illustrated
in the following table:
TCis
n=408
VCis
n=404
Statistical Analysis
Overall survival
(Primary end-point):
Median survival (months)
11.3
10.1
Hazard ratio: 1.122
[97.2% CI: 0.937; 1.342]*
1-year Survival (%)
46
41
Treatment difference: 5.4%
[95% CI: -1.1; 12.0]
2-year Survival (%)
21
14
Treatment difference: 6.2%
[95% CI: 0.2; 12.3]
Median time to progression
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%
55
(weeks)
[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 (%)
95% CI
p-value*
291
45.4
(39.5-51.3)
0.0005
282
47.9
(41.9-53.9)
<0.0001
300
31.7
(26.4-37.3)
--
Number of patients
Pain response rate (%)
95% CI
p-value*
153
34.6
(27.1-42.7)
0.0107
154
31.2
(24.0-39.1)
0.0798
157
21.7
(15.5-28.9)
--
Number of patients
Tumour response rate
(%)
95% CI
p-value*
141
12.1
(7.2-18.6)
0.1112
134
8.2
(4.2-14.2)
0.5853
137
6.6
(3.0-12.1)
--
†
Stratified log rank test
*Threshold for statistical significance=0.0175
**PSA: Prostate-Specific Antigen
Given the fact that docetaxel every week presented a slightly better safety profile than docetaxel every
3 weeks, it is possible that certain patients may benefit from docetaxel every week.
56
No statistical differences were observed between treatment groups for Global Quality of Life.
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 lowered by 27% on average (see section 4.2). Docetaxel clearance was not
modified in patients with mild to moderate fluid retention and there are no data available in patients
with severe fluid retention.
When used in combination, docetaxel does not influence the clearance of doxorubicin and the plasma
levels of doxorubicinol (a doxorubicin metabolite). The pharmacokinetics of docetaxel, doxorubicin
and cyclophosphamide were not influenced by their coadministration.
Phase I study evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice
versa showed no effect by capecitabine on the pharmacokinetics of docetaxel (C
max
and AUC) and no
effect by docetaxel on the pharmacokinetics of a relevant capecitabine metabolite 5’-DFUR.
Clearance of docetaxel in combination therapy with cisplatin was similar to that observed following
monotherapy. The pharmacokinetic profile of cisplatin administered shortly after docetaxel infusion is
similar to that observed with cisplatin alone.
The combined administration of docetaxel, cisplatin and 5-fluorouracil in 12 patients with solid
tumours had no influence on the pharmacokinetics of each individual medicinal product.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard
dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the
pharmacokinetics of docetaxel was observed.
5.3 Preclinical safety data
The carcinogenic potential of docetaxel has not been studied.
Docetaxel has been shown to be mutagenic in the
in vitro
micronucleus and chromosome aberration
test in CHO-K1 cells and in the
in vivo
micronucleus test in the mouse. However, it did not induce
mutagenicity in the Ames test or the CHO/HGPRT gene mutation assay. These results are consistent
with the pharmacological activity of docetaxel.
57
Undesirable effects on the testis observed in rodent toxicity studies suggest that docetaxel may impair
male fertility.
6.1 List of excipients
Concentrate
Polysorbate 80
Ethanol, anhydrous
Solvent
Water for injections.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
Section 6.6.
6.3 Shelf-life
•
18 months.
•
Premix solution: Chemical and physical in-use stability has been demonstrated for 8 hours when
stored either between 2°C and 8°C or at room temperature (below 25°C). From a
microbiological point of view, the product should be used immediately. If not used immediately,
in-use storage times and conditions prior to use are the responsibility of the user and would
normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled
and validated aseptic conditions.
•
Infusion solution: Chemical and physical in-use stability has been demonstrated for 4 hours at
room temperature (below 25°C). From a microbiological point of view, the product should be
used immediately. If not used immediately, in-use storage times and conditions prior to use are
the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless
dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage and other handling
Do not store above 25°C.
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions of the diluted medicinal product, see section 6.3.
6.5 Nature and contents of container
Each carton contains:
•
One vial of concentrate and,
•
One vial of solvent
•
Docetaxel Teva Pharma 80 mg vial
15 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
This vial contains 2.88 ml of a 27.73 mg/ml solution of docetaxel in polysorbate 80
(fill volume: 94.4 mg/3.40 ml). This fill volume has been established during the development of
docetaxel to compensate for liquid loss during preparation of the premix due to foaming,
adhesion to the walls of the vial and "dead-volume". This overfill ensures that after dilution with
the entire contents of the accompanying solvent for docetaxel vial, there is a minimal extractable
58
premix volume of 8 ml containing 10 mg/ml docetaxel which corresponds to the labelled
amount of 80 mg per vial.
Solvent for Docetaxel Teva Pharma 80 mg vial
15 ml clear glass Type I vial with a bromobutyl rubber stopper and a flip-off cap.
Solvent vial contains 5.12 ml of water for injections (fill volume: 6.29 ml). The addition of the
entire contents of the solvent vial to the contents of the Docetaxel Teva Pharma 80 mg
concentrate for solution for infusion vial ensures a premix concentration of 10 mg/ml docetaxel.
6.6 Special precautions for disposal and other handling
Docetaxel Teva Pharma is an antineoplastic agent and, as with other potentially toxic compounds,
caution should be exercised when handling it and preparing Docetaxel solutions. The use of gloves is
recommended.
If Docetaxel Teva Pharma concentrate, premix solution or infusion solution should come into contact
with skin, wash immediately and thoroughly with soap and water. If Docetaxel concentrate, premix
solution or infusion solution should come into contact with mucous membranes, wash immediately
and thoroughly with water.
Preparation for the intravenous administration
a)
Preparation of the Docetaxel Teva Pharma premix solution (10 mg docetaxel/ml)
If the vials are stored under refrigeration, allow the required number of Docetaxel Teva Pharma boxes
to stand at room temperature (below 25°C) for 5 minutes.
Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Teva Pharma vial by partially inverting the vial.
Inject the entire contents of the syringe into the corresponding Docetaxel Teva Pharma vial.
Remove the syringe and needle and mix manually by repeated inversions for at least 45 seconds. Do
not shake.
Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then check that
the solution is homogenous and clear (foaming is normal even after 5 minutes due to the presence of
polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after preparation.
However the chemical and physical stability of the premix solution has been demonstrated for 8 hours
when stored either between 2°C and 8°C or at room temperature (below 25°C).
b)
Preparation of the infusion solution
More than one premix vial may be necessary to obtain the required dose for the patient. Based on the
required dose for the patient expressed in mg, aseptically withdraw the corresponding premix volume
containing 10 mg/ml docetaxel from the appropriate number of premix vials using graduated syringes
fitted with a needle. For example, a dose of 140 mg docetaxel would require 14 ml docetaxel premix
solution.
Inject the required premix volume into a non-PVC 250 ml infusion bag containing either 5% glucose
solution or sodium chloride 9 mg/ml (0.9%) solution for infusion.
If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so
that a concentration of 0.74 mg/ml docetaxel is not exceeded.
59
Mix the infusion bag or bottle manually using a rocking motion.
The Docetaxel Teva Pharma infusion solution should be used within 4 hours and should be aseptically
administered as a 1-hour infusion under room temperature (below 25°C) and normal lighting
conditions.
As with all parenteral products, Docetaxel Teva Pharma premix solution and infusion solution should
be visually inspected prior to use, solutions containing a precipitate should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
8. MARKETING AUTHORISATION NUMBER
Detailed information on this product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
60
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
61
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR
BATCH RELEASE
Name and address of the manufacturers responsible for batch release
Pharmachemie BV.
Swensweg 5
Postbus 552
2003 RN Haarlem
The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
2100 Gödöllő
Hungary
Teva Kutno SA
Sienkiewicza 25
99-300 Kutno
Poland
Teva Czech Industries s.r.o
Ostravská 29
Č.p. 305
747 70 Opava-Komárov
Czech Republic
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance as described in version 9 dated June
2010 presented in Module 1.8.1. of the Marketing Authorisation Application is in place and
functioning before and whilst the product is on the market.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
62
ANNEX III
LABELLING AND PACKAGE LEAFLET
63
A. LABELLING
64
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON – 20 mg
1.
Docetaxel Teva Pharma 20 mg concentrate and solvent for solution for infusion
docetaxel
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each single-dose vial of Docetaxel Teva Pharma concentrate contains 20 mg docetaxel (anhydrous).
Each ml of concentrate contains 27.73 mg docetaxel.
3.
LIST OF EXCIPIENTS
Docetaxel concentrate vial:
polysorbate 80, anhydrous ethanol.
Solvent vial:
water for injections.
See leaflet for further information.
4.
Concentrate and solvent for solution for infusion.
Each carton contains:
•
one vial of 0.72 ml concentrate (20 mg of docetaxel),
•
one vial of 1.28 ml solvent (water for injections).
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
CAUTION: Dilution of concentrate required using the entire contents of the solvent vial.
Reconstituted solution must be further diluted in the infusion diluent before administration.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
KEEP OUT OF THE REACH AND SIGHT OF CHILDREN.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
CYTOTOXIC. To be administered under the supervision of a physician experienced in the use of
cytotoxic agents
65
8.
EXPIRY DATE
EXP:
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
Do not freeze
Store in the original package in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Single-use vials.
Discard unused contents appropriately
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
12. MARKETINGAUTHORISATIONNUMBER(S)
EU/0/00/000/000
13.
BATCH NUMBER
Batch:
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATIONINBRAILLE
Justification for not including Braille accepted.
66
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL – CONCENTRATE 20 mg
6. FURTHER INFORMATION
What Docetaxel Teva Pharma concentrate vial contains:
-
The active substance is docetaxel. Each vial of concentrate contains 80 mg of docetaxel. Each
ml of concentrate contains 27.73 mg docetaxel.
-
The other ingredients are polysorbate 80 and 25.1% (w/w) anhydrous ethanol.
What the solvent vial contains:
Water for injections.
What Docetaxel Teva Pharma looks like and contents of the pack:
Docetaxel Teva Pharma concentrate for solution for infusion is a clear viscous, yellow to brown-
yellow solution.
Each carton contains:
•
one 15 ml clear glass vial with a flip-off cap containing 2.88 ml concentrate and,
•
one 15 ml clear glass vial with a flip-off cap containing 5.12 ml of solvent.
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturer:
Pharmachemie B.V.
Swensweg 5
PO Box 552
2003 RN Haarlem
The Netherlands
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
2100 Gödöllő
Hungary
Teva Kutno SA
Sienkiewicza 25
99-300 Kutno
Poland
Teva Czech Industries s.r.o
Ostravská 29
Č.p. 305
747 70 Opava-Komárov
Czech Republic
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A./AG
Tel/Tél: +32 3 820 73 73
Luxembourg
Teva Pharma Belgium S.A.
Tél: +32 3 820 73 73
88
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Pharma, S.L.U.
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
89
This leaflet was last approved in
{
MM/YYYY
}
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu/
.
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The following information is intended for medical or healthcare professional only:
PREPARATION GUIDE FOR USE WITH DOCETAXEL TEVA PHARMA 80 mg
CONCENTRATE AND SOLVENT FOR SOLUTION FOR INFUSION
__________________________________________________________________________
It is important that you read the entire contents of this procedure prior to the preparation of either the
Docetaxel Teva Pharma premix solution or the Docetaxel Teva Pharma infusion solution
1. FORMULATION
Docetaxel Teva Pharma 80 mg concentrate for solution for infusion is a clear viscous, yellow to
brown-yellow solution containing 27.73 mg/ml docetaxel (anhydrous) in polysorbate 80. The solvent
for Docetaxel Teva Pharma is water for injections.
2. PRESENTATION
Docetaxel Teva Pharma is supplied as single-dose vials.
Each box contains one Docetaxel Teva Pharma vial (80 mg) and one corresponding solvent for
Docetaxel Teva Pharma vial in a carton.
Docetaxel Teva Pharma vials should not be stored above 25°C and should be protected from light.
Docetaxel Teva Pharma should not be used after the expiry date shown on the carton and vials.
2.1 Docetaxel 80 mg vial:
•
The Docetaxel 80 mg vial is a 15 ml clear glass vial with a bromobutyl rubber stopper and a
flip-off cap.
•
The Docetaxel 80 mg vial contains a solution of docetaxel in polysorbate 80 at a concentration
of 27.73 mg/ml.
Each vial contains 80 mg/2.88 ml of a 27.73 mg/ml solution of docetaxel in polysorbate 80 (fill
volume: 94.4 mg/3.40 ml). This fill volume has been established during the development of
docetaxel to compensate for liquid loss during preparation of the premix due to foaming,
adhesion to the walls of the vial and "dead-volume". This overfill ensures that after dilution with
the entire contents of the accompanying solvent for docetaxel vial, there is a minimal extractable
premix volume of 8 ml containing 10 mg/ml docetaxel which corresponds to the labelled
amount of 80 mg per vial.
2.2 Solvent for Docetaxel 80 mg vial:
•
The solvent for Docetaxel 80 mg vial is a 15 ml clear glass vial with a bromobutyl rubber
stopper and a flip-off cap.
•
The solvent for Docetaxel composition is water for injections.
Each solvent vial contains 5.12 ml of water for injections (fill volume: 6.29 ml). The addition of
the entire contents of the solvent vial to the contents of the docetaxel 80 mg concentrate for
solution for infusion vial ensures a premix concentration of 10 mg/ml docetaxel.
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3. RECOMMENDATIONS FOR THE SAFE HANDLING
Docetaxel Teva Pharma is an antineoplastic agent and, as with other potentially toxic compounds,
caution should be exercised when handling it and preparing Docetaxel Teva Pharma solutions. The use
of gloves is recommended.
If Docetaxel Teva Pharma concentrate, premix solution or infusion solution should come into contact
with skin, wash immediately and thoroughly with soap and water. If Docetaxel Teva Pharma
concentrate, premix solution or infusion solution should come into contact with mucous membranes,
wash immediately and thoroughly with water.
4. PREPARATION FOR THE INTRAVENOUS ADMINISTRATION
4.1 Preparation of the Docetaxel Teva Pharma premix solution (10 mg docetaxel/ml)
4.1.1 If the vials are stored under refrigeration, allow the required number of Docetaxel Teva
Pharma boxes to stand at room temperature (below 25°C) for 5 minutes.
4.1.2 Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for
Docetaxel Teva Pharma vial by partially inverting the vial.
4.1.3 Inject the entire contents of the syringe into the corresponding Docetaxel Teva Pharma vial.
4.1.4 Remove the syringe and needle and mix manually by repeated inversions for at least 45
seconds. Do not shake.
4.1.5 Allow the premix vial to stand for 5 minutes at room temperature (below 25°C) and then
check that the solution is homogenous and clear (foaming is normal even after 5 minutes due
to the presence of polysorbate 80 in the formulation).
The premix solution contains 10 mg/ml docetaxel and should be used immediately after
preparation. However the chemical and physical stability of the premix solution has been
demonstrated for 8 hours when stored either between +2°C and +8°C or at room temperature
(below 25°C).
4.2 Preparation of the infusion solution
4.2.1 More than one premix vial may be necessary to obtain the required dose for the patient. Based
on the required dose for the patient expressed in mg, aseptically withdraw the corresponding
premix volume containing 10 mg/ml docetaxel from the appropriate number of premix vials
using graduated syringes fitted with a needle. For example, a dose of 140 mg docetaxel would
require 14 ml docetaxel premix solution.
4.2.2 Inject the required premix volume into a 250 ml non-PVC infusion bag containing either 5%
glucose solution or sodium chloride 9 mg/ml (0.9%) solution for infusion. If a dose greater
than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a
concentration of 0.74 mg/ml docetaxel is not exceeded.
4.2.3
Mix the infusion bag or bottle manually using a rocking motion.
4.2.4
The Docetaxel Teva Pharma infusion solution should be used within 4 hours and should be
aseptically administered as a 1-hour infusion under room temperature (below 25°C) and
normal lighting conditions.
4.2.5
As with all parenteral products, Docetaxel Teva Pharma premix solution and infusion solution
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should be visually inspected prior to use, solutions containing a precipitate should be
discarded.
5. DISPOSAL
All materials that have been utilised for dilution and administration should be disposed of according to
standard procedures.
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Source: European Medicines Agency
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