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 (TAX 327) 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; 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 (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); 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: 
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 generalised 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 paraesthesia, 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).

Tabulated list of adverse reactions in breast cancer for docetaxel 100 mg/m2 single agent 
MedDRA system              Very common                Common adverse            Uncommon adverse organ classes              adverse reactions          reactions                 reactions Infections and             Infections (G3/4:          Infection associated infestations               5.7%; including sepsis     with G4 neutropenia and pneumonia, fatal       (G3/4: 4.6%) in 1.7%)
Blood and lymphatic        Neutropenia (G4:           Thrombocytopenia system disorders           76.4%); Anaemia            (G4: 0.2%)
(G3/4: 8.9%); Febrile neutropenia
Immune system              Hypersensitivity


MedDRA system             Very common                 Common adverse            Uncommon adverse organ classes             adverse reactions           reactions                 reactions disorders                 (G3/4: 5.3%)
Metabolism and            Anorexia nutrition disorders
Nervous system            Peripheral sensory disorders                 neuropathy (G3:
4.1%); Peripheral motor neuropathy (G3/4:
4%); Dysgeusia
(severe:
0.07%)
Cardiac disorders                                     Arrhythmia (G3/4:         Cardiac failure 0.7%)
Vascular disorders                                    Hypotension;
Hypertension;
Haemorrhage
Respiratory, thoracic     Dyspnoea (severe: and mediastinal           2.7%) disorders
Gastrointestinal          Stomatitis (G3/4:           Constipation (severe:     Oesophagitis (severe: disorders                 5.3%); Diarrhoea            0.2%); Abdominal          0.4%) (G3/4: 4%); Nausea          pain (severe: 1%);
(G3/4: 4%); Vomiting        Gastrointestinal
(G3/4: 3%)                  haemorrhage (severe:
0.3%)
Skin and subcutaneous     Alopecia; Skin tissue disorders          reaction (G3/4: 5.9%);
Nail disorders (severe:
2.6%)
Musculoskeletal and       Myalgia (severe:            Arthralgia connective tissue         1.4%) disorders
General disorders and     Fluid retention (severe:    Infusion site reaction; administration site       6.5%); Asthenia             Non-cardiac chest pain conditions                (severe: 11.2%); 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%)

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
Not known: Leucopenia


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 1000 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 organ              Very common adverse            Common adverse reactions classes                          reactions
Infections and infestations      Infections (G3/4: 5%)
Blood and lymphatic              Neutropenia (G4: 54.2%);       Febrile neutropenia system disorders                 Anaemia (G3/4: 10.8%);
Thrombocytopenia (G4:
1.7%)
Immune system disorders                                         Hypersensitivity (not severe) Metabolism and nutrition         Anorexia disorders
Nervous system disorders         Peripheral sensory             Peripheral motor neuropathy neuropathy (G3/4: 0.8%)        (G3/4: 2.5%)
Cardiac disorders                                               Arrhythmia (no severe) Vascular disorders                                              Hypotension Gastrointestinal disorders       Nausea (G3/4: 3.3%);           Constipation Stomatitis (G3/4: 1.7%);
Vomiting (G3/4: 0.8%);
Diarrhoea (G3/4: 1.7%)
Skin and subcutaneous tissue     Alopecia; Skin reaction        Nail disorders (severe: 0.8%) disorders                        (G3/4: 0.8%)
Musculoskeletal and                                             Myalgia connective tissue disorders
General disorders and            Asthenia (severe: 12.4%);
administration site conditions   Fluid retention (severe:
0.8%); Pain
Investigations                                                  G3/4 Blood bilirubin increased (< 2%)

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

MedDRA system             Very common              Common adverse         Uncommon adverse organ classes             adverse reactions        reactions              reactions Infections and            Infection (G3/4: 7.8%) infestations


MedDRA system            Very common               Common adverse         Uncommon adverse organ classes            adverse reactions         reactions              reactions Blood and lymphatic      Neutropenia (G4: system disorders         91.7%); Anaemia
(G3/4: 9.4%); Febrile neutropenia
Thrombocytopenia
(G4: 0.8%)
Immune system                                      Hypersensitivity disorders                                          (G3/4: 1.2%)
Metabolism and                                     Anorexia nutrition disorders
Nervous system           Peripheral sensory    Peripheral motor disorders                neuropathy (G3: 0.4%) neuropathy (G3/4:
0.4%)
Cardiac disorders                              Cardiac failure;
Arrhythmia (no severe)
Vascular disorders                                                        Hypotension Gastrointestinal         Nausea (G3/4: 5%);
disorders                Stomatitis (G3/4:
7.8%); Diarrhoea
(G3/4: 6.2%);
Vomiting (G3/4: 5%);
Constipation
Skin and                 Alopecia; Nail subcutaneous tissue      disorders (severe: disorders                0.4%); Skin reaction
(no severe)
Musculoskeletal and                                Myalgia connective tissue disorders
General disorders and    Asthenia (severe:         Infusion site administration site      8.1%); Fluid retention    reaction conditions               (severe: 1.2%); Pain
Investigations                                     G3/4 Blood             G3/4 AST increased (< bilirubin increased    1%); G3/4 ALT
(< 2.5%); G3/4         increased (< 1%)
Blood alkaline phosphatase increased (< 2.5%)

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

MedDRA system            Very common                Common adverse       Uncommon adverse organ classes            adverse reactions          reactions            reactions Infections and           Infection (G3/4: 5.7%) infestations
Blood and lymphatic      Neutropenia (G4:           Febrile system disorders         51.5%); Anaemia            neutropenia
(G3/4: 6.9%);
Thrombocytopenia
(G4: 0.5%)
Immune system            Hypersensitivity disorders                (G3/4: 2.5%)


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

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

MedDRA system organ                 Very common adverse                  Common adverse classes                             reactions                            reactions Blood and lymphatic system          Neutropenia (G3/4: 32%);
disorders                           Febrile neutropenia (includes neutropenia associated with fever and antibiotic use) or neutropenic sepsis
Metabolism and nutrition            Anorexia disorders
Psychiatric disorders               Insomnia
Nervous system disorders            Paraesthesia; Headache;
Dysgeusia; Hypoaesthesia
Eye disorders                       Lacrimation increased;
Conjunctivitis
Cardiac disorders                                                        Cardiac failure Vascular disorders                  Lymphoedema
Respiratory, thoracic and           Epistaxis; Pharyngolaryngeal mediastinal disorders               pain; Nasopharyngitis;
Dyspnoea; Cough; Rhinorrhoea


MedDRA system organ                Very common adverse              Common adverse classes                            reactions                        reactions Gastrointestinal disorders         Nausea; Diarrhoea; Vomiting;
Constipation; Stomatitis;
Dyspepsia; Abdominal pain
Skin and subcutaneous tissue       Alopecia; Erythema; Rash; Nail disorders                          disorders
Musculoskeletal and                Myalgia; Arthralgia; Pain in connective tissue disorders        extremity; Bone pain; Back pain
General disorders and              Asthenia; Oedema peripheral;     Lethargy administration site conditions     Pyrexia; Fatigue; Mucosal inflammation; Pain; Influenza like illness; Chest pain; Chills
Investigations                     Weight increased

Description of selected adverse reactions in breast cancer 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 Herceptin 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 organ               Very common adverse            Common adverse reactions classes                           reactions
Infections and infestations                                      Oral candidiasis (G3/4: < 1%) Blood and lymphatic system        Neutropenia (G3/4: 63%);       Thrombocytopenia (G3/4: 3%) disorders                         Anaemia (G3/4: 10%)
Metabolism and nutrition          Anorexia (G3/4: 1%);           Dehydration (G3/4: 2%) disorders                         Decreased appetite
Nervous system disorders          Dysgeusia (G3/4: < 1%);        Dizziness; Headache (G3/4: < 1%); Paraesthesia (G3/4: < 1%)      Neuropathy peripheral
Eye disorders                     Lacrimation increased
Respiratory, thoracic and         Pharyngolaryngeal pain         Dyspnoea (G3/4: 1%); Cough mediastinal disorders             (G3/4: 2%)                     (G3/4: < 1%); Epistaxis (G3/4: < 1%)
Gastrointestinal disorders        Stomatitis (G3/4: 18%);        Abdominal pain upper; Dry mouth Diarrhoea (G3/4: 14%);
Nausea (G3/4: 6%);
Vomiting (G3/4: 4%);
Constipation (G3/4: 1%);
Abdominal pain (G3/4:
2%); Dyspepsia
Skin and subcutaneous tissue      Hand-foot syndrome             Dermatitis; Rash erythematous disorders                         (G3/4: 24%); Alopecia          (G3/4: < 1%) ; Nail discolouration; (G3/4: 6%); Nail disorders     Onycholysis (G3/4: 1%)
(G3/4: 2%)
Musculoskeletal and               Myalgia (G3/4: 2%)             Pain in extremity (G3/4: < 1%); connective tissue disorders       Arthralgia (G3/4: 1%)          Back pain (G3/4: 1%) General disorders and             Asthenia (G3/4: 3%);           Lethargy; Pain administration site conditions    Pyrexia (G3/4: 1%);
Fatigue/weakness (G3/4:
5%); Oedema peripheral
(G3/4: 1%)
Investigations                                                   Weight decreased; G3/4 Blood bilirubin increased (9%)

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

MedDRA system organ              Very common adverse               Common adverse reactions classes                          reactions
Infections and infestations      Infection (G3/4: 3.3%)
Blood and lymphatic system       Neutropenia (G3/4: 32%);          Thrombocytopenia (G3/4: 0.6%); disorders                        Anaemia (G3/4: 4.9%)              Febrile neutropenia Immune system disorders                                            Hypersensitivity (G3/4: 0.6%) Metabolism and nutrition         Anorexia (G3/4: 0.6%) disorders
Nervous system disorders         Peripheral sensory neuropathy     Peripheral motor neuropathy (G3/4: 1.2%); Dysgeusia           (G3/4: 0%)
(G3/4: 0%)
Eye disorders                                                      Lacrimation increased (G3/4: 0.6%)
Cardiac disorders                                                  Cardiac left ventricular function decrease (G3/4: 0.3%)


MedDRA system organ              Very common adverse              Common adverse reactions classes                          reactions
Respiratory, thoracic and                                         Epistaxis (G3/4: 0%); Dyspnoea mediastinal disorders                                             (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     Alopecia; Nail disorders (no     Exfoliative rash (G3/4: 0.3%) disorders                        severe)
Musculoskeletal and                                               Arthralgia (G3/4: 0.3%); Myalgia connective tissue disorders                                       (G3/4: 0.3%) General disorders and            Fatigue (G3/4: 3.9%); Fluid administration site conditions   retention (severe: 0.6%)


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 adverse organ classes           reactions                    reactions            reactions Infections and          Infection (G3/4: 2.4%);
infestations            Neutropenic infection
(G3/4: 2.6%)
Blood and lymphatic     Anaemia (G3/4: 3%) system disorders        Neutropenia (G3/4:
59.2%)
Thrombocytopenia
(G3/4: 1.6%)
Febrile neutropenia
(G3/4: NA)
Immune system                                        Hypersensitivity disorders                                            (G3/4: 0.6%)
Metabolism and          Anorexia (G3/4: 1.5%) nutrition disorders
Nervous system          Dysgeusia (G3/4: 0.6%);      Peripheral motor     Syncope (G3/4: 0%); disorders               Peripheral sensory           neuropathy (G3/4:    Neurotoxicity (G3/4: neuropathy (G3/4:            0%);                 0%);
< 0.1%)                                           Somnolence (G3/4: 0%) Eye disorders           Conjunctivitis (G3/4: <      Lacrimation
0.1%)                        increased (G3/4: <
0.1%)
Cardiac disorders                                    Arrhythmia (G3/4: 0.2%)
Vascular disorders      Hot flush (G3/4: 0.5%)       Hypotension          Lymphoedema (G3/4: 0%);          (G3/4: 0%)
Phlebitis (G3/4:
0%)
Respiratory, thoracic                                Cough (G3/4: 0%) and mediastinal disorders


MedDRA system            Very common adverse         Common adverse       Uncommon adverse organ classes            reactions                   reactions            reactions 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                 Alopecia (persisting: < subcutaneous tissue      3%); Skin disorder disorders                (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
Reproductive system      Amenorrhoea (G3/4: and breast disorders     NA)
General disorders        Asthenia (G3/4: 10.0%);
and administration       Pyrexia (G3/4: NA);
site conditions          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 docetaxel 75 mg/m2 in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer

Nervous system disorders

In study TAX 316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm. At the end of the follow-up period (median follow-up time of 8 years), peripheral sensory neuropathy was observed to be ongoing in 10 patients (1.3%) in TAC arm, and in 2 patients (0.3%) in FAC arm.

In GEICAM 9805 study, peripheral sensory neuropathy that started during the treatment period persisted into the follow-up period in 10 patients (1.9%) in TAC arm and 4 patients (0.8%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), peripheral sensory neuropathy was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Cardiac disorders

In study TAX 316, 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. At the end of the follow-up period (actual median follow-up time of 10 years and 5 months), no patients had CHF in TAC arm and 1 patient in TAC arm died because of dilated cardiomyopathy, and CHF was observed to be ongoing in 1 patient (0.2%) in FAC arm.


Skin and subcutaneous tissue disorders

In study TAX 316, alopecia persisting into the follow-up period after the end of chemotherapy was reported in 687 of 744 TAC patients (92.3%) and 645 of 736 FAC patients (87.6%). At the end of the follow-up period (actual median follow-up time of 8 years), alopecia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In GEICAM 9805 study, alopecia that started during the treatment period and persisted into the follow- up period 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. At the end of the follow-up period (median follow-up time of 10 years and 5 months), alopecia was observed to be ongoing in 3 patients (0.6%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Reproductive system and breast disorders

In TAX 316, amenorrhoea that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 202 of 744 TAC patients (27.2%) and 125 of 736 FAC patients (17.0%). Amenorrhea was observed to be ongoing at the end of the follow-up period (median follow-up time of 8 years) in 121 of 744 TAC patients (16.3%) and 86 FAC patients (11.7%).

In GEICAM 9805 study, amenorrhoea that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 18 patients (3.4%) in TAC arm and 5 patients (1.0%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), amenorrhoea was observed to be ongoing in 7 patients (1.3%) in TAC arm, and in 4 patients (0.8%) in FAC arm.

General disorders and administration site conditions

In study TAX 316, peripheral oedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was observed in 119 of 744 TAC patients (16.0%) and 23 of 736 FAC patients (3.1%). At the end of the follow-up period (actual median follow-up time of
8 years), peripheral oedema was ongoing in 19 TAC patients (2.6%) and 4 FAC patients (0.5%).

In study TAX 316, lymphoedema that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 11 of 744 TAC patients (1.5%) and 1 of 736 FAC patients (0.1%). At the end of the follow-up period (actual median follow-up time of 8 years), lymphoedema was observed to be ongoing in 6 TAC patients (0.8%) and 1 FAC patient (0.1%).

In study TAX 316, asthenia that started during the treatment period and persisted into the follow-up period after the end of chemotherapy was reported in 236 of 744 TAC patients (31.7%) and 180 of 736 FAC patients (24.5%). At the end of the follow-up period (actual median follow-up time of 8 years), asthenia was observed to be ongoing in 29 TAC patients (3.9%) and 16 FAC patients (2.2%).

In study GEICAM 9805, peripheral oedema that started during the treatment period persisted into the follow-up period in 4 patients (0.8%) in TAC arm and in 2 patients (0.4%) in FAC arm. At the end of the follow-up period (median follow-up time of 10 years and 5 months), no patients (0%) in TAC arm had peripheral oedema and it was observed to be ongoing in 1 patient (0.2%) in FAC arm.
Lymphoedema that started during the treatment period persisted into the follow-up period in 5 patients (0.9%) in TAC arm and 2 patients (0.4%) in FAC arm. At the end of the follow-up period, lymphoedema was observed to be ongoing in 4 patients (0.8%) in TAC arm, and in 1 patient (0.2%) in FAC arm.

Asthenia that started during the treatment period and persisted into the follow-up period was observed to be ongoing in 12 patients (2.3%) in TAC arm and 4 patients (0.8%) in FAC arm. At the end of the follow-up period, asthenia was observed to be ongoing in 2 patients (0.4%) in TAC arm, and in 2 patients (0.4%) in FAC arm.


Acute leukaemia/myelodysplastic syndrome

After 10 years of follow-up in study TAX 316, acute leukaemia was reported in 3 of 744 TAC patients (0.4%) and in 1 of 736 FAC patients (0.1%). One TAC patient (0.1%) and 1 FAC patient (0.1%) died due to AML during the follow-up period (median follow-up time of 8 years). Myelodysplastic syndrome was reported in 2 of 744 TAC patients (0.3%) and in 1 of 736 FAC patients (0.1%).

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

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 (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 organ classes Very common adverse                     Common adverse reactions reactions

Infections and infestations       Neutropenic infection;
Infection (G3/4: 11.7%)
Blood and lymphatic system        Anaemia (G3/4: 20.9%);
disorders                         Neutropenia (G3/4: 83.2%);
Thrombocytopenia (G3/4:
8.8%);
Febrile neutropenia
Immune system disorders           Hypersensitivity (G3/4: 1.7%)
Metabolism and nutrition          Anorexia (G3/4: 11.7%) disorders
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%) 

MedDRA system organ classes Very common adverse                     Common adverse reactions reactions

Cardiac disorders                                                   Arrhythmia (G3/4: 1.0%) 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%)
General disorders and             Lethargy (G3/4: 19.0%);
administration site conditions    Fever (G3/4: 2.3%);
Fluid retention
(severe/life-threatening: 1%)

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               Common adverse               Uncommon organ classes           adverse reactions         reactions                    adverse reactions Infections and          Infection (G3/4: infestations            6.3%); Neutropenic infection
Neoplasms benign,                                 Cancer pain (G3/4: 0.6%) malignant and unspecified (incl.
cysts and polyps)
Blood and lymphatic     Neutropenia (G3/4:        Febrile neutropenia system disorders        76.3%); Anaemia
(G3/4: 9.2%);
Thrombocytopenia
(G3/4: 5.2%)
Immune system                                     Hypersensitivity (no disorders                                         severe)
Metabolism and          Anorexia (G3/4: 0.6%) nutrition disorders
Nervous system          Dysgeusia/Parosmia;       Dizziness disorders               Peripheral sensory neuropathy (G3/4:
0.6%)
Eye disorders                                     Lacrimation increased; Conjunctivitis


MedDRA system              Very common                Common adverse               Uncommon organ classes              adverse reactions          reactions                    adverse reactions Ear and labyrinth                                     Hearing impaired disorders
Cardiac disorders                                     Myocardial ischaemia      Arrhythmia (G3/4: (G3/4: 1.7%)              0.6%)
Vascular disorders                                    Venous disorder (G3/4: 0.6%)
Gastrointestinal           Nausea (G3/4: 0.6%);       Constipation;
disorders                  Stomatitis (G3/4:          Oesophagitis/dysphagia/ 4.0%); Diarrhoea           odynophagia (G3/4: 0.6%);
(G3/4: 2.9%);              Abdominal pain;
Vomiting (G3/4: 0.6%)      Dyspepsia;
Gastrointestinal haemorrhage (G3/4: 0.6%)
Skin and                   Alopecia (G3/4:            Rash pruritic; Dry skin; subcutaneous tissue        10.9%)                     Skin exfoliative (G3/4: disorders                                             0.6%)
Musculoskeletal and                                   Myalgia (G3/4: 0.6%) connective tissue disorders
General disorders and      Lethargy (G3/4: administration site        3.4%); Pyrexia (G3/4: conditions                 0.6%); Fluid retention;
Oedema
Investigations                                        Weight increased 
Induction chemotherapy followed by chemoradiotherapy (TAX 324)

MedDRA system               Very common adverse         Common adverse               Uncommon organ classes               reactions                   reactions                    adverse reactions
Infections and              Infection (G3/4: 3.6%)      Neutropenic infection infestations
Neoplasms benign,                                       Cancer pain (G3/4: 1.2%) malignant and unspecified (incl. cysts and polyps)
Blood and lymphatic         Neutropenia (G3/4: system disorders            83.5%); Anaemia
(G3/4: 12.4%);
Thrombocytopenia
(G3/4: 4.0%); Febrile neutropenia
Immune system                                                                        Hypersensitivity disorders
Metabolism and              Anorexia (G3/4: nutrition disorders         12.0%)
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%)


MedDRA system            Very common adverse       Common adverse                 Uncommon organ classes            reactions                 reactions                      adverse reactions
Cardiac disorders                                  Arrhythmia (G3/4: 2.0%)        Ischaemia myocardial
Vascular disorders                                                                Venous disorder Gastrointestinal         Nausea (G3/4: 13.9%);     Dyspepsia (G3/4: 0.8%); disorders                Stomatitis (G3/4:         Gastrointestinal pain (G3/4: 20.7%); Vomiting          1.2%); Gastrointestinal
(G3/4: 8.4%);             haemorrhage (G3/4:0.4%)
Diarrhoea (G3/4:
6.8%);
Oesophagitis/dysphagia
/odynophagia (G3/4:
12.0%); Constipation
(G3/4: 0.4%)
Skin and subcutaneous    Alopecia (G3/4: 4.0%);    Dry skin; Desquamation tissue disorders         Rash pruritic
Musculoskeletal and                                Myalgia (G3/4: 0.4%) connective tissue disorders
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%)
Investigations           Weight decreased                                         Weight increased 
Combination therapy with docetaxel for adjuvant treatment of patients with operable breast cancer whose tumours over-express HER2 and who received either AC-TH or TCH related to study treatment, occurring at any time during the study: safety population (incidence of ≥5% for non-cardiac ARs; incidence of ≥ 1% for cardiac ARs)


                                                 AC-TH n=1068                 TCH      n=1056
Adverse Reaction                             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/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) 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 Rhinitisc                                    64 (6.0)       1 (0.1)      47 (4.5)      0 Rigors, chills                               63 (5.9)       0            54 (5.1)      0 Infection with unknown ANC                   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) Bilirubina                                   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

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Second primary malignancies (frequency not known), including non-Hodgkin lymphoma have been reported in association with docetaxel when used in combination with other anticancer treatments known to be associated with second primary malignancies. Acute myeloid leukaemia and myelodysplastic syndrome have been reported (frequency uncommon) in pivotal clinical studies in breast cancer with TAC regimen.

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 multi-organ failure, has been reported.

Immune system disorders

Some cases of anaphylactic shock, sometimes fatal, have been reported.
Hypersensitivity reactions (frequency not known) have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

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.


Cardiac disorders
Rare cases of myocardial infarction have been reported.

Ventricular arrhythmia including ventricular tachycardia (frequency not known), sometimes fatal, has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/ or cyclophosphamide.

Vascular disorders

Venous thromboembolic events have rarely been reported.
Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome and cases of interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure, sometimes fatal, have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

Gastrointestinal disorders

Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, have been reported with a potential fatal outcome (frequency not known).

Rare occurrences of dehydration have been reported as a consequence of gastrointestinal events, including enterocolitis and gastrointestinal perforation.
Rare cases of ileus and intestinal obstruction have been reported.

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Cases of cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme, and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel.
Scleroderma-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 gastrointestinal disorders.

General disorders and administration site conditions

Radiation recall phenomena have rarely been reported.
Injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation (frequency not known).

Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Dehydration and pulmonary oedema have rarely been reported.


Metabolism and nutrition disorders

Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia, and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular with diarrhoea. Tumour lysis syndrome, potentially fatal, has been reported (frequency not known).

Musculoskeletal disorder

Myositis has been reported with docetaxel (frequency not known).
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 event should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/