Bosulif

Posology Adult patients with newly-diagnosed CP Ph+ CML The recommended dose is 400 mg bosutinib once daily. Adult patients with CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy The recommended dose is 500 mg bosutinib once daily.

In clinical studies for both indications, treatment with bosutinib continued until disease progression or intolerance to therapy. Paediatric patients with newly-diagnosed CP Ph+ CML or with CP Ph+ CML with resistance or intolerance to prior therapy The recommended dosage of bosutinib for newly-diagnosed paediatric patients is 300 mg/m2 body surface area (BSA) orally once daily and the recommended dosage for paediatric patients resistant or intolerant (R/I) to prior therapies is 400 mg/m2 BSA orally once daily; dose recommendations are provided in Table 1.

As appropriate, the desired dose can be attained by combining different strengths of bosutinib film-coated tablets and/or hard capsules. 1 m2 400 mg* 500 mg* * maximum starting dose (corresponding to maximum starting dose in adult indication) Abbreviations: AP=accelerated phase; BP=blast phase; BSA=body surface area; CML=chronic myeloid leukaemia; CP=chronic phase; ND=newly-diagnosed; Ph+=Philadelphia chromosome-positive; R/I=resistant or intolerant.

Dose adjustments In adult patients with CML who are resistant or intolerant to prior therapy, doses can be escalated to 600 mg in those with unsatisfactory response or with signs of progression and in the absence of any Grade 3 or 4 or persistent Grade 2 adverse events.

In adult patients with newly-diagnosed CP CML, doses can be escalated by 100 mg increments to a maximum of 600 mg once daily if patients fail to demonstrate breakpoint cluster region Abelson (BCR-ABL) transcripts ≤ 10% at months 3 and do not have a grade 3 or 4 adverse reaction at the time of escalation and all Grade 2 non-haematological toxicities are resolved to at least Grade 1.

1 m2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above BSA-adjusted recommended dose. 1 m2 and an insufficient response after 3 months consider increasing dose similarly to adult recommendations in 100 mg increments.

If there is inadequate clinical response and further dose escalation cannot be performed in paediatric patients, treatment will be stopped. The maximum dose in paediatric patients is 600 mg once daily in previously treated CML and 500 mg once daily in newly-diagnosed CML.

Summary of safety profile A total of 1 372 leukaemia adult patients received at least 1 dose of single-agent bosutinib. 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).

The safety analyses included data from a completed extension study. 3%) patients. 3%). 7%) patients. 0%). 13 Tabulated list of adverse reactions 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 4 – Adverse reactions for bosutinib Infections and infestations Very common Nasopharyngitis Respiratory tract infectiona Common Influenzab Pneumoniac Bronchitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uncommon Tumour lysis syndrome** Blood and lymphatic system disorders Very common Thrombocytopeniad Anaemiae Neutropeniaf Common Leukopeniag Uncommon Febrile neutropenia Granulocytopenia Immune system disorders Common Drug hypersensitivity Uncommon Anaphylactic shock Metabolism and nutrition disorders Very common Decreased appetite Common Hypophosphataemiah Dehydration Hyperkalaemiai Nervous system disorders Very common Headache Dizziness Common Dysgeusia Ear and labyrinth disorders Common Tinnitus Cardiac disorders Common Pericardial effusion, Cardiac failurej, Cardiac ischaemick Uncommon Pericarditis Vascular disorders Common Hypertensionl Respiratory, thoracic and mediastinal disorders Very common Cough Dyspnoea Pleural effusion Common Pulmonary hypertensionm Uncommon Respiratory failure Acute pulmonary oedeman Not known Interstitial lung disease 14 Gastrointestinal disorders Very common Diarrhoea Nausea Abdominal paino Vomiting Common Gastritis Gastrointestinal haemorrhagep Pancreatitis acuteq Hepatobiliary disorders Common Hepatic function abnormalr Hepatotoxicitys Uncommon Liver injuryt Skin and subcutaneous tissue disorders Very common Rashu Common Pruritus Acne Urticaria Photosensitivity reactionv Uncommon Drug eruption Exfoliative rash Erythema multiforme Cutaneous vasculitis** 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 Fatiguew Pyrexia Oedemax Common Chest painy Pain Investigations Very common Alanine aminotransferase increasedz Aspartate aminotransferase increased Lipase increasedaa Blood creatinine increased Common Amylase increasedbb Blood creatine phosphokinase increased Blood bilirubin increasedcc Gamma-glutamyltransferase increased Electrocardiogram QT prolongeddd a Respiratory tract infection includes Lower respiratory tract infection, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection b Influenza includes H1N1 influenza, Influenza c Pneumonia includes Atypical pneumonia, Pneumonia, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal d Thrombocytopenia includes Platelet count decreased, Thrombocytopenia e Anaemia includes Anaemia, Haemoglobin decreased, Red blood cell count decreased f Neutropenia includes Neutropenia, Neutrophil count decreased g Leukopenia includes Leukopenia, White blood cell count decreased 15 h Hypophosphataemia includes Blood phosphorus decreased, Hypophosphataemia i Hyperkalaemia includes Blood potassium increased, Hyperkalaemia j Cardiac failure includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure k Cardiac ischaemic includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischaemia, Troponin increased l Hypertension includes the Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis m Pulmonary hypertension includes Pulmonary arterial hypertension, Pulmonary arterial pressure increased, Pulmonary hypertension n Acute pulmonary oedema includes Acute pulmonary oedema, Pulmonary oedema o Abdominal pain includes Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain p Gastrointestinal haemorrhage includes Anal haemorrhage, Gastric haemorrhage, Gastrointestinal haemorrhage, Intestinal haemorrhage, Lower gastrointestinal haemorrhage, Rectal haemorrhage, Upper gastrointestinal haemorrhage q Pancreatitis acute includes Pancreatitis, Pancreatitis acute r Hepatic function […]

Liver function abnormalities Treatment with bosutinib in adult and paediatric patients is associated with elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). Transaminase elevations generally occurred early in the course of treatment (of the patients who experienced transaminase elevations of any grade, > 80% experienced their first event within the first 3 months).

Patients receiving bosutinib should have liver function tests prior to treatment initiation and monthly for the first 3 months of treatment, and as clinically indicated. Patients with transaminase elevations should be managed by withholding bosutinib temporarily (with consideration given to dose reduction after recovery to Grade 1 or baseline), and/or discontinuation of bosutinib.

8). Diarrhoea and vomiting Treatment with bosutinib in adult and paediatric patients is associated with diarrhoea and vomiting; therefore, patients with recent or ongoing clinically significant gastrointestinal disorder should use this medicinal product with caution and only after a careful benefit-risk assessment as respective patients were excluded from the clinical studies.

Patients with diarrhoea and vomiting should be managed using standard-of-care treatment, including an anti-diarrhoeal or antiemetic medicinal product and/or fluid replacement. 8). The antiemetic agent, domperidone, has the potential to increase QT interval (QTc) prolongation and to induce “torsade de pointes”- arrhythmias; therefore, co-administration with domperidone should be avoided.

It should only be used, if other medicinal products are not efficacious. In these situations an individual benefit-risk assessment is mandatory and patients should be monitored for occurrence of QTc prolongation. Myelosuppression Treatment with bosutinib in adult and paediatric patients is associated with myelosuppression, defined as anaemia, neutropenia, and thrombocytopenia.

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