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 phase III part of the study and 79 patients in the phase II part) who received docetaxel in combination with cisplatin and 5- fluorouracil (clinically important treatment related adverse events are presented).
• 174 and 251 head and neck cancer patients who received docetaxel in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).
These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade 3-4 = G3/4; grade 4 = G4) and the COSTART and the MedDRA terms. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from 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 is reversible and not cumulative; the median day nadir was 7 days and the median duration of severe neutropenia (<500 cells/mm3) is 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 trial in breast cancer patients failing anthracycline treatment are presented (see capecitabine Summary of Product Characteristics).

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 hyperpigmentation, 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 generalised rash/erythema (see section 4.4).

Tabulated list of adverse reactions in breast cancer for Docetaxel 100 mg/m² single agent MedDRA System               Very common              Common adverse reactions              Uncommon Organ classes            adverse reactions           ≥ 1 to < 10 % of patients         adverse reactions ≥ 10 % of patients                                             ≥ 0.1 to < 1% of patients


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 (0.5%) 

Blood and the         Neutropenia (G4: 76.4%)      Thrombocytopenia (G4: 0.2%) lymphatic system      Anaemia (G3/4: 8.9%) disorders             Febrile neutropenia
Nervous system        Peripheral sensory disorders             neuropathy (G3: 4.1%)
Peripheral motor neuropathy (G3/4: 4%)
Dysgeusia (severe 0.07%)
Respiratory, thoracic Dyspnoea (severe 2.7%) and mediastinal disorders
Gastrointestinal      Stomatitis (G3/4: 5.3%)      Constipation (severe 0.2%)       Oesophagitis disorders             Diarrhoea (G3/4: 4%)         Abdominal pain (severe 1%)       (severe 0.4%) Nausea (G3/4: 4%)            Gastrointestinal
Vomiting (G3/4: 3%)          haemorrhage
(severe 0.3%)
Skin and            Alopecia subcutaneous tissue Skin reaction (G3/4: 5.9%) disorders           Nail disorders (severe
2.6%)
Musculoskeletal,    Myalgia (severe 1.4%)      Arthralgia connective tissue and bone disorders
Metabolism and      Anorexia nutrition disorders
Infections and        Infections (G3/4: 5.7%;      Infection associated with G4 infestations          including sepsis and         neutropenia (G3/4: 4.6%) pneumonia, fatal in 1.7%)
Vascular disorders                                 Hypotension
Hypertension
Haemorrhage
General disorders     Fluid retention (severe:     Infusion site reaction and administration    6.5%)                        Non-cardiac chest pain (severe site conditions       Asthenia (severe 11.2%)      0.4%)
Pain
Immune system         Hypersensitivity disorders             (G3/4:5.3%)

Description of selected adverse reactions in breast cancer for docetaxel 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 Docetaxel 75 mg/m² single agent
MedDRA System          Very common adverse reactions             Common adverse reactions Organ classes               ≥ 10 % of patients                   ≥ 1 to < 10 % of patients Investigations                                               G3/4 Blood bilirubin increased (<2%) 
Cardiac disorders                                            Arrhythmia (not severe) Blood and the         Neutropenia (G4: 54.2%)                Febrile neutropenia lymphatic system      Anaemia (G3/4: 10.8%) disorders             Thrombocytopenia (G4: 1.7%)
Nervous system        Peripheral sensory neuropathy          Peripheral motor neuropathy disorders             (G3/4:0.8%)                            (G3/4:2.5%) Gastrointestinal      Nausea (G3/4: 3.3%)                    Constipation disorders             Stomatitis (G3/4: 1.7%)
Vomiting (G3/4: 0.8%)
Diarrhoea (G3/4: 1.7%)
Skin and            Alopecia                                 Nail disorders (severe 0.8%) subcutaneous tissue Skin reaction (G3/4: 0.8%) disorders
Musculoskeletal,                                             Myalgia connective tissue and bone disorders
Metabolism and        Anorexia nutrition disorders
Infections and        Infections (G3/4: 5%) infestations
Vascular disorders                                           Hypotension General disorders Asthenia (severe 12.4%) and administration Fluid retention (severe 0.8%) site conditions    Pain
Immune system                                                Hypersensitivity (not severe) disorders



Tabulated list of adverse reactions in breast cancer for Docetaxel 75 mg/m² in combination with doxorubicin
MedDRA System         Very common adverse            Common adverse           Uncommon adverse Organ classes              reactions                    reactions                 reactions ≥ 10 % of patients        ≥ 1 to < 10 % of patients     ≥ 0.1 to < 1% of patients


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 (not severe)
Blood and the         Neutropenia (G4: 91.7%) lymphatic system      Anaemia (G3/4: 9.4%) disorders             Febrile neutropenia
Thrombocytopenia
(G4:0.8%)
Nervous system        Peripheral sensory         Peripheral motor disorders             neuropathy (G3: 0.4%)      neuropathy (G3/4: 0.4%) Gastrointestinal    Nausea (G3/4: 5%) disorders           Stomatitis (G3/4: 7.8%)
Diarrhoea (G3/4: 6.2%)
Vomiting (G3/4: 5%)
Constipation
Skin and            Alopecia subcutaneous tissue Nail disorders (severe disorders           0.4%)
Skin reaction (not severe)
Musculoskeletal,                                 Myalgia connective tissue and bone disorders
Metabolism and                                   Anorexia nutrition disorders
Infections and        Infection (G3/4: 7.8%) infestations
Vascular disorders                                                            Hypotension General disorders Asthenia (severe 8.1%)         Infusion site reaction and administration Fluid retention (severe site conditions    1.2%)
Pain
Immune system                                    Hypersensitivity disorders                                        (G3/4:1.2%)

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

MedDRA System         Very common adverse            Common adverse            Uncommon adverse Organ classes              reactions                    reactions                  reactions ≥ 10 % of patients        ≥ 1 to < 10 % of patients      ≥ 0.1 to < 1% of patients


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 the       Neutropenia (G4: 51.5%) Febrile neutropenia lymphatic system    Anaemia (G3/4: 6.9%) disorders           Thrombocytopenia
(G4:0.5%)
Nervous system      Peripheral sensory disorders           neuropathy (G3: 3.7%)
Peripheral motor neuropathy (G3/4: 2%)
Gastrointestinal    Nausea (G3/4: 9.6%)        Constipation disorders           Vomiting (G3/4: 7.6%)
Diarrhoea (G3/4: 6.4%)
Stomatitis (G3/4: 2%)
Skin and            Alopecia subcutaneous        Nail disorders (severe tissue disorders    0.7%)
Skin reaction (G3/4: 0.2%)
Musculoskeletal,    Myalgia (severe 0.5%) connective tissue and bone disorders
Metabolism and      Anorexia nutrition disorders
Infections and      Infection (G3/4: 5.7%) infestations

Vascular disorders                              Hypotension (G3/4: 0.7%) General disorders Asthenia (severe 9.9%)        Infusion site reaction and administration Fluid retention (severe      Pain site conditions    0.7%)
Pyrexia (G3/4: 1.2%)
Immune system      Hypersensitivity disorders          (G3/4:2.5%)

Tabulated list of adverse reactions in breast cancer for Docetaxel 100mg/m² in combination with trastuzumab
MedDRA System          Very common adverse reactions              Common adverse reactions Organ classes                ≥ 10 % of patients                  ≥ 1 to < 10% of patients Investigations         Weight increased
Cardiac disorders                                              Cardiac failure Blood and the          Neutropenia (G3/4: 32%) lymphatic system       Febrile neutropenia (includes disorders              neutropenia associated with fever and antibiotic use) or neutropenic sepsis
Nervous system         Paraesthesia disorders              Headache
Dysgeusia
Hypoaesthesia
Eye disorders          Lacrimation increased
Conjunctivitis
Respiratory, thoracic Epistaxis and mediastinal       Pharyngolaryngeal pain disorders             Nasopharyngitis
Dyspnoea
Cough
Rhinorrhoea
Gastrointestinal      Nausea disorders             Diarrhoea
Vomiting
Constipation
Stomatitis
Dyspepsia
Abdominal pain
Skin and              Alopecia subcutaneous tissue Erythema disorders             Rash
Nail disorders
Musculoskeletal,      Myalgia connective tissue and Arthralgia bone disorders        Pain in extremity
Bone pain
Back pain
Metabolism and        Anorexia nutrition disorders
Vascular disorders    Lymphoedema

General disorders and Asthenia                                   Lethargy administration site   Oedema peripheral conditions            Pyrexia
Fatigue
Mucosal inflammation
Pain
Influenza-like illness
Chest pain
Chills
Psychiatric disorders Insomnia


Description of selected adverse reactions for docetaxel 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 trastuzumab plus docetaxel (23% versus 17% for patients treated with docetaxel alone).

Tabulated list of adverse reactions in breast cancer for Docetaxel 75 mg/m² in combination with capecitabine
MedDRA System             Very common adverse reactions              Common adverse reactions Organ classes                  ≥ 10 % of patients                    ≥ 1 to < 10 % of patients 
Investigations                                                    Weight decreased G3/4 Blood bilirubin increased (9%)
Blood and the           Neutropenia (G3/4: 63%)                   Thrombocytopenia (G3/4: 3%) lymphatic system        Anaemia (G3/4: 10%) disorders
Nervous system          Dysgeusia (G3/4: <1%)                     Dizziness disorders               Paraesthesia (G3/4: <1%)                  Headache (G3/4: <1%) Neuropathy peripheral
Eye disorders           Lacrimation increased
Respiratory, thoracic   Pharyngolaryngeal pain (G3/4: 2%)         Dyspnoea (G3/4: 1%) and mediastinal                                                   Cough (G3/4: <1%) disorders                                                         Epistaxis (G3/4: <1%) 
Gastrointestinal      Stomatitis (G3/4: 18%)                      Abdominal pain upper disorders             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 Hand-foot syndrome (G3/4: 24%)              Dermatitis tissue disorders      Alopecia (G3/4: 6%)                         Rash erythematous (G3/4: <1%) Nail disorders (G3/4: 2%)                   Nail discolouration
Onycholysis (G3/4: 1%)
Musculoskeletal,        Myalgia (G3/4: 2%)                        Pain in extremity (G3/4: <1%) connective tissue and   Arthralgia (G3/4: 1%)                     Back pain (G3/4: 1%) bone disorders
Metabolism and          Anorexia (G3/4: 1%)                       Dehydration (G3/4: 2%) nutrition disorders     Decreased appetite
Infections and                                                    Oral candidiasis (G3/4: <1%) infestations
General disorders and   Asthenia (G3/4: 3%)                       Lethargy administration site     Pyrexia (G3/4: 1%)                        Pain conditions              Fatigue/ weakness (G3/4: 5%)
Oedema peripheral (G3/4: 1%)

Tabulated list of adverse reactions in prostate cancer for Docetaxel 75 mg/m² in combination with prednisone or prednisolone
MedDRA System             Very common adverse reactions             Common adverse reactions Organ classes                 ≥ 10 % of patients                   ≥ 1 to < 10 % of patients Cardiac disorders                                                 Cardiac left ventricular function decrease (G3/4: 0.3%)
Blood and the           Neutropenia (G3/4: 32%)                   Thrombocytopenia; (G3/4: 0.6%) lymphatic system        Anaemia (G3/4: 4.9%)                      Febrile neutropenia disorders
Nervous system          Peripheral sensory neuropathy (G3/4:      Peripheral motor neuropathy (G3/4: disorders               1.2%)                                     0%) Dysgeusia (G3/4: 0%)
Eye disorders                                                     Lacrimation increased (G3/4: 0.6%) Respiratory,                                                      Epistaxis (G3/4: 0%) thoracic and                                                      Dyspnoea (G3/4: 0.6%) mediastinal                                                       Cough (G3/4: 0%) disorders


Gastrointestinal      Nausea (G3/4: 2.4%) disorders             Diarrhoea (G3/4: 1.2%)
Stomatitis/Pharyngitis (G3/4: 0.9%)
Vomiting (G3/4: 1.2%)
Skin and subcutaneous Alopecia                                    Exfoliative rash (G3/4: 0.3%) tissue disorders      Nail disorders (not severe)


Musculoskeletal,                                                  Arthralgia (G3/4: 0.3%) connective tissue and                                             Myalgia (G3/4: 0.3%) bone disorders
Metabolism and          Anorexia (G3/4: 0.6%) nutrition disorders
Infections and          Infection (G3/4: 3.3%) infestations
General disorders and   Fatigue (G3/4: 3.9%) administration site     Fluid retention (severe 0.6%) conditions
Immune system                                                     Hypersensitivity (G3/4: 0.6%) disorders

Tabulated list of adverse reactions in breast cancer for adjuvant therapy with Docetaxel 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer - pooled data
MedDRA System                 Very common adverse            Common adverse           Uncommon Organ classes              reactions ≥ 10 % of patients           reactions        adverse reactions ≥1 to <10% of         ≥0.1 to <1% of patients              patients


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 %);
Thrombocytopenia
(G3/4:1.6%);
Febrile neutropenia
(G3/4: NA)

Nervous system          Dysgeusia (G3/4: 0.6%);         Peripheral motor    Syncope (G3/4: 0%) disorders               Peripheral sensory              neuropathy          Neurotoxicity neuropathy (G3/4: <0.1%)        (G3/4: 0%);         (G3/4:0%);
Somnolence
(G3/4: 0%)


Eye disorders           Conjunctivitis (G3/4:<0.1%)     Lacrimation increased
(G3/4: < 0.1%);
Respiratory, thoracic                                   Cough (G3/4: 0%) and mediastinal disorders

Gastrointestinal      Nausea (G3/4: 5.0%);              Abdominal pain disorders             Stomatitis (G3/4: 6.0 %);         (G3/4: 0.4%)
Vomiting (G3/4: 4.2%);
Diarrhoea (G3/4: 3.4%);
Constipation (G3/4: 0.5%)
Skin and subcutaneous Alopecia (persisting: <3%) tissue disorders      Skin disorder (G3/4: 0.6%);
Nail disorders (G3/4: 0.4%)

Musculoskeletal and     Myalgia (G3/4: 0.7%);
connective tissue       Arthralgia (G3/4: 0.2%) disorders

Metabolism and          Anorexia (G3/4: 1.5 %) nutrition disorders

Infections and          Infection (G3/4: 2.4 %);
infestations            Neutropenic infection
(G3/4: 2.6%)

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

Immune system                                           Hypersensitivity disorders                                               (G3/4: 0.6%)


Reproductive system     Amenorrhoea (G3/4: NA) and breast disorders

Description of selected adverse reactions for adjuvant therapy with Docetaxel 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer
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
G-CSF prophylaxis              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 (Grade 3-4)          2 (1.8)                    5 (1.2) 
Tabulated list of adverse reactions in gastric adenocarcinoma cancer for Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil
MedDRA System           Very common adverse reactions            Common adverse reactions Organ classes                ≥ 10 % of patients                  ≥ 1 to < 10 % of patients 
Cardiac disorders                                               Arrhythmia (G3/4: 1.0%) 
Blood and the           Anaemia (G3/4: 20.9%) lymphatic system        Neutropenia (G3/4: 83.2%) disorders               Thrombocytopenia (G3/4: 8.8%)
Febrile neutropenia
Nervous system          Peripheral sensory neuropathy           Dizziness (G3/4: 2.3%) disorders               (G3/4: 8.7%)                            Peripheral motor neuropathy (G3/4: 1.3%)

Eye disorders                                                   Lacrimation increased (G3/4: 0%) Ear and labyrinth                                               Hearing impaired (G3/4: 0%) disorders

Gastrointestinal        Diarrhoea (G3/4: 19.7%)                 Constipation (G3/4: 1.0 %) disorders               Nausea (G3/4: 16%)                      Gastrointestinal pain (G3/4: 1.0%) Stomatitis (G3/4: 23.7%)                Oesophagitis/dysphagia/odynophagia Vomiting (G3/4: 14.3%)                  (G3/4: 0.7%)

Skin and                Alopecia (G3/4: 4.0%)                   Rash pruritus (G3/4: 0.7%) subcutaneous tissue                                             Nail disorders (G3/4: 0.7%) disorders                                                       Skin exfoliation (G3/4: 0%) 
Metabolism and          Anorexia (G3/4: 11.7%) nutrition disorders

Infections and          Neutropenic infection infestations            Infection (G3/4: 11.7%)
General disorders       Lethargy (G3/4: 19.0%) and administration      Pyrexia (G3/4: 2.3%) site conditions         Fluid retention
(severe/life-threatening: 1%)
Immune system           Hypersensitivity (G3/4: 1.7) disorders
Description of selected adverse reactions in gastric adenocarcinoma cancer for Docetaxel 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 Docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil

• Induction chemotherapy followed by radiotherapy (TAX 323)
MedDRA System      Very common adverse         Common adverse                Uncommon adverse Organ classes      reactions                   reactions                     reactions ≥ 10 % of patients          ≥ 1 to < 10 % of patients     ≥ 0.1 to < 1 % of patients
Investigations                                  Weight increased
Cardiac disorders                               Myocardial ischaemia         Arrhythmia (G3/4:0.6%) (G3/4: 1.7%)
Blood and the          Neutropenia (G3/4:76.3%) Febrile neutropeniaa lymphatic system       Anaemia (G3/4: 9.2) disorders              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       Nausea (G3/4: 0.6%)        Constipation disorders              Stomatitis (G3/4: 4.0%)    Oesophagitis/dysphagia/ Diarrhoea (G3/4: 2.9%)     odynophagia (G3/4: 0.6%)
Vomiting (G3/4: 0.6%)      Abdominal pain
Dyspepsia
Gastrointestinal haemorrhage (G3/4: 0.6%)


Skin and               Alopecia (G3/4: 10.9%)     Rash pruritic subcutaneous tissue                               Dry skin disorders                                         Skin exfoliative
(G3/4: 0.6%)
Musculoskeletal,                                  Myalgia (G3/4: 0.6%) connective tissue and bone disorders
Metabolism and        Anorexia (G3/4: 0.6%) nutrition disorders

Infections and         Infection (G3/4: 6.3%) infestations           Neutropenic infection
Neoplasms benign                                  Cancer pain (G3/4: 0.6%) and malignant
(including 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                                        Hypersensitivity disorders                                            (not severe)
 a
Febrile neutropenia: grade ≥2 fever concomitant with grade 4 neutropenia requiring i.v. antibiotics and/or hospitalization.
• Induction chemotherapy followed by radiotherapy (TAX 324) 
MedDRA System         Very common adverse               Common adverse             Uncommon adverse Organ classes              reactions                       reactions                   reactions ≥ 10 % of patients           ≥ 1 to < 10 % of patients       ≥ 0.1 to < 1 % of patients
Investigations         Weight decreased                                             Weight increased Cardiac disorders                                    Arrhythmia (G3/4:2.0%)         Ischaemia myocardial Blood and the          Neutropenia (G3/4: 83.5%) lymphatic system       Anaemia (G3/4: 12.4%) disorders              Thrombocytopenia
(G3/4: 4.0%)
Febrile neutropeniaa
Nervous system         Dysgeusia/Parosmia (G3/4: Dizziness (G3/4: 2.0%) disorders              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: 20.7%)      Gastrointestinal pain Vomiting (G3/4: 8.4%)         (G3/4: 1.2%)
Diarrhoea (G3/4: 6.8%)        Gastrointestinal
Oesophagitis/dysphagia/       haemorrhage (G3/4: 0.4%) odynophagia (G3/4: 12.0%)
Constipation (G3/4: 0.4%)
Skin and              Alopecia (G3/4: 4.0%)          Dry skin subcutaneous tissue Rash pruritic                    Desquamation disorders
Musculoskeletal,                                     Myalgia (G3/4: 0.4%) connective tissue and bone disorders
Metabolism and         Anorexia (G3/4: 12.0%) nutrition disorders
Infections and         Infection (G3/4: 3.6%)        Neutropenic infection infestations
Neoplasms benign                                     Cancer pain (G3/4: 1.2%) and malignant
(including 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 docetaxel 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 n=1068                     TCH 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 Haemoglobina                             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) Leucocytesa                              929 (87.0)  643 (60.2)         877 (83.0)  507 (48.0) Neutrophilsa                             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/                              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) SGPT (ALT)a                              579 (54.2)  19 (1.8)           561 (53.1)  25 (2.4) Fluid retentiona,b                       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) SGOT (AST)a                              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 Plateletsa                               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 Alkaline phosphatasea                    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 neutropenia            135 (12.6)  20 (1.9)           98 (9.3)    16 (1.5) Abdominal pain or cramping               132 (12.4)  4 (0.4)            141 (13.4)  5 (0.5) 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 neutropenia)              116 (10.9)      4 (0.4)        70 (6.6)        3 (0.3) Allergic reaction/hypersensitivity       105 (9.8)       15 (1.4)       139 (13.2)      26 (2.5) Bone pain                                104 (9.7)       4 (0.4)        67 (6.3)        1 (0.1) Infection with Grade 3/4 neutropenia     98 (9.2)        98 (9.2)       81 (7.7)        81 (7.7) Painc                                    86 (8.1)        4 (0.4)        57 (5.4)        0 Conjunctivitis                           86 (8.1)        0              35 (3.3)        0 Dizziness /lightheadedness               78 (7.3)        7 (0.7)        70 (6.6)        4 (0.4) 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) 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 function        37 (3.5)        5 (0.5)       15 (1.4)        1 (0.1) 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 docetaxel in combination with trastuzumab.
TCH = Docetaxel 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 infusion of the drug.

Eye Disorders: Very rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion 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, impaired hearing and/or hearing loss have been reported.

Respiratory, thoracic and mediastinal disorders: Acute respiratory distress syndrome interstitial pneumonia / pneumonitis, interstitial lung disease, pulmonary fibrosis, pulmonary edema, 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 erythematous 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 change usually preceded by peripheral lymphoedema have been reported with docetaxel. Cases of permanent alopecia (frequency not known) have been reported.
Neoplasms benign and malignant (including 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.

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.

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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/