Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile for all indications

The adverse reactions considered to be possibly or probably related to the administration of docetaxel have been obtained in:.
• 1312 and 121 patients who received 100 mg/m² and 75 mg/m² of docetaxel as a single agent, respectively
• 258 patients who received docetaxel in combination with doxorubicin • 406 patients who received docetaxel in combination with cisplatin • 92 patients treated with docetaxel in combination with trastuzumab, • 255 patients who received docetaxel in combination with capecitabine, • 332 patients who received docetaxel in combination with prednisone or prednisolone (clinically important treatment related adverse events are presented).
• 1276 patients (744 and 532 in TAX 316 and GEICAM 9805, respectively) who received docetaxel in combination with doxorubicin and cyclophosphamide (clinically important treatment related adverse events are presented).
• 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patients in the phase II part) who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).
• 174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).

These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade3-4 = 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, stomatits, 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 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).

Tabulated list of adverse reactions in breast cancer for TAXOTERE 100 mg/m² single agent 
MedDRA System Organ          Very common adverse            Common adverse            Uncommon adverse classes                      reactions                      reactions                 reactions 
Investigations                                              G3/4 Blood bilirubin increased (< 5%);
G3/4 Blood alkaline phosphatase increased
(< 4%);
G3/4 AST increased
(< 3%);
G3/4 ALT increased
(< 2%)
Cardiac disorders                                           Arrhythmia (G3/4: 0.7%) Cardiac failure 
Blood and lymphatic          Neutropenia (G4: 76.4%);       Thrombocytopenia (G4: system disorders             Anaemia (G3/4: 8.9%);          0.2%)
Febrile neutropenia


Nervous system disorders Peripheral sensory neuropathy (G3: 4.1%);
Peripheral motor neuropathy (G3/4: 4%);
Dysgeusia (severe:
0.07%)

MedDRA System Organ          Very common adverse             Common adverse              Uncommon adverse classes                      reactions                       reactions                   reactions 
Respiratory, thoracic and    Dyspnoea (severe: 2.7%) mediastinal disorders
Gastrointestinal disorders   Stomatitis (G3/4: 5.3%);        Constipation (severe:   Oesophagitis (severe: Diarrhoea (G3/4: 4%);           0.2%);                  0.4%)
Nausea (G3/4: 4%);              Abdominal pain (severe:
Vomiting (G3/4: 3%)             1%);
Gastrointestinal haemorrhage (severe:
0.3%)
Skin and subcutaneous        Alopecia;
tissue disorders             Skin reaction (G3/4:
5.9%);
Nail disorders (severe:
2.6%)
Musculoskeletal and          Myalgia (severe: 1.4%)          Arthralgia connective tissue disorders
Metabolism and nutrition    Anorexia disorders
Infections and infestations Infections (G3/4: 5.7%;          Infection associated with including sepsis and             G4 neutropenia (G3/4: pneumonia, fatal in 1.7%)        4.6%)
Vascular disorders                                           Hypotension; Hypertension;
Haemorrhage
General disorders and        Fluid retention (severe:        Infusion site reaction; administration site          6.5%);                          Non-cardiac chest pain conditions                   Asthenia (severe: 11.2%);       (severe: 0.4%) Pain
Immune system disorders      Hypersensitivity (G3/4:
5.3%)


Description of selected adverse reactions in breast cancer for TAXOTERE 100 mg/m2 single agent 
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.

Tabulated list of adverse reactions in non-small cell lung cancer for TAXOTERE 75 mg/m² single agent 
MedDRA System Organ classes           Very common adverse                   Common adverse reactions reactions

Investigations                                                              G3/4 Blood bilirubin increased (< 2%)
Cardiac disorders                                                           Arrhythmia (no severe) 
Blood and lymphatic system            Neutropenia (G4: 54.2%);              Febrile neutropenia 
MedDRA System Organ classes            Very common adverse               Common adverse reactions reactions
 disorders                              Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4: 1.7%)

Nervous system disorders               Peripheral sensory neuropathy     Peripheral motor neuropathy (G3/4: 0.8%)                      (G3/4: 2.5%)


Gastrointestinal disorders             Nausea (G3/4: 3.3%);              Constipation Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhea (G3/4: 1.7%)
Skin and subcutaneous tissue           Alopecia;                         Nail disorders (severe: 0.8%) disorders                              Skin reaction (G3/4: 0.8%)
Musculoskeletal and connective                                           Myalgia tissue disorders
Metabolism and nutrition disorders     Anorexia
Infections and infestations            Infections (G3/4: 5%)
Vascular disorders                                                       Hypotension General disorders and                  Asthenia (severe: 12.4%);
administration site conditions         Fluid retention (severe: 0.8%); Pain
Immune system disorders                                                  Hypersensitivity (no severe) 

Tabulated list of adverse reactions in breast cancer for TAXOTERE 75 mg/m² in combination with doxorubicin

MedDRA System Organ               Very common adverse          Common adverse                Uncommon adverse classes                           reactions                    reactions                     reactions 
Investigations                                                 G3/4 Blood bilirubin          G3/4 AST increased increased (< 2.5%);           (< 1%);
G3/4 Blood alkaline           G3/4 ALT increased phosphatase increased         (< 1%)
(< 2.5%)
Cardiac disorders                                              Cardiac failure; Arrhythmia (no severe)

Blood and lymphatic system        Neutropenia (G4: 91.7%);
disorders                         Anaemia (G3/4: 9.4%);
Febrile neutropenia;
Thrombocytopenia (G4:
0.8%)

Nervous system disorders          Peripheral sensory           Peripheral motor neuropathy (G3: 0.4%)        neuropathy (G3/4: 0.4%)


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 Alopecia;
disorders                    Nail disorders (severe:
0.4%);
Skin reaction (no severe)
Musculoskeletal and                                            Myalgia connective tissue disorders
Metabolism and nutrition                                       Anorexia disorders
MedDRA System Organ              Very common adverse           Common adverse               Uncommon adverse classes                          reactions                     reactions                    reactions 
Infections and infestations      Infection (G3/4: 7.8%)
Vascular disorders                                                                          Hypotension General disorders and            Asthenia (severe: 8.1%);      Infusion site reaction administration site conditions   Fluid retention (severe:
1.2%);
Pain
Immune system disorders                                        Hypersensitivity (G3/4: 1.2%)


Tabulated list of adverse reactions in non-small cell lung cancer for TAXOTERE 75 mg/m² in combination with cisplatin

MedDRA System Organ              Very common adverse           Common adverse               Uncommon adverse classes                          reactions                     reactions                    reactions 
Investigations                                                 G3/4 Blood bilirubin         G3/4 AST increased increased (2.1%);            (0.5%);
G3/4 ALT increased           G3/4 Blood alkaline
(1.3%)                       phosphatase increased
(0.3%)
Cardiac disorders                                              Arrhythmia (G3/4: 0.7%)      Cardiac failure Blood and lymphatic system       Neutropenia (G4: 51.5%);      Febrile neutropenia disorders                        Anaemia (G3/4: 6.9%);
Thrombocytopenia (G4:
0.5%)
Nervous system disorders         Peripheral sensory neuropathy (G3: 3.7%);
Peripheral motor neuropathy (G3/4: 2%)
Gastrointestinal disorders       Nausea (G3/4: 9.6%);          Constipation Vomiting (G3/4: 7.6%);
Diarrhoea (G3/4: 6.4%);
Stomatitis (G3/4: 2%)
Skin and subcutaneous            Alopecia;
tissue disorders                 Nail disorders (severe:
0.7%);
Skin reaction (G3/4: 0.2%)
Musculoskeletal and              Myalgia (severe: 0.5%) connective tissue disorders
Metabolism and nutrition         Anorexia disorders
Infections and infestations      Infection (G3/4: 5.7%)
Vascular disorders                                             Hypotension (G3/4: 0.7%) General disorders and            Asthenia (severe: 9.9%);      Infusion site reaction; administration site conditions   Fluid retention (severe:      Pain
0.7%);
Fever (G3/4: 1.2%)
Immune system disorders          Hypersensitivity (G3/4:
2.5%)

Tabulated list of adverse reactions in breast cancer for TAXOTERE 100 mg/m² in combination with trastuzumab

MedDRA System Organ           Very common adverse reactions            Common adverse reactions classes
Investigations                Weight increased
Cardiac disorders                                                      Cardiac failure Blood and lymphatic      Neutropenia (G3/4: 32%);
system disorders         Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis
Nervous system disorders Paresthesia; Headache; Dysgeusia;
MedDRA System Organ          Very common adverse reactions             Common adverse reactions classes
Hypoaesthesia
Eye disorders                Lacrimation increased; Conjunctivitis

Respiratory, thoracic and    Epistaxis; Pharyngolaryngeal pain;
mediastinal disorders        Nasopharyngitis; Dyspnoea;
Cough; Rhinorrhoea
Gastrointestinal disorders   Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis; Dyspepsia;
Abdominal pain
Skin and subcutaneous        Alopecia; Erythema; Rash; Nail tissue disorders             disorders
Musculoskeletal and          Myalgia; Arthralgia; Pain in extremity;
connective tissue            Bone pain; Back pain disorders
Metabolism and nutrition     Anorexia disorders
Vascular disorders           Lymphoedema
General disorders and        Asthenia; Oedema peripheral; Pyrexia; Lethargy administration site          Fatigue; Mucosal inflammation; Pain;
conditions                   Influenza like illness; Chest pain; Chills Psychiatric disorders        Insomnia

Description of selected adverse reactions in breast cancer for TAXOTERE 100 mg/m2 in combination with trastuzumab

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/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).

Tabulated list of adverse reactions in breast cancer for TAXOTERE 75 mg/m² in combination with capecitabine

MedDRA System Organ classes                 Very common adverse             Common adverse reactions reactions

Investigations                                                              Weight decreased; G3/4 Blood bilirubin increased
(9%)
Blood and lymphatic system disorders        Neutropenia (G3/4: 63%);        Thrombocytopenia (G3/4: 3%) Anaemia (G3/4: 10%)
Nervous system disorders                    Dysgeusia (G3/4: < 1%);         Dizziness; Paraesthesia (G3/4: < 1%)       Headache (G3/4: < 1%);
Neuropathy peripheral
Eye disorders                               Lacrimation increased
Respiratory, thoracic and mediastinal       Pharyngolaryngeal pain (G3/4: Dyspnoea (G3/4: 1%); disorders                                   2%)                           Cough (G3/4: < 1%); Epistaxis (G3/4: < 1%)
Gastrointestinal disorders                  Stomatitis (G3/4: 18%);       Abdominal pain upper; Diarrhoea (G3/4: 14%);        Dry mouth
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4: 2%);
Dyspepsia
Skin and subcutaneous tissue disorders      Hand-foot syndrome (G3/4:     Dermatitis; MedDRA System Organ classes              Very common adverse            Common adverse reactions reactions

24%);                          Rash erythematous (G3/4:
Alopecia (G3/4: 6%);           < 1%);
Nail disorders (G3/4: 2%)      Nail discolouration;
Onycholysis (G3/4: 1%)
Musculoskeletal and connective tissue    Myalgia (G3/4: 2%);            Pain in extremity (G3/4: < 1%); disorders                                Arthralgia (G3/4: 1%)          Back pain (G3/4: 1%) Metabolism and nutrition disorders       Anorexia (G3/4: 1%);           Dehydration (G3/4: 2%) Decreased appetite
Infections and infestations                                           Oral candidiasis (G3/4: < 1%) General disorders and administration     Asthenia (G3/4: 3%);         Lethargy; site conditions                          Pyrexia (G3/4: 1%);          Pain Fatigue/weakness (G3/4: 5%);
Oedema peripheral (G3/4: 1%)

Tabulated list of adverse reactions in prostate cancer for TAXOTERE 75 mg/m² in combination with prednisone or prednisolone

MedDRA System Organ classes                 Very common adverse            Common adverse reactions reactions

Cardiac disorders                                                          Cardiac left ventricular function decrease (G3/4: 0.3%)
Blood and lymphatic system disorders        Neutropenia (G3/4: 32%);       Thrombocytopenia (G3/4: 0.6%); Anaemia (G3/4: 4.9%)           Febrile neutropenia
Nervous system disorders                    Peripheral sensory neuropathy Peripheral motor neuropathy (G3/4: (G3/4: 1.2%);                  0%)
Dysgeusia (G3/4: 0%)
Eye disorders                                                              Lacrimation increased (G3/4: 0.6%) Respiratory, thoracic and mediastinal                                      Epistaxis (G3/4: 0%); disorders                                                                  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;                      Exfoliative rash (G3/4: 0.3%) Nail disorders (no severe)
Musculoskeletal and connective bone                                        Arthralgia (G3/4: 0.3%); disorders                                                                  Myalgia (G3/4: 0.3%) Metabolism and nutrition disorders          Anorexia (G3/4: 0.6%)
Infections and infestations                 Infection (G3/4: 3.3%)
General disorders and administration site   Fatigue (G3/4: 3.9%);
conditions                                  Fluid retention (severe: 0.6%) Immune system disorders                                                    Hypersensitivity (G3/4: 0.6%) 

Tabulated list of adverse reactions in breast cancer 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 - pooled data

MedDRA System Organ          Very common adverse       Common adverse              Uncommon adverse classes                      reactions                 reactions                   reactions 
Investigations                                         Weight increased (G3/4: 0%);
Weight decreased
(G3/4: 0.2%)
Cardiac disorders                                      Arrhythmia (G3/4: 0.2%); 
Blood and lymphatic          Anaemia (G3/4: 3%);
system disorders             Neutropenia (G3/4: 59.2
%);
MedDRA System Organ          Very common adverse        Common adverse               Uncommon adverse classes                      reactions                  reactions                    reactions 
Thrombocytopenia
(G3/4:1.6%);
Febrile neutropenia
(G3/4: NA)
Nervous system disorders     Dysgeusia (G3/4: 0.6%);    Peripheral motor             Syncope (G3/4: 0%) Peripheral sensory         neuropathy (G3/4: 0%);       Neurotoxicity (G3/4: neuropathy (G3/4:                                       0%);
<0.1%)                                                  Somnolence (G3/4: 0%) Eye disorders                Conjunctivitis (G3/4:      Lacrimation increased <0.1%)                     (G3/4: < 0.1%);

Respiratory, thoracic and                               Cough (G3/4: 0%) mediastinal disorders
Gastrointestinal disorders  Nausea (G3/4: 5.0%);        Abdominal pain (G3/4: Stomatitis (G3/4: 6.0 %);   0.4%)
Vomiting (G3/4: 4.2%);
Diarrhoea (G3/4: 3.4%);
Constipation (G3/4:
0.5%)
Skin and subcutaneous       Alopecia tissue disorders            (persisting: <3%)
Skin disorder (G3/4:
0.6%);
Nail disorders (G3/4:
0.4%)
Musculoskeletal and         Myalgia (G3/4: 0.7%);
connective tissue disorders Arthralgia (G3/4: 0.2%)
Metabolism and nutrition    Anorexia (G3/4: 1.5 %) disorders
Infections and infestations Infection (G3/4: 2.4 %);
Neutropenic infection
(G3/4: 2.6%)

Vascular disorders           Hot flush (G3/4: 0.5%)     Hypotension (G3/4: 0%) Phlebitis (G3/4: 0%);        Lymphoedema (G3/4: 0%)
General disorders and        Asthenia (G3/4: 10%);
administration site conditions                   Pyrexia (G3/4:NA);
Oedema peripheral
(G3/4: 0.2%)
Immune system disorders                                 Hypersensitivity (G3/4: 0.6%)
Reproductive system and      Amenorrhoea (G3/4: NA) breast disorders


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

Cardiac disorders
.
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 GEICAM 9805 study, 3 patients (0.6 %) in TAC arm and 3 patients (0.6 %) in FAC arm developed congestive heart failure during the follow-up period. One patient in TAC arm died because of dilated cardiomyopathy.

Nervous system disorders
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 study TAX316.

Skin and subcutaneous tissue disorders

In study TAX316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients and 645 of 736 FAC patients. At the end of the follow-up period (actual median follow-up time of 96 months), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study, alopecia persisted into the follow-up period (median follow-up time of 10 years and 5 months) and was observed to be ongoing in 49 patients (9.2 %) in TAC arm and 35 patients (6.7 %) in FAC arm. Alopecia related to study drug started or worsened during the follow-up period in 42 patients (7.9 %) in TAC arm and 30 patients (5.8 %) in FAC arm.

General disorders and administration site conditions

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 in TAC arm and in 1 of the 2 patients in FAC arm at the end of the chemotherapy, and did not resolve during the follow-up period (median follow-up time of 10 years and 5 months). Asthenia persisted into the follow-up period (median follow-up time of 10 years and 5 months) and was observed to be ongoing in 12 patients (2.3 %) in TAC arm and 4 patients (0.8 %) in FAC arm.

Reproductive system and breast disorders
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 GEICAM 9805 study, amenorrhoea persisted into the follow-up period (median follow-up time of 10 years and 5 months) and was observed to be ongoing in 18 patients (3.4 %) in TAC arm and 5 patients (1.0 %) in FAC arm

Acute leukaemia / Myelodysplastic syndrome
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.
After 10 years of follow-up in GEICAM 9805 study, acute leukaemia occurred in 1 of 532 (0.2%) patients in TAC arm . No cases were reported in patients in FAC arm. No patient was diagnosed with myelodysplastic syndrome in either treatment groups.

Neutropenic complications
The table below shows that the incidence of Grade 4 neutropenia, febrile neutropenia and neutropenic infection was decreased in patients who received primary G-CSF prophylaxis after it was made mandatory in the TAC arm – GEICAM study.

Neutropenic complications in patients receiving TAC with or without primary G-CSF prophylaxis (GEICAM 9805)

Without primary                  With primary
G-CSF prophylaxis               G-CSF prophylaxis
(n = 111)                       (n = 421) n (%)                           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                       2 (1.8)                         5 (1.2) (Grade 3-4)



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                Common adverse reactions reactions

Cardiac disorders                                                         Arrhythmia (G3/4: 1.0%) 
Blood and lymphatic system             Anaemia (G3/4: 20.9%);
disorders                              Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4: 8.8%);
Febrile neutropenia

Nervous system disorders               Peripheral sensory neuropathy      Dizziness (G3/4: 2.3%); (G3/4: 8.7%)                       Peripheral motor neuropathy
(G3/4: 1.3%)
Eye disorders                                                             Lacrimation increased (G3/4: 0%)
Ear and labyrinth disorders                                               Hearing impaired (G3/4: 0%) 
Gastrointestinal disorders             Diarrhoea (G3/4: 19.7%);           Constipation (G3/4: 1.0%); Nausea (G3/4: 16%);                Gastrointestinal pain (G3/4:
Stomatitis (G3/4: 23.7%);          1.0%);
Vomiting (G3/4: 14.3%)             Oesophagitis/dysphagia/odynop hagia (G3/4: 0.7%)
Skin and subcutaneous tissue           Alopecia (G3/4: 4.0%)              Rash pruritus (G3/4: 0.7%); disorders                                                                 Nail disorders (G3/4: 0.7%); Skin exfoliation (G3/4: 0%)
Metabolism and nutrition disorders     Anorexia (G3/4: 11.7%)
Infections and infestations            Neutropenic infection;
Infection (G3/4: 11.7%)
General disorders and administration   Lethargy (G3/4: 19.0%);
site conditions                        Fever (G3/4: 2.3%);
Fluid retention (severe/life- threatening: 1%)
Immune system disorders                Hypersensitivity (G3/4: 1.7%)



Description of selected adverse reactions in gastric adenocarcinoma cancer for TAXOTERE 75 mg/m2 in combination with cisplatin and 5-fluorouracil

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).

Tabulated list of adverse reactions in head and neck cancer for TAXOTERE 75 mg/m² in combination with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)

MedDRA System Organ           Very common adverse      Common adverse             Uncommon adverse classes                       reactions                reactions                  reactions 
Investigations                                         Weight increased Cardiac disorders                                      Myocardial ischemia        Arrhythmia (G3/4: 0.6%) (G3/4:1.7%)



MedDRA System Organ            Very common adverse            Common adverse                 Uncommon adverse classes                        reactions                      reactions                      reactions 
Blood and lymphatic            Neutropenia (G3/4:                          a Febrile neutropenia system disorders               76.3%);
Anemia (G3/4: 9.2%);
Thrombocytopenia (G3/4:
5.2%)


Nervous system                 Dysgeusia/Parosmia;            Dizziness disorders                      Peripheral sensory neuropathy (G3/4: 0.6%)
Eye disorders                                                 Lacrimation increased; Conjunctivitis



Ear and labyrinth                                             Hearing impaired disorders

Gastrointestinal disorders Nausea (G3/4: 0.6%);               Constipation; Stomatitis (G3/4: 4.0%);           Esophagitis/dysphagia/
Diarrhea (G3/4: 2.9%);             odynophagia (G3/4:
Vomiting (G3/4: 0.6%)              0.6%);
Abdominal pain;
Dyspepsia;
Gastrointestinal haemorrhage (G3/4:
0.6%)
Skin and subcutaneous          Alopecia (G3/4: 10.9%)         Rash pruritic; tissue disorders                                              Dry skin; Skin exfoliative (G3/4:
0.6%)
Musculoskeletal and                                           Myalgia (G3/4: 0.6%) connective tissue disorders
Metabolism and nutrition       Anorexia (G3/4: 0.6%) disorders
Infections and                 Infection (G3/4: 6.3%);
infestations                   Neutropenic infection
Neoplasms benign,                                             Cancer pain (G3/4: 0.6%) malignant and unspecified (incl cysts and polyps)
Vascular disorders                                            Venous disorder (G3/4: 0.6%)
General disorders and          Lethargy (G3/4: 3.4%);
administration site            Pyrexia (G3/4: 0.6%);
conditions                     Fluid retention;
Oedema
Immune system disorders                                       Hypersensitivity (no severe)

 a
Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring i.v. antibiotics and/or hospitalization.

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA System                  Very common adverse            Common adverse                 Uncommon adverse Organ classes                  reactions                      reactions                      reactions 
Investigations                 Weight decreased                                              Weight increased Cardiac disorders                                             Arrhythmia (G3/4: 2.0%)        Ischemia myocardial MedDRA System                  Very common adverse            Common adverse                  Uncommon adverse Organ classes                  reactions                      reactions                       reactions 
Blood and lymphatic            Neutropenia (G3/4: system disorders               83.5%);
Anemia (G3/4: 12.4%);
Thrombocytopenia
(G3/4: 4.0%);
a
Febrile neutropenia
Nervous system                 Dysgeusia/Parosmia             Dizziness (G3/4: 2.0%); disorders                      (G3/4: 0.4%);                  Peripheral motor Peripheral sensory             neuropathy (G3/4: 0.4%) neuropathy (G3/4: 1.2%)
Eye disorders                                                 Lacrimation increased           Conjunctivitis Ear and labyrinth              Hearing impaired disorders                      (G3/4: 1.2%)
Gastrointestinal               Nausea (G3/4: 13.9%);          Dyspepsia (G3/4: 0.8%); disorders                      Stomatitis (G3/4:              Gastrointestinal pain 20.7%);                        (G3/4: 1.2%);
Vomiting (G3/4: 8.4%);         Gastrointestinal
Diarrhea (G3/4: 6.8%);         haemorrhage (G3/4:
Esophagitis/dysphagia/         0.4%) odynophagia (G3/4:
12.0%);
Constipation (G3/4:
0.4%)
Skin and subcutaneous          Alopecia (G3/4: 4.0%);         Dry skin ; tissue disorders               Rash pruritic                  Desquamation Musculoskeletal,                                              Myalgia (G3/4: 0.4%) connective tissue bone disorders
Metabolism and nutrition       Anorexia (G3/4: 12.0%) disorders
Infections and                 Infection (G3/4: 3.6%)         Neutropenic infection infestations
Neoplasms benign,                                             Cancer pain (G3/4: malignant and                                                 1.2%) unspecified (incl cysts and polyps)
Vascular disorders                                                                            Venous disorder General disorders and          Lethargy (G3/4: 4.0%);
administration site            Pyrexia (G3/4: 3.6%);
conditions                     Fluid retention (G3/4:
1.2%);
Oedema (G3/4: 1.2%)
Immune system                                                                                 Hypersensitivity disorders a
Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring i.v. antibiotics and/or hospitalization.


Combination therapy with TAXOTERE for adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2 and who received either AC-TH or TCH

Adverse Events (AEs) Related to Study Treatment, Occurring at Any Time During the Study: Safety Population (incidence of ≥ 5% for non-cardiac AEs; incidence of ≥ 1% for cardiac AEs) 
AC-TH                                           TCH n=1068                                         n=1056
Adverse Event                        Overall               Grade 3/4                Overall               Grade 3/4 (NCI-CTC term)                        n (%)                  n (%)                   n (%)                  n (%) Alopecia                      1047 (98.0)            0                       1012 (95.8)            0 a
Haemoglobin                   1036 (97.0)            34 (3.2)                1017 (96.3)            61 (5.8) 

Nausea                            931 (87.2)   57 (5.3)     853 (80.8)   49 (4.6) a
Leucocytes                        929 (87.0)   643 (60.2)   877 (83.0)   507 (48.0) a
Neutrophils                       922 (86.3)   761 (71.3)   859 (81.3)   696 (65.9) Fatigue                           868 (81.3)   71 (6.6)     849 (80.4)   73 (6.9) Stomatitis/pharyngitis            694 (65.0)   32 (3.0)     547 (51.8)   15 (1.4) Vomiting                          591 (55.3)   68 (6.4)     416 (39.4)   32 (3.0) a
SGPT (ALT)                        579 (54.2)   19 (1.8)     561 (53.1)   25 (2.4) a,b
Fluid retention                   558 (52.2)   16 (1.5)     539 (51.0)   15 (1.4) Myalgia                           544 (50.9)   52 (4.9)     353 (33.4)   15 (1.4) Diarrhoea                         484 (45.3)   55 (5.1)     589 (55.8)   52 (4.9) Neuropathy-sensory                478 (44.8)   20 (1.9)     316 (29.9)   6 (0.6) a
SGOT (AST)                        454 (42.5)   9 (0.8)      401 (38.0)   11 (1.0) Arthralgia                        424 (39.7)   32 (3.0)     230 (21.8)   11 (1.0) Nail changes                      423 (39.6)   0            246 (23.3)   0 a
Platelets                         350 (32.8)   13 (1.2)     667 (63.2)   57 (5.4) Irregular menses                  311 (29.1)   213 (19.9)   340 (32.2)   226 (21.4) Taste disturbance                 290 (27.2)   0            312 (29.5)   0 Constipation                      289 (27.1)   10 (0.9)     232 (22.0)   6 (0.6) Rash/desquamation                 277 (25.9)   14 (1.3)     241 (22.8)   4 (0.4) Hot flashes/flushes               230 (21.5)   0            192 (18.2)   0 Tearing                           228 (21.3)   3 (0.3)      109 (10.3)   0 a
Alkaline phosphatase              206 (19.3)   3 (0.3)      215 (20.4)   3 (0.3) Anorexia                          205 (19.2)   5 (0.5)      222 (21.0)   5 (0.5) Dyspepsia/heartburn               203 (19.0)   3 (0.3)      211 (20.0)   4 (0.4) Headache                          175 (16.4)   6 (0.6)      160 (15.2)   3 (0.3) Dyspnea                           166 (15.5)   16 (1.5)     157 (14.9)   18 (1.7) Weight gain                       159 (14.9)   3 (0.3)      154 (14.6)   2 (0.2) Infection without                 135 (12.6)   20 (1.9)     98 (9.3)     16 (1.5) neutropenia
Abdominal pain or                 132 (12.4)   4 (0.4)      141 (13.4)   5 (0.5) cramping
Insomnia                          119 (11.1)   1 (0.1)      93 (8.8)     0 Febrile neutropenia               116 (10.9)   116 (10.9)   103 (9.8)    103 (9.8) Fever (without                    116 (10.9)   4 (0.4)      70 (6.6)     3 (0.3) neutropenia)
Allergic                          105 (9.8)    15 (1.4)     139 (13.2)   26 (2.5) reaction/hypersensitivity
Bone pain                         104 (9.7)    4 (0.4)      67 (6.3)     1 (0.1) Infection with Grade 3/4          98 (9.2)     98 (9.2)     81 (7.7)     81 (7.7) neutropenia
Painc                             86 (8.1)     4 (0.4)      57 (5.4)     0 Conjunctivitis                    86 (8.1)     0            35 (3.3)     0 Dizziness /                       78 (7.3)     7 (0.7)      70 (6.6)     4 (0.4) lightheadedness
Creatininea                       72 (6.7)     5 (0.5)      102 (9.7)    6 (0.6) Hand-foot skin reaction           72 (6.7)     15 (1.4)     29 (2.7)     0 Epistaxis                         72 (6.7)     0            104 (9.8)    4 (0.4) Weight loss                       71 (6.6)     0            56 (5.3)     1 (0.1) Dry skin                      69 (6.5)           0                    41 (3.9)              0 Cough                         66 (6.2)           2 (0.2)              36 (3.4)              0 c
Rhinitis                      64 (6.0)           1 (0.1)              47 (4.5)              0 Rigors, chills                63 (5.9)           0                    54 (5.1)              0 Infection with unknown        59 (5.5)           59 (5.5)             38 (3.6)              38 (3.6) ANC
Neuropathy-motor              57 (5.3)           4 (0.4)              38 (3.6)              3 (0.3) a
Bilirubin                     54 (5.1)           4 (0.4)              61 (5.8)              4 (0.4) Injection site reaction       50 (4.7)           1 (0.1)              61 (5.8)              2 (0.2) Mouth dryness                 43 (4.0)           0                    29 (2.7)              0 Cardiac left ventricular      37 (3.5)           5 (0.5)              15 (1.4)              1 (0.1) function
Palpitations                  36 (3.4)           0                    47 (4.5)              0 Sinus tachycardia             19 (1.8)           0                    23 (2.2)              0 Hypotension                   10 (0.9)           0                    13 (1.2)              2 (0.2) 
AC-TH = doxorubicin and cyclophosphamide, followed by TAXOTERE in combination with trastuzumab.
TCH = TAXOTERE in combination with trastuzumab and carboplatin.
 a
Regardless of causality b
Fluid retention AEs are defined as "oedema only", or "weight gain only", or "lung oedema only", or "oedema and weight gain", or "oedema and lung oedema", or "oedema + weight gain + lung oedema". "Fluid retention" corresponds to the NCI-CTC term "oedema".
 c
COSTART term

The 3 year cumulative incidence of all symptomatic cardiac events was 2.36% and 1.16% in the AC-TH and TCH arms, respectively (versus 0.52% in the AC-T control arm, see CLINICAL TRIALS section). The 3 year cumulative incidence of CHF events (Grade 3 or 4) was 1.9% and 0.4% in the AC-TH and TCH arms, respectively (versus 0.3% in the AC-T control arm).

Post-marketing experience

Cardiac disorders
Rare cases of myocardial infarction have been reported.
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.

Nervous system disorders
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the medicinal product.

Eye disorders
Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during infusion of the medicinal product and in association with hypersensitivity reactions have been reported.
These were reversible upon discontinuation of the infusion. Cases of lacrimation with or without conjunctivitis, as cases of lacrimal duct obstruction resulting in excessive tearing have been rarely reported.
Cases of Cystoid Macular Oedema (CMO) have been reported in patients treated with docetaxel.

Ear and labyrinth disorders
Rare cases of ototoxicity, hearing impaired and/or hearing loss have been reported.

Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome, interstitial pneumonia / pneumonitis, interstitial lung disease, pulmonary fibrosis, respiratory failure, and radiation recall phenomena have rarely been reported, and may be associated with fatal outcome. 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.

Skin and subcutaneous tissue disorders
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, have been reported with docetaxel. In some cases concomitant factors may have contributed to the development of these effects. Sclerodermal-like changes usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia (frequency not known) have been reported.

Renal and urinary disorders
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.

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.

Vascular disorders
Venous thromboembolic events have rarely been reported.

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.

Immune system disorders
Some cases of anaphylactic shock, sometimes fatal, have been reported.

Hepatobiliary disorders
Very rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.

Metabolism and nutrition disorders
Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia.