BOSUTINIB

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML. Posology Newly-diagnosed CP Ph+ CML The recommended dose is 400 mg bosutinib once daily. CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy The recommended dose is 500 mg bosutinib once daily.

In clinical trials for both indications, treatment with bosutinib continued until disease progression or intolerance to therapy. Dose adjustments In the Phase 1/2 clinical study in patients with CML who were resistant or intolerant to prior therapy, dose escalations from 500 mg to 600 mg once daily with food were allowed in patients who failed to demonstrate complete haematological response (CHR) by Week 8 or complete cytogenetic response (CCyR) by Week 12 and did not have Grade 3 or higher adverse events possibly-related to the investigational product.

In the Phase 3 clinical study in patients with newly-diagnosed CP CML treated with bosutinib 400 mg, dose escalations by 100 mg increments to a maximum of 600 mg once daily with food were permitted if the patient failed to demonstrate breakpoint cluster region-Abelson (BCR-ABL) transcripts ≤ 10% at Month 3, did not have a Grade 3 or 4 adverse reaction at the time of escalation, and all Grade 2 non- haematological toxicities were resolved to at least Grade 1.

In the Phase 4 clinical study in patients with Ph+ CML previously treated with 1 or more TKI(s), dose escalations from 500 mg to 600 mg once daily with food were allowed in patients with unsatisfactory response or with signs of disease progression in the absence of any Grade 3 or 4 or persistent Grade 2 adverse events.

7%) patients had dose escalations to 600 mg daily. 6%) received dose escalations to 500 mg daily. 4% of patients in the bosutinib treatment group had further dose escalations to 600 mg daily. 6%) had a dose escalation up to 600 mg daily.

Doses greater than 600 mg/day have not been studied and, therefore, should not be given. Dose adjustments for adverse reactions Non-haematological adverse reactions If clinically significant moderate or severe non-haematological toxicity develops, bosutinib should be interrupted, and may be resumed at a dose reduced by 100 mg taken once daily after the toxicity has resolved.

4). Doses less than 300 mg/day have been used in patients; however, efficacy has not been established. 5 × ULN and may be resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of bosutinib should be considered.

4). 4). 0 × 109/L and platelets ≥ 50 × 109/L. Resume treatment with bosutinib at the same dose if recovery occurs within 2 weeks. If blood counts remain low for > 2 weeks, upon recovery reduce dose by 100 mg and resume treatment. If cytopoenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment.

Doses less than 300 mg/day have been used; however, efficacy has not been established. a ANC = absolute neutrophil count Special populations Elderly patients (≥ 65 years) No specific dose recommendation is necessary in the elderly. Since there is limited information in the elderly, caution should be exercised in these patients.

5×ULN were excluded from CML studies. Increasing exposure (area under curve [AUC]) in patients with moderate and severe renal impairment during studies was observed. 2). 2). Dose escalation to 400 mg once daily with food for patients with moderate renal impairment or to 300 mg once daily for patients with severe renal impairment may be considered if they do not experience severe or persistent moderate adverse reactions and if they do not achieve an adequate haematological, cytogenetic, or molecular response.

2). In patients with severe renal impairment (CLCr < 30 mL/min, calculated by the Cockcroft-Gault formula), the recommended dose of […]

Summary of safety profile A total of 1,372 leukaemia 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).

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.

0 months), respectively. The safety analyses included data from a completed extension study. 3%) patients. 3%). 7%) patients. 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, 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 […]

Liver function abnormalities Treatment with bosutinib 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 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 antidiarrhoeal 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 is associated with myelosuppression, defined as anaemia, neutropenia, and thrombocytopenia.

Complete blood counts should be performed weekly for the first month and then monthly thereafter, or as clinically indicated. 8). Fluid retention Treatment with bosutinib may be associated with fluid retention including pericardial effusion, pleural effusion, pulmonary oedema and/or peripheral oedema.

Patients should be monitored and managed using standard-of-care treatment. 8). Serum lipase Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis. 2). Infections Bosutinib may predispose patients to bacterial, fungal, viral, or protozoan infections.

Proarrhythmic potential Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. 5]). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect. Monitoring for an effect on the QTc is advisable and a baseline electrocardiogram (ECG) is recommended prior to initiating therapy with bosutinib and as clinically indicated.

Hypokalaemia or hypomagnesaemia must be corrected prior to bosutinib administration and should be monitored periodically during therapy. Renal impairment Treatment with bosutinib may result in a clinically significant decline in renal function in CML patients.

A decline over time in estimated glomerular filtration rate (eGFR) has been observed in patients treated with bosutinib in clinical studies. 73 m2 at 5 years for patients on treatment. 73 m2 at 10 years for patients on treatment. 73 m2 at 10 years for patients on treatment.

73 m2 at 4 years for patients on treatment. It is important that renal function is assessed prior to treatment initiation and closely monitored during therapy with bosutinib, with particular attention in those patients who have pre-existing renal compromise or in those patients exhibiting risk factors for renal dysfunction, including concomitant use of medicinal products with potential for nephrotoxicity, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs).

In a renal impairment […]

1. 2).