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.

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.

1 months (range: 0. 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.

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.

1. 2).