Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Aventis Pharma S.A. 20 avenue Raymond Aron 92165 Antony Cedex France
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with baseline neutrophil count of < 1,500 cells/mm3.
Patients with severe liver impairment (see sections 4.2 and 4.4).
Contraindications for other medicinal products also apply, when combined with docetaxel.
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).
Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of complete blood counts should be conducted on all patients receiving docetaxel. Patients should be retreated with docetaxel when neutrophils recover to a level ≥ 1,500 cells/mm³ (see section 4.2).
In the case of severe neutropenia (< 500 cells/mm3 for seven days or more) during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are recommended (see section 4.2).
In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored (see sections 4.2 and 4.8).
In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored (see sections 4.2 and 4.8).
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.
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).
Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely.
In patients treated with docetaxel at 100 mg/m2 as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in those patients with elevated liver function test (LFTs) is 75 mg/m2 and LFTs should be measured at baseline and before each cycle (see section 4.2).
For patients with serum bilirubin levels > ULN and/or ALT and AST > 3.5 times the ULN concurrent with serum alkaline phosphatase levels > 6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.
In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 × ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin > 1 x ULN; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.
There are no data available in patients with severely impaired renal function treated with docetaxel.
The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).
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.
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).
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be considered (see section 4.2).
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.
Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow up period. In patients treated with the TAC regimen for node positive breast cancer, the risk of CHF has been shown to be higher during the first year after treatment (see sections 4.8 and 5.1).
In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up.
Patients with 4+ nodes
As the benefit observed in patient with 4+ nodes was not statistically significant on disease-free survival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis (see section 5.1).
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.
This medicinal product contains 50 vol % ethanol (alcohol), i.e. up to 0.395 g (0.5 ml) per vial, equivalent to 10 ml of beer or 4 ml wine per vial.
Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.
The amount of alcohol in this medicinal product may alter the effects of other medicinal products.
The amount of alcohol in this medicinal product may impair the patients ability to drive or use machines.
In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450-3A such as ciclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with these medicinal products as concomitant therapy since there is a potential for a significant interaction.
Docetaxel is highly protein bound (> 95%). Although the possible in vivo interaction of docetaxel with concomitantly administered medicinal product has not been investigated formally, in vitro interactions with tightly protein-bound agents such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of digitoxin.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co-administration. Limited data from a single uncontrolled study were suggestive of an interaction between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was about 50% higher than values previously reported for carboplatin monotherapy.
Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.
Clinical cases consistent with an increase in docetaxel toxicity were reported when it was combined with ritonavir. The mechanism behind this interaction is a CYP3A4 inhibition, the main isoenzyme involved in docetaxel metabolism by ritonavir. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require co-administration of a strong CYP3A4 inhibitor such as azole antifungals, ritonavir and some macrolides (clarithromycin, telithromycin).
There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other cytotoxic medicinal products, docetaxel may cause foetal harm when administered to pregnant women. Therefore, docetaxel must not be used during pregnancy unless clearly indicated.
Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.
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.
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.
No studies on the effects on the ability to drive and use machines have been performed.
The adverse reactions considered to be possibly or probably related to the administration of docetaxel have been obtained in:
These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade 3-4 = G3/4; grade 4 = G4), the COSTART and the MedDRA terms. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse reactions of docetaxel alone are: neutropenia (which was reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe neutropenia (< 500 cells/mm³) was 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and asthenia. The severity of adverse events of docetaxel may be increased when docetaxel is given in combination with other chemotherapeutic agents.
For combination with trastuzumab, adverse events (all grades) reported in ≥ 10% are displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the trastuzumab combination arm compared to docetaxel monotherapy.
For combination with capecitabine, the most frequent treatment-related undesirable effects (≥ 5%) reported in a phase III study in breast cancer patients failing anthracycline treatment are presented (see capecitabine summary of product characteristics).
The following adverse reactions are frequently observed with docetaxel:
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).
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.
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.
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).
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions | Uncommon adverse reactions |
| Infections and infestations | Infections (G3/4: 5.7%; including sepsis and pneumonia, fatal in 1.7%) | Infection associated with G4 neutropenia (G3/4: 4.6%) | |
| Blood and lymphatic system disorders | Neutropenia (G4: 76.4%); Anaemia (G3/4: 8.9%); Febrile neutropenia | Thrombocytopenia (G4: 0.2%) | |
| Immune system disorders | Hypersensitivity (G3/4: 5.3%) | ||
| Metabolism and nutrition disorders | Anorexia | ||
| Nervous system disorders | Peripheral sensory neuropathy (G3: 4.1%); Peripheral motor neuropathy (G3/4: 4%); Dysgeusia (severe: 0.07%) | ||
| Cardiac disorders | Arrhythmia (G3/4: 0.7%) | Cardiac failure | |
| Vascular disorders | Hypotension; Hypertension; Haemorrhage | ||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea (severe: 2.7%) | ||
| Gastrointestinal disorders | Stomatitis (G3/4: 5.3%); Diarrhoea (G3/4: 4%); Nausea (G3/4: 4%); Vomiting (G3/4: 3%) | Constipation (severe: 0.2%); Abdominal pain (severe: 1%); Gastrointestinal haemorrhage (severe: 0.3%) | Oesophagitis (severe: 0.4%) |
| Skin and subcutaneous tissue disorders | Alopecia; Skin reaction (G3/4: 5.9%); Nail disorders (severe: 2.6%) | ||
| Musculoskeletal and connective tissue disorders | Myalgia (severe: 1.4%) | Arthralgia | |
| General disorders and administration site conditions | Fluid retention (severe: 6.5%); Asthenia (severe: 11.2%); Pain | Infusion site reaction; Non-cardiac chest pain (severe: 0.4%) | |
| Investigations | G3/4 Blood bilirubin increased (< 5%); G3/4 Blood alkaline phosphatase increased (< 4%); G3/4 AST increased (< 3%); G3/4 ALT increased (< 2%) |
Rare: bleeding episodes associated with grade ¾ thrombocytopenia.
Reversibility data are available among 35.3% of patients who developed neurotoxicity following docetaxel treatment at 100 mg/m² as single agent. The events were spontaneously reversible within 3 months.
Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions were reversible within 21 days.
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.
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions |
| Infections and infestations | Infections (G3/4: 5%) | |
| Blood and lymphatic system disorders | Neutropenia (G4: 54.2%); Anaemia (G3/4: 10.8%); Thrombocytopenia (G4: 1.7%) | Febrile neutropenia |
| Immune system disorders | Hypersensitivity (no severe) | |
| Metabolism and nutrition disorders | Anorexia | |
| Nervous system disorders | Peripheral sensory neuropathy (G3/4: 0.8%) | Peripheral motor neuropathy (G3/4: 2.5%) |
| Cardiac disorders | Arrhythmia (no severe) | |
| Vascular disorders | Hypotension | |
| Gastrointestinal disorders | Nausea (G3/4: 3.3%); Stomatitis (G3/4: 1.7%); Vomiting (G3/4: 0.8%); Diarrhoea (G3/4: 1.7%) | Constipation |
| Skin and subcutaneous tissue disorders | Alopecia; Skin reaction (G3/4: 0.8%) | Nail disorders (severe: 0.8%) |
| Musculoskeletal and connective tissue disorders | Myalgia | |
| General disorders and administration site conditions | Asthenia (severe: 12.4%); Fluid retention (severe: 0.8%); Pain | |
| Investigations | G3/4 Blood bilirubin increased (< 2%) |
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions | Uncommon adverse reactions |
| Infections and infestations | Infection (G3/4: 7.8%) | ||
| Blood and lymphatic system disorders | Neutropenia (G4: 91.7%); Anaemia (G3/4: 9.4%); Febrile neutropenia; Thrombocytopenia (G4: 0.8%) | ||
| Immune system disorders | Hypersensitivity (G3/4: 1.2%) | ||
| Metabolism and nutrition disorders | Anorexia | ||
| Nervous system disorders | Peripheral sensory neuropathy (G3: 0.4%) | Peripheral motor neuropathy (G3/4: 0.4%) | |
| Cardiac disorders | Cardiac failure; Arrhythmia (no severe) | ||
| Vascular disorders | Hypotension | ||
| Gastrointestinal disorders | Nausea (G3/4: 5%); Stomatitis (G3/4: 7.8%); Diarrhoea (G3/4: 6.2%); Vomiting (G3/4: 5%); Constipation | ||
| Skin and subcutaneous tissue disorders | Alopecia; Nail disorders (severe: 0.4%); Skin reaction (no severe) | ||
| Musculoskeletal and connective tissue disorders | Myalgia | ||
| General disorders and administration site conditions | Asthenia (severe: 8.1%); Fluid retention (severe: 1.2%); Pain | Infusion site reaction | |
| Investigations | G3/4 Blood bilirubin increased (< 2.5%); G3/4 Blood alkaline phosphatase increased (< 2.5%) | G3/4 AST increased (< 1%); G3/4 ALT increased (< 1%) |
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions | Uncommon adverse reactions |
| Infections and infestations | Infection (G3/4: 5.7%) | ||
| Blood and lymphatic system disorders | Neutropenia (G4: 51.5%); Anaemia (G3/4: 6.9%); Thrombocytopenia (G4: 0.5%) | Febrile neutropenia | |
| Immune system disorders | Hypersensitivity (G3/4: 2.5%) | ||
| Metabolism and nutrition disorders | Anorexia | ||
| Nervous system disorders | Peripheral sensory neuropathy (G3: 3.7%);Peripheral motor neuropathy (G3/4: 2%) | ||
| Cardiac disorders | Arrhythmia (G3/4: 0.7%) | Cardiac failure | |
| Vascular disorders | Hypotension (G3/4: 0.7%) | ||
| Gastrointestinal disorders | Nausea (G3/4: 9.6%); Vomiting (G3/4: 7.6%); Diarrhoea (G3/4: 6.4%); Stomatitis (G3/4: 2%) | Constipation | |
| Skin and subcutaneous tissue disorders | Alopecia; Nail disorders (severe: 0.7%); Skin reaction (G3/4: 0.2%) | ||
| Musculoskeletal and connective tissue disorders | Myalgia (severe: 0.5%) | ||
| General disorders and administration site conditions | Asthenia (severe: 9.9%); Fluid retention (severe: 0.7%); Fever (G3/4: 1.2%) | Infusion site reaction;Pain | |
| Investigations | G3/4 Blood bilirubin increased (2.1%); G3/4 ALT increased (1.3%) | G3/4 AST increased (0.5%); G3/4 Blood alkaline phosphatase increased (0.3%) |
| 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 |
Very common: Haematological toxicity was increased in patients receiving trastuzumab and docetaxel, compared with docetaxel alone (32% grade ¾ neutropenia versus 22%, using NCI-CTC criteria). Note that this is likely to be an underestimate since docetaxel alone at a dose of 100 mg/m² is known to result in neutropenia in 97% of patients, 76% grade 4, based on nadir blood counts. The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).
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.
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions |
| Infections and infestations | Oral candidiasis (G3/4: < 1%) | |
| Blood and lymphatic system disorders | Neutropenia (G3/4: 63%); Anaemia (G3/4: 10%) | Thrombocytopenia (G3/4: 3%) |
| Metabolism and nutrition disorders | Anorexia (G3/4: 1%); Decreased appetite | Dehydration (G3/4: 2%) |
| Nervous system disorders | Dysgeusia (G3/4: < 1%); Paraesthesia (G3/4: < 1%) | Dizziness; Headache (G3/4: < 1%); Neuropathy peripheral |
| Eye disorders | Lacrimation increased | |
| Respiratory, thoracic and mediastinal disorders | Pharyngolaryngeal pain (G3/4: 2%) | Dyspnoea (G3/4: 1%); Cough (G3/4: < 1%); Epistaxis (G3/4: < 1%) |
| Gastrointestinal disorders | Stomatitis (G3/4: 18%); Diarrhoea (G3/4: 14%); Nausea (G3/4: 6%); Vomiting (G3/4: 4%); Constipation (G3/4: 1%); Abdominal pain (G3/4: 2%); Dyspepsia | Abdominal pain upper; Dry mouth |
| Skin and subcutaneous tissue disorders | Hand-foot syndrome (G3/4: 24%); Alopecia (G3/4: 6%); Nail disorders (G3/4: 2%) | Dermatitis; Rash erythematous (G3/4: < 1%); Nail discolouration; Onycholysis (G3/4: 1%) |
| Musculoskeletal and connective tissue disorders | Myalgia (G3/4: 2%); Arthralgia (G3/4: 1%) | Pain in extremity (G3/4: < 1%); Back pain (G3/4: 1%) |
| General disorders and administration site conditions | Asthenia (G3/4: 3%); Pyrexia (G3/4: 1%); Fatigue/weakness (G3/4: 5%); Oedema peripheral (G3/4: 1%) | Lethargy;Pain |
| Investigations | Weight decreased; G3/4 Blood bilirubin increased (9%) |
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions |
| Infections and infestations | Infection (G3/4: 3.3%) | |
| Blood and lymphatic system disorders | Neutropenia (G3/4: 32%); Anaemia (G3/4: 4.9%) | Thrombocytopenia (G3/4: 0.6%); Febrile neutropenia |
| Immune system disorders | Hypersensitivity (G3/4: 0.6%) | |
| Metabolism and nutrition disorders | Anorexia (G3/4: 0.6%) | |
| Nervous system disorders | Peripheral sensory neuropathy (G3/4: 1.2%);Dysgeusia (G3/4: 0%) | Peripheral motor neuropathy (G3/4: 0%) |
| Eye disorders | Lacrimation increased (G3/4: 0.6%) | |
| Cardiac disorders | Cardiac left ventricular function decrease (G3/4: 0.3%) | |
| Respiratory, thoracic and mediastinal disorders | Epistaxis (G3/4: 0%); Dyspnoea (G3/4: 0.6%); Cough (G3/4: 0%) | |
| Gastrointestinal disorders | Nausea (G3/4: 2.4%); Diarrhoea (G3/4: 1.2%); Stomatitis/Pharyngitis (G3/4: 0.9%); Vomiting (G3/4: 1.2%) | |
| Skin and subcutaneous tissue disorders | Alopecia; Nail disorders (no severe) | Exfoliative rash (G3/4: 0.3%) |
| Musculoskeletal and connective bone disorders | Arthralgia (G3/4: 0.3%); Myalgia (G3/4: 0.3%) | |
| General disorders and administration site conditions | Fatigue (G3/4: 3.9%); Fluid retention (severe: 0.6%) |
| 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: 2.6%) | ||
| Blood and lymphatic system disorders | Anaemia (G3/4: 3%); Neutropenia (G3/4: 59.2%); Thrombocytopenia (G3/4: 1.6%); Febrile neutropenia (G3/4: NA) | ||
| Immune system disorders | Hypersensitivity (G3/4: 0.6%) | ||
| Metabolism and nutrition disorders | Anorexia (G3/4: 1.5%) | ||
| Nervous system disorders | Dysgeusia (G3/4: 0.6%); Peripheral sensory neuropathy (G3/4: <0.1%) | Peripheral motor neuropathy (G3/4: 0%) | Syncope (G3/4: 0%); Neurotoxicity (G3/4: 0%); Somnolence (G3/4: 0%) |
| Eye disorders | Conjunctivitis (G3/4: <0.1%) | Lacrimation increased (G3/4: <0.1%) | |
| Cardiac disorders | Arrhythmia (G3/4: 0.2%) | ||
| Vascular disorders | Hot flush (G3/4: 0.5%) | Hypotension (G3/4: 0%);Phlebitis (G3/4: 0%) | Lymphoedema (G3/4: 0%) |
| Respiratory, thoracic and mediastinal disorders | Cough (G3/4: 0%) | ||
| Gastrointestinal disorders | Nausea (G3/4: 5.0%); Stomatitis (G3/4: 6.0%); Vomiting (G3/4: 4.2%); Diarrhoea (G3/4: 3.4%); Constipation (G3/4: 0.5%) | Abdominal pain (G3/4: 0.4%) | |
| Skin and subcutaneous tissue disorders | Alopecia (G3/4: <0.1%); Skin disorder (G3/4: 0.6%); Nail disorders (G3/4: 0.4%) | ||
| Musculoskeletal and connective tissue disorders | Myalgia (G3/4: 0.7%);Arthralgia (G3/4: 0.2%) | ||
| Reproductive system and breast disorders | Amenorrhoea (G3/4: NA) | ||
| General disorders and administration site conditions | Asthenia (G3/4: 10.0%); Pyrexia (G3/4: NA); Oedema peripheral (G3/4: 0.2%) | ||
| Investigations | Weight increased (G3/4: 0%); Weight decreased (G3/4: 0.2%) |
Description of selected adverse reactions for adjuvant therapy with TAXOTERE 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer
Peripheral sensory neuropathy was observed to be ongoing during follow-up in 10 patients out of the 84 patients with peripheral sensory neuropathy at the end of the chemotherapy in the node positive breast cancer study (TAX316).
In study TAX316, 26 patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm experienced congestive heart failure. All except one patient in each arm were diagnosed with CHF more than 30 days after the treatment period. Two patients in the TAC arm and 4 patients in the FAC arm died because of cardiac failure.
In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 TAC patients and 645 FAC patients.
At the end of the follow-up period, alopecia was observed to be ongoing in 29 TAC patients (4.2%) and 16 FAC patients (2.4%).
Amenorrhoea was observed to be ongoing during follow-up in 121 patients out of the 202 patients with amenorrhoea at the end of the chemotherapy in study TAX316.
In study TAX316, peripheral oedema was observed to be ongoing in 19 patients out of the 119 patients with peripheral oedema in the TAC arm and 4 patients out of the 23 patients with peripheral oedema in the FAC arm.
In study GEICAM 9805, lymphoedema was observed to be ongoing in 4 of the 5 patients with lymphoedema at the end of the chemotherapy.
After 10 years of follow up in study TAX316, acute leukaemia was reported in 4 of 744 TAC patients and in 1 of 736 FAC patients. Myelodysplastic syndrome was reported in 2 of 744 TAC patients and in 1 of 736 FAC patients.
At a median follow-up time of 77 months, acute leukaemia occurred in 1 of 532 (0.2%) patients who received docetaxel, doxorubicin, and cyclophosphamide in the GEICAM 9805 study. No cases were reported in patients who received fluorouracil, doxorubicin and cyclophosphamide. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.
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.
| Without primary G-CSF prophylaxis (n = 111) n (%) | With primary G-CSF prophylaxis (n = 421) n (%) | |
| Neutropenia (Grade 4) | 104 (93.7) | 135 (32.1) |
| Febrile neutropenia | 28 (25.2) | 23 (5.5) |
| Neutropenic infection | 14 (12.6) | 21 (5.0) |
| Neutropenic infection (Grade 3-4) | 2 (1.8) | 5 (1.2) |
Tabulated list of adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions |
| Infections and infestations | Neutropenic infection;Infection (G3/4: 11.7%) | |
| Blood and lymphatic system disorders | Anaemia (G3/4: 20.9%); Neutropenia (G3/4: 83.2%); Thrombocytopenia (G3/4: 8.8%); Febrile neutropenia | |
| Immune system disorders | Hypersensitivity (G3/4: 1.7%) | |
| Metabolism and nutrition disorders | Anorexia (G3/4: 11.7%) | |
| Nervous system disorders | Peripheral sensory neuropathy (G3/4: 8.7%) | Dizziness (G3/4: 2.3%);Peripheral motor neuropathy (G3/4: 1.3%) |
| Eye disorders | Lacrimation increased (G3/4: 0%) | |
| Ear and labyrinth disorders | Hearing impaired (G3/4: 0%) | |
| Cardiac disorders | Arrhythmia (G3/4: 1.0%) | |
| Gastrointestinal disorders | Diarrhoea (G3/4: 19.7%);Nausea (G3/4: 16%);Stomatitis (G3/4: 23.7%);Vomiting (G3/4: 14.3%) | Constipation (G3/4: 1.0%);Gastrointestinal pain (G3/4: 1.0%);Oesophagitis/dysphagia/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%) |
| General disorders and administration site conditions | Lethargy (G3/4: 19.0%); Fever (G3/4: 2.3%); Fluid retention (severe/life-threatening: 1%) |
Description of selected adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil
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).
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%) | ||
| Blood and lymphatic system disorders | Neutropenia (G3/4: 76.3%); Anaemia (G3/4: 9.2%); Thrombocytopenia (G3/4: 5.2%) | Febrile neutropenia | |
| Immune system disorders | Hypersensitivity (no severe) | ||
| Metabolism and nutrition disorders | Anorexia (G3/4: 0.6%) | ||
| Nervous system disorders | Dysgeusia/Parosmia; Peripheral sensory neuropathy (G3/4: 0.6%) | Dizziness | |
| Eye disorders | Lacrimation increased; Conjunctivitis | ||
| Ear and labyrinth disorders | Hearing impaired | ||
| Cardiac disorders | Myocardial ischemia (G3/4:1.7%) | Arrhythmia (G3/4: 0.6%) | |
| Vascular disorders | Venous disorder (G3/4: 0.6%) | ||
| Gastrointestinal disorders | Nausea (G3/4: 0.6%); Stomatitis (G3/4: 4.0%); Diarrhoea (G3/4: 2.9%); Vomiting (G3/4: 0.6%) | Constipation; Esophagitis/dysphagia/ odynophagia (G3/4: 0.6%); Abdominal pain;Dyspepsia; Gastrointestinal haemorrhage (G3/4: 0.6%) | |
| Skin and subcutaneous tissue disorders | Alopecia (G3/4: 10.9%) | Rash pruritic; Dry skin; Skin exfoliative (G3/4: 0.6%) | |
| Musculoskeletal and connective tissue disorders | Myalgia (G3/4: 0.6%) | ||
| General disorders and administration site conditions | Lethargy (G3/4: 3.4%); Pyrexia (G3/4: 0.6%); Fluid retention;Oedema | ||
| Investigations | Weight increased |
Induction chemotherapy followed by chemoradiotherapy (TAX 324):
| MedDRA system organ classes | Very common adverse reactions | Common adverse reactions | Uncommon adverse reactions |
| Infections and infestations | Infection (G3/4: 3.6%) | Neutropenic infection | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Cancer pain (G3/4: 1.2%) | ||
| Blood and lymphatic system disorders | Neutropenia (G3/4: 83.5%); Anaemia (G3/4: 12.4%); Thrombocytopenia (G3/4: 4.0%); Febrile neutropenia | ||
| Immune system disorders | Hypersensitivity | ||
| Metabolism and nutrition disorders | Anorexia (G3/4: 12.0%) | ||
| Nervous system disorders | Dysgeusia/Parosmia (G3/4: 0.4%); Peripheral sensory neuropathy (G3/4: 1.2%) | Dizziness (G3/4: 2.0%); Peripheral motor neuropathy (G3/4: 0.4%) | |
| Eye disorders | Lacrimation increased | Conjunctivitis | |
| Ear and labyrinth disorders | Hearing impaired (G3/4: 1.2%) | ||
| Cardiac disorders | Arrhythmia (G3/4: 2.0%) | Ischemia myocardial | |
| Vascular disorders | Venous disorder | ||
| Gastrointestinal disorders | Nausea (G3/4: 13.9%); Stomatitis (G3/4: 20.7%); Vomiting (G3/4: 8.4%); Diarrhoea (G3/4: 6.8%); Esophagitis/dysphagia/ odynophagia (G3/4: 12.0%); Constipation (G3/4: 0.4%) | Dyspepsia (G3/4: 0.8%); Gastrointestinal pain (G3/4: 1.2%); Gastrointestinal haemorrhage (G3/4: 0.4%) | |
| Skin and subcutaneous tissue disorders | Alopecia (G3/4: 4.0%); Rash pruritic | Dry skin ; Desquamation | |
| Musculoskeletal, connective tissue bone 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 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cases of acute myeloid leukaemia and myelodysplastic syndrome have been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.
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.
Some cases of anaphylactic shock, sometimes fatal, have been reported.
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.
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been rarely reported.
Rare cases of ototoxicity, hearing impaired and/or hearing loss have been reported.
Rare cases of myocardial infarction have been reported.
Venous thromboembolic events have rarely been reported.
Acute respiratory distress syndrome and cases of interstitial pneumonia and pulmonary fibrosis sometimes fatal have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.
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.
Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some cases concomitant factors may have contributed to the development of these effects. Sclerodermal-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of persisting alopecia have been reported.
Renal insufficiency and renal failure have been reported. In about 20% of these cases there were no risk factors for acute renal failure such as concomitant nephrotoxic medicinal products and gastro-intestinal disorders.
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.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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