Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequent treatment-related adverse reactions reported in the two phase II and one phase III trials in patients with transitional cell carcinoma of the urothelium (450 patients treated with vinflunine) were haematological disorders, mainly neutropenia and anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis/mucositis, vomiting, abdominal pain and diarrhoea and general disorders such as asthenia/fatigue.

Tabulated list of adverse reactions
Adverse reactions are listed below by System Organ Class, frequency and grade of severity (NCI CTC version 2.0). Frequency of adverse reactions is defined using the following convention: 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, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions observed in patients with transitional cell carcinoma of the urothelium treated with vinflunine


System Organ Class       Frequency         Adverse Reactions          Worst NCI Grade per patient (%)
All grades   Grade 3-4
Infections and infestations Common      Neutropenic infection               2.4         2.4 Infections (viral, bacterial,       7.6         3.6 fungal)
Uncommon     Neutropenic sepsis                 0.2          0.2
Neoplasm benign,           Uncommon     Tumor pain                         0.2          0.2 malignant and unspecified
Blood and lymphatic        Very common Neutropenia                         79.6        54.6 system disorders                       Leucopenia                          84.5        45.2 Anaemia                             92.8        17.3
Thrombocytopenia                    53.5         4.9
Common      Febrile neutropenia                 6.7          6.7
Immune system disorders Common         Hypersensitivity                    1.3          0.2 Endocrine disorders        Uncommon    Syndrome of Inappropriate
Antidiuretic Hormone                0.4 b       0.4 b
Secretion (SIADH) a
Metabolism and nutrition Very common Hyponatraemia                         39.8        11.7 disorders                              Decreased appetite                  34.2         2.7 Common      Dehydration                         4.4          2.0
Psychiatric disorders      Common      Insomnia                            5.1          0.2 Nervous system disorders Very          Peripheral sensory                  11.3         0.9 Common      neuropathy
Common      Syncope                             1.1          1.1
Headache                            6.2          0.7
Dizziness                           5.3          0.4
Neuralgia                           4.4          0.4
Dysgeusia                           3.3           0
Neuropathy                          1.3           0
Uncommon    Peripheral motor neuropathy         0.4           0
Rare        Posterior Reversible
0.03b        0.03b
Encephalopathy Syndromea
Eye disorders              Uncommon    Visual disturbance                  0.4           0 Ear and Labyrinth          Common      Ear pain                            1.1           0 disorders                  Uncommon    Vertigo                             0.9          0.4 Tinnitus                            0.9           0
Cardiac disorders          Common      Tachycardia                         1.8          0.2 Uncommon    Myocardial ischaemia                0.7          0.7
Myocardial infarction               0.2          0.2
Vascular disorders         Common      Hypertension                        3.1          1.6 Vein thrombosis                     3.6          0.4
Phlebitis                           2.4           0
Hypotension                         1.1          0.2
Respiratory, thoracic and Common       Dyspnoea                            4.2          0.4 mediastinal disorders                  Cough                               2.2           0 Uncommon    Acute respiratory distress          0.2          0.2 syndrome
Pharyngolaryngeal pain              0.9           0
Gastrointestinal disorders Very common Constipation                        54.9        15.1 Abdominal pain                      21.6         4.7
Vomiting                            27.3         2.9
Nausea                              40.9         2.9
Stomatitis                          27.1         2.7
Diarrhoea                           12.9           0.9
Common      Ileus                               2.7            2.2
Dysphagia                           2.0            0.4
Buccal disorders                    4.0            0.2
Dyspepsia                           5.1            0.2
Uncommon    Odynophagia                         0.4            0.2
Gastric disorders                   0.8             0
Oesophagitis                        0.4            0.2
Gingival disorders                  0.7             0
Skin and subcutaneous              Very common Alopecia                            28.9           NA tissue disorders                   Common      Rash                                1.8             0 Urticaria                           1.1             0
Pruritus                            1.1             0
Hyperhidrosis                       1.1             0
Uncommon    Dry skin                            0.9             0
Erythema                            0.4             0
Musculoskeletal and                Very common Myalgia                             16.7           3.1 connective tissue                  Common      Muscular weakness                   1.8            0.7 disorders                                      Arthralgia                          7.1            0.4 Back pain                           4.9            0.4
Pain in jaw                         5.6             0
Pain in extremity                   2.4             0
Bone pain                           2.9             0
Musculoskeletal pain                2.7            0.2
Renal and urinary                  Uncommon    Renal failure                       0.2            0.2 disorders
General disorders and              Very common Asthenia/Fatigue                    55.3           15.8 administration site                            Injection site reaction             26.4            0.4 conditions                                     Pyrexia                             11.7            0.4 Common      Chest pain                          4.7             0.9
Chills                              2.2             0.2
Pain                                3.1             0.2
Oedema                              1.1              0
Uncommon    Extravasation                       0.7              0
Investigations                     Very common Weight decreased                    24.0            0.4 Uncommon    Transaminases increased             0.4              0
Weight increased                    0.2              0 a adverse reactions reported from post-marketing experience b frequency calculated on the basis of non-TCCU clinical trial

Adverse reactions in all indications
Adverse reactions occurring in patients with transitional cell carcinoma of the urothelium and in patients with other disease than this indication and potentially severe or adverse reactions that are a class effect of the vinca alkaloids are described below:

Blood and lymphatic system disorders
Grade 3/4 neutropenia was observed in 43.8% of patients. Severe anaemia and thrombocytopenia were less common (respectively 8.8 and 3.1%). Febrile neutropenia defined as ANC < 1,000/mm3and fever ≥ 38.5°C of unknown origin without clinically microbiologically documented infection (NCI CTC version 2.0) was observed in 5.2% of patients. Infection with Grade 3/4 neutropenia was observed in 2.8% of patients.
Overall 8 patients (0.6% of the treated population) died from infection as a complication occurring during neutropenia.

Gastrointestinal disorders

Constipation is a class effect of the vinca alkaloids: 11.8% of patients experienced severe constipation during treatment with vinflunine. Grade 3/4 ileus reported in 1.9% of patients was reversible when managed by medical care. Constipation is managed by medical care (see section 4.4).

Nervous system disorders
Sensory peripheral neuropathy is a class effect of the vinca alkaloids. Grade 3 was experienced by 0.6% patients. All resolved during the study.
Rare cases of Posterior Reversible Encephalopathy Syndrome have been reported (see section 4.4).

Cardiovascular disorders
Cardiac effects are a known class effect of the vinca alkaloids. Myocardial infarction or ischaemia were experienced by 0.5% of the patients and most of them had a pre-existing cardiovascular disease or risk factors. One patient died after myocardial infarction and another one due to a cardiopulmonary arrest.
Few QT interval prolongations have been observed after the administration of vinflunine.

Respiratory, thoracic and mediastinal disorders
Dyspnoea occurred in 3.2% of the patients but was rarely severe (Grade 3/4: 1.2%).
Bronchospam was reported in one patient treated with vinflunine for a different setting from the indication.

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
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectM edic@moh.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).