BOSUTINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BOSUTINIB (BOSUTINIB).
Bosutinib is a tyrosine kinase inhibitor that inhibits the BCR-ABL kinase, including many imatinib-resistant mutations, and Src family kinases.
| Metabolism | Primarily metabolized by CYP3A4; minor contributions from other CYP enzymes. |
| Excretion | Primarily fecal (approx. 68% as unchanged drug and metabolites) and renal (approx. 25%, with <0.2% as unchanged drug in urine). |
| Half-life | Terminal elimination half-life approximately 33 hours (range 22-60 hr) after oral administration, supporting once-daily dosing. |
| Protein binding | 96% bound to plasma proteins, primarily to albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Approximately 3.6 L/kg (range 2.8-4.6 L/kg), indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is 74% (range 60-85%) under fasted conditions; absorption is increased by food (high-fat meal increases AUC by 1.7-fold), but dosing is recommended with food to reduce variability. |
| Onset of Action | Time to peak plasma concentration (Tmax) is 4-6 hours post-dose; clinical response (e.g., cytogenetic response) may be observed within 3-6 months of continuous therapy. |
| Duration of Action | With once-daily oral dosing, sustained target inhibition (e.g., BCR-ABL kinase) over 24 hours; treatment is typically chronic until disease progression or unacceptable toxicity. |
400 mg orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | CrCl 30-50 mL/min: 300 mg orally once daily. CrCl <30 mL/min: 200 mg orally once daily. Not recommended for CrCl <15 mL/min. |
| Liver impairment | Child-Pugh A: 400 mg orally once daily. Child-Pugh B: 200 mg orally once daily. Child-Pugh C: 100 mg orally once daily. |
| Pediatric use | No established pediatric dosing; not recommended for patients <18 years. |
| Geriatric use | No specific dose adjustment based solely on age; monitor renal function. Start at 400 mg orally once daily with food. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for BOSUTINIB (BOSUTINIB).
| Breastfeeding | No human data available. Bosutinib and its metabolites are likely excreted into breast milk based on physicochemical properties and animal data. M/P ratio unknown. Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose due to potential serious adverse reactions in nursing infants. |
| Teratogenic Risk | Bosutinib is embryotoxic and fetotoxic in animal studies. Human data are limited, but based on its mechanism of tyrosine kinase inhibition, there is potential for teratogenicity. First trimester exposure carries the highest risk of structural abnormalities. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and impaired fetal development. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Hypersensitivity to bosutinib or any excipients"]
| Precautions | ["Cardiovascular toxicity: Can cause myocardial infarction, stroke, and heart failure; especially in patients with cardiovascular risk factors.","Hepatotoxicity: Elevations in liver enzymes and bilirubin; monitor liver function.","Myelosuppression: Thrombocytopenia, neutropenia, anemia; monitor blood counts.","Gastrointestinal toxicity: Diarrhea, nausea, vomiting; manage with supportive care.","Fluid retention: Edema, pleural effusion, pericardial effusion.","Renal toxicity: Elevations in serum creatinine; monitor renal function.","Fetal harm: Can cause fetal harm; advise pregnant women of risk.","Pancreatitis: Elevated lipase; monitor pancreatic enzymes."] |
| Food/Dietary | Take with food to reduce gastrointestinal side effects. Avoid grapefruit and grapefruit juice as they inhibit CYP3A4 and can increase bosutinib levels. |
Loading safety data…
| Fetal Monitoring | Monitor maternal complete blood count, hepatic function, serum lipase and amylase, serum electrolytes, and blood pressure. Fetal monitoring includes serial ultrasound for growth, amniotic fluid volume, and anatomy. Perform fetal echocardiography due to potential cardiotoxicity. Monitor for signs of maternal fluid retention and pleural effusion. |
| Fertility Effects | Bosutinib may impair male and female fertility based on animal studies. In male rats, testicular atrophy and decreased sperm count were observed. In female rats, disrupted estrous cycles and reduced fertility occurred. Human data are lacking; however, potential for temporary or permanent infertility exists. |
| Clinical Pearls | Bosutinib is a dual Src/Abl tyrosine kinase inhibitor indicated for chronic-phase, accelerated-phase, or blast-phase Ph+ CML with resistance or intolerance to prior therapy. Monitor liver function tests frequently due to risk of hepatotoxicity; dose reduction or interruption may be needed. Diarrhea is common and often dose-limiting; manage with antidiarrheals and hydration. Avoid strong CYP3A4 inhibitors or inducers; adjust bosutinib dose accordingly. QT interval prolongation can occur; monitor ECG and electrolytes. Pancreate-related adverse events including pancreatitis have been reported; monitor lipase and amylase. |
| Patient Advice | Take bosutinib exactly as prescribed, with food to reduce gastrointestinal upset. · Do not crush or chew tablets; swallow whole. · Report any signs of liver problems (yellowing skin/eyes, dark urine, right upper quadrant pain) or pancreatitis (severe abdominal pain, nausea, vomiting). · Expect diarrhea; proactively use antidiarrheal medications and maintain fluid intake to prevent dehydration. · Avoid grapefruit and grapefruit juice while on bosutinib. · Inform your doctor about all medications you are taking, including over-the-counter drugs and supplements, due to potential interactions. · Do not change dose or stop bosutinib without consulting your doctor. |