1. Name Of The Medicinal Product
Docetaxel Actavis 20mg/0.5ml concentrate and solvent for solution for infusion
2. Qualitative And Quantitative Composition
Each single dose vial contains docetaxel 20mg/0.5ml.
Each single dose vial contains 40mg/ml of docetaxel.
Each single dose vial contains 10mg/ml of docetaxel after reconstitution with the accompanying solvent.
Excipients:
Each single dose 20mg/0.5ml vial of concentrate contains 50mg ethanol absolute.
Each single dose vial of solvent contains 9.53% (w/w) ethanol absolute.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Concentrate and solvent for solution for infusion.
The concentrate is a clear, oily, yellow solution.
The solvent is a clear colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Breast cancer
Docetaxel in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node- positive breast cancer.
Docetaxel in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition.
Docetaxel monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent.
Docetaxel in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2 and who previously have not received chemotherapy for metastatic disease.
Docetaxel in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.
Non-small cell lung cancer
Docetaxel is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.
Docetaxel in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not previously received chemotherapy for this condition.
Prostate cancer
Docetaxel in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer.
Gastric Adenocarcinoma
Docetaxel in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for metastatic disease.
Head and neck cancer
Docetaxel in combination with cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck.
4.2 Posology And Method Of Administration
The use of docetaxel should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy. After reconstitution of the concentrate vial with the approproiate solvent, the premix solution should be homogenous and clear (foaming is normal even after 3 minutes due to the presence of polysorbate 80 in the formulation). (see section 6.6 for instructions on the dilution of the product before administration).
Recommended dosage
For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16mg per day (e.g. 8mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see section 4.4). Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities.
For prostate cancer, given the concurrent use of prednisone or prednisolone the recommended premedication regimen is oral dexamethasone 8mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.4).
Docetaxel is administered as a one-hour infusion every three weeks.
Breast cancer
In the adjuvant treatment of operable node-positive breast cancer, the recommended dose of docetaxel is 75mg/m2 administered 1-hour after doxorubicin 50mg/m2 and cyclophosphamide 500mg/m2 every 3 weeks for 6 cycles (see also Dosage adjustments during treatment).
For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dosage of docetaxel is 100mg/m2 in monotherapy. In first-line treatment, docetaxel 75mg/m2 is given in combination therapy with doxorubicin (50mg/m2).
In combination with trastuzumab the recommended dose of docetaxel is 100mg/m2 every three weeks, with trastuzumab administered weekly. In the pivotal trial the initial docetaxel infusion was started the day following the first dose of trastuzumab. The subsequent docetaxel doses were administered immediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab was well tolerated. For trastuzumab dosage and administration, see trastuzumab summary of product characteristics.
In combination with capecitabine, the recommended dose of docetaxel is 75mg/m2 every three weeks, combined with capecitabine at 1250mg/m2 twice daily (within 30 minutes after a meal) for 2 weeks followed by 1-week rest period. For capecitabine dose calculation according to body surface area, see capecitabine summary of product characteristics.
Non-small cell lung cancer
In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen is docetaxel 75mg/m2 immediately followed by cisplatin 75mg/m2 over 30-60 minutes. For treatment after failure of prior platinum-based chemotherapy, the recommended dosage is 75mg/m² as a single agent.
Prostate cancer
The recommended dose of docetaxel is 75mg/m2. Prednisone or prednisolone 5mg orally twice daily is administered continuously (see section 5.1).
Gastric adenocarcinoma
The recommended dose of docetaxel is 75mg/m2 as a 1 hour infusion, followed by cisplatin 75mg/m2, as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750mg/m2 per day given as a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion.
Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the risk of hematological toxicities (See also Dosage adjustments during treatment).
Head and neck cancer
Patients must receive premedication with antiemetics and appropriate hydration (prior to and after cisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities. All patients on the docetaxel-containing arm of the TAX 323 and TAX 324 studies, received prophylactic antibiotics.
• Induction chemotherapy followed by radiotherapy (TAX 323)
For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75mg/m2 as a 1 hour infusion followed by cisplatin 75mg/m2 over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.
• Induction chemotherapy followed by chemoradiotherapy (TAX 324)
For the induction treatment of patients with locally advanced (technically unresectable, low probability of surgical cure, and aiming at organ preservation) squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100mg/m2 administered as a 30-minute to 3 hour infusion, followed by 5-fluorouracil 1000mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.
For cisplatin and 5-fluorouracil dose modifications, see the corresponding summary of product characteristics.
Dosage adjustments during treatment
General
Docetaxel should be administered when the neutrophil count is 3. In patients who experienced either febrile neutropenia, neutrophil < 500cells/mm3 for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 100mg/m2 to 75mg/m2 and/or from 75 to 60mg/m². If the patient continues to experience these reactions at 60mg/m², the treatment should be discontinued.
Adjuvant therapy for breast cancer
In the pivotal trial in patients who received adjuvant therapy for breast cancer and who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide prophylactic coverage (eg, day 4 to 11) in all subsequent cycles. Patients who continued to experience this reaction should remain on G-CSF and have their docetaxel dose reduced to 60mg/m².
However, in clinical practice neutropenia could occur earlier. Thus the use of G-CSF should be considered function of the neutropenic risk of the patient and current recommendations. Patients who experience Grade 3 or 4 stomatitis should have their dose decreased to 60mg/m².
In combination with cisplatin
For patients who are dosed initially at docetaxel 75mg/m2 in combination with cisplatin and whose nadir of platelet count during the previous course of therapy is < 25000cells/mm3, or in patients who experience febrile neutropenia, or in patients with serious non-hematologic toxicities, the docetaxel dosage in subsequent cycles should be reduced to 65mg/m2. For cisplatin dosage adjustments, see manufacturer's summary of product characteristics.
In combination with capecitabine
• For capecitabine dose modifications, see capecitabine summary of product characteristics.
• For patients developing the first appearance of a Grade 2 toxicity, which persists at the time of the next docetaxel/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at 100% of the original dose.
• For patients developing the second appearance of a Grade 2 toxicity, or the first appearance of a Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1, then resume treatment with docetaxel 55mg/m².
• For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the docetaxel dose.
For trastuzumab dose modifications, see trastuzumab summary of product characteristics
In combination with cisplatin and 5-fluorouracil:
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the docetaxel dose should be reduced from 75 to 60mg/m2. If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45mg/m2. In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60mg/m2. Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level> 1,500cells/mm3 and platelets recover to a level> 100,000cells/mm3. Discontinue treatment if these toxicities persist. (See section 4.4).
Recommended dose modifications for gastrointestinal toxicities in patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (5-FU):
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For cisplatin and 5-fluorouracil dose adjustments, see the corresponding summary of product characteristics.
In the pivotal SCCHN trials patients who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide prophylactic coverage (eg, day 6-15) in all subsequent cycles.
Special populations
Patients with hepatic impairment
Based on pharmacokinetic data with docetaxel at 100mg/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 75mg/m2 (see sections 4.4 and 5.2). For those patients with serum bilirubin> ULN and/or ALT and AST> 3.5 times the ULN associated with alkaline phosphatase> 6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical trial excluded patients with ALT and/or AST> 1.5 × ULN associated with alkaline phosphatase> 2.5 × ULN, and bilirubin> 1 x ULN; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.
Children and adolescents
The experience in children and adolescents is limited.
Elderly
Based on a population pharmacokinetic analysis, there are no special instructions for use in the elderly.
In combination with capecitabine, for patients 60 years of age or more, a starting dose reduction of capecitabine to 75% is recommended (see capecitabine summary of product characteristics)
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Docetaxel must not be used in patients with baseline neutrophil count of < 1,500cells/mm3.
Docetaxel must not be used in patients with severe liver impairment since there is no data available (see sections 4.2 and 4.4).
Contraindications for other medicinal products also apply, when combined with docetaxel.
4.4 Special Warnings And Precautions For Use
For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16mg per day (e.g. 8mg 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 8mg, 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 3 (see section 4.2).
In the case of severe neutropenia (< 500cells/mm3 for seven days or more) during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are recommended (see section 4.2).
In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored, (see sections 4.2 and 4.8).
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 localized cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel.
Cutaneous reactions
Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema followed by desquamation has been observed. Severe symptoms such as eruptions followed by desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see section 4.2).
Fluid retention
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely.
Patients with liver impairment
In patients treated with docetaxel at 100mg/m2 as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in those patients with elevated liver function test (LFTs) is 75mg/m2 and LFTs should be measured at baseline and before each cycle (see section 4.2).
For patients with serum bilirubin levels> ULN and/or ALT and AST> 3.5 times the ULN concurrent with serum alkaline phosphatase levels> 6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical trial excluded patients with ALT and/or AST> 1.5 × ULN associated with alkaline phosphatase> 2.5 × ULN, and bilirubin> 1 x ULN; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.
Patients with renal impairment
There are no data available in patients with severely impaired renal function treated with docetaxel.
Nervous system
The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).
Cardiac toxicity
Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin) - containing chemotherapy. This may be moderate to severe and has been associated with death (see section 4.8).
When patients are candidates for treatment with docetaxel in combination with trastuzumab, they should undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For more details see Summary of Product Characteristics of trastuzumab.
Others
Contraceptive measures must be taken by both men and women during treatment and for at least 6 months after cessation of therapy (see section 4.6).
Additional cautions for use in adjuvant treatment of breast cancer
Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be considered (see section 4.2).
Gastrointestinal reactions
Symptoms such as early abdominal pain and tenderness, fever, diarrhea, 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.
Leukemia
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukemia 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 no 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
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
Elderly patients treated with TCF should be closely monitored.
Ethanol
Docetaxel contains 100mg of ethanol absolute per ml concentrate. The solvent contains 9.53% (w/w) ethanol absolute. This may be harmful in patients suffering from alcoholism.
The ethanol content of this medicinal product should be taken into account when used children or in high-risk groups such as patients with liver disease, or epilepsy.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
There have been no formal clinical studies to evaluate the interactions of docetaxel with other medicinal products.
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 ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with these drugs 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 medication 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.
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.'
The ethanol content of this medicinal product may alter the effects of other medicines.
4.6 Pregnancy And Lactation
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 drugs, 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.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
The ethanol content of this medicinal product may impair the ability to drive or use machines.
4.8 Undesirable Effects
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).
• 744 patients who received docetaxel in combination with doxorubicin and cyclophosphamide (clinically important treatment related adverse events are presented).
• 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patients in the phase II part) who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).
• 174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).
These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade3-4 = G3/4; grade 4 = G4) and the COSTART terms. Frequencies are defined as: very common (
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which was reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe neutropenia (< 500 cells/mm3) was 7 days), anemia, alopecia, nausea, vomiting, stomatitis, diarrhea 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
For combination with capecitabine, the most frequent treatment-related undesirable effects (
The following adverse reactions are frequently observed with docetaxel:
Nervous system disorders
The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paresthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.
Skin and subcutaneous tissue disorders
Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion. Less frequently, severe symptoms such as eruptions followed by desquamation which rarely lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.
General disorders and administration site conditions
Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein. Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).
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 drug fever or chills. Severe reactions were characterised by hypotension and/or bronchospasm or generalized rash/erythema (see section 4.4).
Docetaxel 100 mg/m² single agent:
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Blood and Lymphatic system disorders
Rare: bleeding episodes associated with grade 3/4 thrombocytopenia
Nervous system disorders
Reversibility data are available among 35.3% of patients who developed neurotoxicity following docetaxel treatment at 100 mg/m² as single agent. The events were spontaneously reversible within 3 months.
Skin and subcutaneous tissue disorders
Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions were reversible within 21 days.
General disorders and administration site conditions
The median cumulative dose to treatment discontinuation was more than 1,000 mg/m2 and the median time to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks). The onset of moderate and severe retention is delayed (median cumulative dose: 818.9 mg/m2) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7 mg/m2); however, it has been reported in some patients during the early courses of therapy.
Docetaxel 75mg/m² single agent:
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