Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Bosulif is indicated for the treatment of adult patients with:
Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML.
The recommended dose is 400 mg bosutinib once daily.
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.
In the Phase ½ 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. Whereas, in the Phase 3 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 ½ clinical study in patients with CML who were resistant or intolerant to prior therapy who started treatment at ≤500 mg, 93 (93/558; 16.7%) patients had dose escalations to 600 mg daily.
In the Phase 3 study in patients with newly-diagnosed CP CML who started bosutinib treatment at 400 mg, a total of 46 patients (17.2%) received dose escalations to 500 mg. In addition, 5.6% of patients in the bosutinib treatment group had further dose escalations to 600 mg.
Doses greater than 600 mg/day have not been studied and, therefore, should not be given.
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. If clinically appropriate, re-escalation to the dose prior to the dose reduction taken once daily should be considered (see section 4.4). Doses less than 300 mg/day have been used in patients; however, efficacy has not been established.
Elevated liver transaminases: If elevations in liver transaminases >5 × institutional upper limit of normal (ULN) occur, bosutinib should be interrupted until recovery to ≤2.5 × ULN and may be resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of bosutinib should be considered. If transaminase elevations ≥3 × ULN occur concurrently with bilirubin elevations >2 × ULN and alkaline phosphatase <2 × ULN, bosutinib should be discontinued (see section 4.4).
Diarrhoea: For NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade 3-4 diarrhoea, bosutinib should be interrupted and may be resumed at 400 mg once daily upon recovery to grade ≤1 (see section 4.4).
Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as described in Table 1.
Table 1. Dose adjustments for neutropenia and thrombocytopenia:
| ANCa <1.0 × 109/L | Hold bosutinib until ANC ≥1.0 × 109/L and platelets ≥50 × 109/L. |
| and/or 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
No specific dose recommendation is necessary in the elderly. Since there is limited information in the elderly, caution should be exercised in these patients.
Patients with serum creatinine >1.5×ULN were excluded from CML studies. Increasing exposure (area under curve [AUC]) in patients with moderate and severe renal impairment during studies was observed.
In patients with moderate renal impairment (creatinine clearance [CLCr] 30 to 50 mL/min, estimated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily with food (see sections 4.4 and 5.2).
In patients with severe renal impairment (CLCr <30 mL/min, estimated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 200 mg daily with food (see sections 4.4 and 5.2).
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.
In patients with moderate renal impairment (CLCr 30 to 50 mL/min, calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 400 mg daily (see sections 4.4 and 5.2).
In patients with severe renal impairment (CLCr <30 mL/min, calculated by the Cockcroft-Gault formula), the recommended dose of bosutinib is 300 mg daily (see sections 4.4 and 5.2).
Dose escalation to 500 mg once daily for patients with moderate renal impairment or to 400 mg once daily in patients with severe renal impairment may be considered in those who did not experience severe or persistent moderate adverse reactions, and if they do not achieve an adequate haematological, cytogenetic, or molecular response.
In clinical studies, patients with uncontrolled or significant cardiac disease (e.g., recent myocardial infarction, congestive heart failure or unstable angina) were excluded. Caution should be exercised in patients with relevant cardiac disorders (see section 4.4).
In clinical studies, patients with recent or ongoing clinically significant gastrointestinal disorder (e.g., severe vomiting and/or diarrhoea) were excluded. Caution should be exercised in patients with recent or ongoing clinically significant gastrointestinal disorder (see section 4.4).
The safety and efficacy of bosutinib in children and adolescents less than 18 years of age have not been established. No data are available.
Bosulif should be taken orally once daily with food (see section 5.2). If a dose is missed by more than 12 hours, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.
Experience with bosutinib overdose in clinical studies was limited to isolated cases. Patients who take an overdose of bosutinib should be observed and given appropriate supportive treatment.
Shelf life: 4 years.
This medicinal product does not require any special storage conditions.
White opaque 3-ply PVC/Polychlorotrifluoroethene/PVC blister sealed with push-through foil backing containing either 14 or 15 tablets.
Bosulif 100 mg film-coated tablets: Each carton contains 28, 30 or 112 tablets.
Bosulif 400 mg film-coated tablets: Each carton contains 28 or 30 tablets.
Bosulif 500 mg film-coated tablets: Each carton contains 28 or 30 tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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