Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of safety profile
A total of 1,372 leukaemia patients received at least 1 dose of single-agent bosutinib. The median duration of therapy was 26.30 months (range: 0.03 to 170.49 months). These patients were either newly-diagnosed, with CP CML or were resistant or intolerant to prior therapy with chronic, accelerated, or blast phase CML or Ph+ acute lymphoblastic leukaemia (ALL). Of these patients, 268 (400 mg starting dose) and 248 (500 mg starting dose) are from the 2 Phase 3 studies in previously untreated CML patients, 60 (400 mg starting dose) are from a Phase 2 study in previously untreated CML patients, 570 and 63 (Phase 2: 500 mg starting dose) are from 2 Phase 1/2 studies in previously treated Ph+ leukaemias, and 163 (500 mg starting dose) are from a Phase 4 study in previously treated CML. The median duration of therapy was 55.1 months (range: 0. 2 to 60.05 months), 61.6 months (0.03 to 145.86 months), 15.3 months (range: 0.3 to 21.8 months), 11.1 months (range: 0.03 to 170.49 months), 30.2 months (range: 0.2 to 85.6 months), and 37.80 months (range: 0.16 to 50.0 months), respectively. The safety analyses included data from a completed extension study.

At least 1 adverse reaction of any toxicity grade was reported for 1,349 (98.3%) patients. The most frequent adverse reactions reported for  20% of patients were diarrhoea (80.4%), nausea (41.5%), abdominal pain (35.6%), thrombocytopenia (34.4%), vomiting (33.7%), rash (32.8%), ALT increased (28.0%), anaemia (27.2%), pyrexia (23.4%), AST increased (22.5%), fatigue (32.0%), and headache (20.3%). At least 1 Grade 3 or Grade 4 adverse reaction was reported for 943 (68.7%) patients. The Grade 3 or Grade 4 adverse reactions reported for  5% of patients were thrombocytopenia (19.7%), ALT increased (14.6%), neutropenia (10.6%), diarrhoea (10.6%), anaemia (10.3%), lipase increased (10.1%), AST increased (6.7%), and rash (5.0%).

Tabulated list of adverse reactions
The following adverse reactions were reported in patients in bosutinib clinical studies (Table 2). These represent an evaluation of the adverse reaction data from 1,372 patients with either newly-diagnosed CP CML or with chronic, accelerated, or blast phase CML resistant or intolerant to prior therapy or Ph+ ALL who have received at least 1 dose of single-agent bosutinib. These adverse reactions are presented by system organ class and frequency. Frequency categories 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 the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 - Adverse reactions for bosutinib

Infections and infestations
Very common        Respiratory tract infection (including Lower respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection), Nasopharyngitis
Common             Pneumonia (including Atypical pneumonia, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal), Influenza
(including Influenza H1N1), Bronchitis
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uncommon           Tumour lysis syndrome**
Blood and lymphatic system disorders
Very common        Thrombocytopenia (including Platelet count decreased), Neutropenia (including Neutrophil count decreased), Anaemia (including haemoglobin decreased, Red blood cell count decreased)
Common             Leukopenia (including White blood cell count decreased) Uncommon           Febrile neutropenia, Granulocytopenia
Immune system disorders
Common             Drug hypersensitivity
Uncommon           Anaphylactic shock
Metabolism and nutrition disorders
Very common        Decreased appetite
Common             Dehydration, Hyperkalaemia (including Blood potassium increased), Hypophosphataemia (including Blood phosphorus decreased)
Nervous system disorders
Very common        Dizziness, Headache
Common             Dysgeusia
Ear and labyrinth disorders
Common             Tinnitus
Cardiac disorders
Common             Pericardial effusion
Uncommon           Pericarditis
Vascular disorders
Common             Hypertension (including Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertensive crisis)
Respiratory, thoracic and mediastinal disorders
Very common        Pleural effusion, Dyspnoea, Cough
Common             Pulmonary hypertension (including Pulmonary arterial hypertension, Pulmonary arterial pressure increased), Respiratory failure
Uncommon           Acute pulmonary oedema (including Pulmonary oedema) Not known          Interstitial lung disease
Gastrointestinal disorders
Very common        Diarrhoea, Vomiting, Nausea, Abdominal pain (including Abdominal discomfort, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain)
Common             Gastrointestinal haemorrhage (including Anal haemorrhage, Gastric haemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage, 
Rectal haemorrhage, Upper gastrointestinal haemorrhage), Pancreatitis (including Pancreatitis acute), Gastritis
Hepatobiliary disorders
Common            Hepatotoxicity (including Hepatitis, Hepatitis toxic, Liver disorder), Hepatic function abnormal (including Hepatic enzyme increased, Liver function test abnormal, Liver function test increased, Transaminases increased)
Uncommon          Liver injury (including Drug-induced liver injury, Hepatocellular injury) Skin and subcutaneous tissue disorders
Very common       Rash (including Rash macular, Rash maculo-papular, Rash papular, Rash pruritic), Pruritus
Common            Photosensitivity reaction (including Polymorphic light eruption), Urticaria, Acne
Uncommon          Erythema multiforme, Exfoliative rash, Drug eruption Not known         Stevens-Johnson Syndrome**, Toxic epidermal necrolysis** Musculoskeletal and connective tissue disorders
Very common       Arthralgia, Back pain
Common            Myalgia
Renal and urinary disorders
Common            Acute kidney injury, Renal failure, Renal impairment General disorders and administration site conditions
Very common       Oedema (including Eyelid oedema, Face oedema, Generalised oedema, Localised oedema, Oedema peripheral, Periorbital oedema, Periorbital swelling, Peripheral swelling, Swelling, Swelling of eyelid), Pyrexia, Fatigue (including Asthenia, Malaise)
Common            Chest pain (including Chest discomfort), Pain
Investigations
Very common       Lipase increased (including Hyperlipasaemia), Alanine aminotransferase increased (including Alanine aminotransferase abnormal), Aspartate aminotransferase increased, Blood creatinine increased
Common            Electrocardiogram QT prolonged (including Long QT syndrome) , Amylase increased (including Hyperamylasaemia), Blood creatine phosphokinase increased, Gamma-glutamyltransferase increased, Blood bilirubin increased (including Hyperbilirubinaemia, Bilirubin conjugated increased, Blood bilirubin unconjugated increased)
**
Adverse reaction identified post marketing.

Description of selected adverse reactions
The descriptions included below are based on the safety population of 1,372 patients who received at least 1 dose of bosutinib and had either newly-diagnosed CP CML or were resistant or intolerant to prior therapy with CP, AP, or BP CML, or Ph+ ALL.

Blood and lymphatic system disorders
Of the 372 (27.1%) patients with reports of adverse reactions of anaemia, 6 patients discontinued bosutinib due to anaemia. Maximum toxicity of Grade 1 occurred in 95 (25.5%) patients, Grade 2 in 135 (36.3%) patients, Grade 3 in 113 patients (30.4%), and Grade 4 in 29 (7.8%) patients. Among these patients, the median time to first event was 29 days (range: 1 to 3,999 days) and the median duration per event was 22 days (range: 1 to 3,682 days).

Of the 209 (15.2%) patients with reports of adverse reactions of neutropenia, 19 patients discontinued bosutinib due to neutropenia. Maximum toxicity of Grade 1 occurred in 19 patients (9.1%), Grade 2 in 45 (21.5%) patients, Grade 3 in 95 (45.5%) patients, and Grade 4 in 50 (23.9%) patients. Among these patients, the median time to first event was 56 days (range: 1 to 1,769 days), and the median duration per event was 15 days (range: 1 to 913 days).


Of the 472 (34.4%) patients with reports of adverse reactions of thrombocytopenia, 42 patients discontinued bosutinib due to thrombocytopenia. Maximum toxicity of Grade 1 occurred in 114 (24.2%) patients, Grade 2 in 88 (18.6%) patients, Grade 3 in 172 (36.4%) patients, and Grade 4 in 98 (20.8%) patients. Among these patients, the median time to first event was 28 days (range: 1 to 1,688 days), and median duration per event was 15 days (range: 1 to 3,921 days).

Hepatobiliary disorders
Among patients with reports of adverse reactions of elevations in either ALT or AST (all grades), the median time of onset observed was 29 days with a range of onset 1 to 3,995 days for ALT and AST.
The median duration of an event was 17 days (range: 1 to 1,148 days), and 15 days (range: 1 to 803 days) for ALT and AST, respectively.

Two cases consistent with drug-induced liver injury (defined as concurrent elevations in ALT or AST ≥ 3 × ULN with total bilirubin > 2 × ULN and with alkaline phosphatase < 2 × ULN) without alternative causes have occurred in 2/1,711 (0.1%) subjects treated with bosutinib.

Hepatitis B reactivation
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4).

Gastrointestinal disorders
Of the 1,103 (80.4%) patients that experienced diarrhoea, 14 patients discontinued bosutinib due to this event. Concomitant medicinal products were given to treat diarrhoea in 756 (68.5%) patients.
Maximum toxicity of Grade 1 occurred in 575 (52.1%) patients, Grade 2 in 383 (34.7%) patients, Grade 3 in 144 (13.1%) patients; 1 patient (0.1%) experienced a Grade 4 event. Among patients with diarrhoea, the median time to first event was 2 days (range: 1 to 2,702 days) and the median duration of any grade of diarrhoea was 2 days (range: 1 to 4,247 days).

Among the 1,103 patients with diarrhoea, 218 patients (19.8%) were managed with treatment interruption and of these 208 (95.4%) were rechallenged with bosutinib. Of those who were rechallenged, 201 (96.6%) did not have a subsequent event or did not discontinue bosutinib due to a subsequent event of diarrhoea.

Cardiac disorders
Seven patients (0.5%) experienced QTcF prolongation (greater than 500 ms). Eleven (0.8%) patients experienced QTcF increase > 60 ms from baseline. Patients with uncontrolled or significant cardiovascular disease including QTc prolongation, at baseline, were not included in clinical studies (see sections 5.1 and 5.3).

Cardiovascular toxicity including cardiac failure, left ventricular dysfunction and cardiac ischaemia have been reported in patients receiving bosutinib.

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