5 WARNINGS AND PRECAUTIONS
5.1 Gastrointestinal Toxicity
Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement.
Among 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1–268).
Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6)].
5.3 Hepatic Toxicity
Bosutinib may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]).
Perform hepatic enzyme tests monthly for the first 3 months of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)].
5.5 Fluid Retention
Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema.
5.6 Renal Toxicity
|Renal Function Status||N||Normal|
|Mild to Moderate|
|Moderate to Severe|
|Abbreviations: eGFR=estimated glomerular filtration rate; N/n=number of patients.|
Notes: eGFR was calculated using Modification in Diet in Renal Disease method (MDRD).
Notes: Grading is based on Kidney Disease Improving Global Outcomes (KDIGO) Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m2.
|Normal||527||115 (21.8)||330 (62.6)||50 (9.5)||23 (4.4)||3 (0.6)||5 (0.9)|
|Mild||672||10 (1.5)||259 (38.5)||271 (40.3)||96 (14.3)||26 (3.9)||6 (0.9)|
|Mild to Moderate||137||0||6 (4.4)||40 (29.2)||66 (48.2)||24 (17.5)||1 (0.7)|
|Moderate to Severe||33||0||1 (3.0)||1 (3.0)||8 (24.2)||19 (57.6)||4 (12.1)|
|Total||1370||125 (9.1)||596 (43.5)||362 (26.4)||193 (14.1)||72 (5.2)||17 (1.2)|
5.7 Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].