BOSULIF
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BOSULIF (BOSULIF).
Bosutinib is a tyrosine kinase inhibitor that targets BCR-ABL kinase, as well as SRC family kinases. It inhibits the phosphorylation of tyrosine residues in proteins involved in the BCR-ABL signaling pathway, thereby inhibiting cell proliferation and inducing apoptosis in Philadelphia chromosome-positive (Ph+) leukemia cells.
| Metabolism | Primarily metabolized by CYP3A4; minor contributions from CYP3A5 and CYP2D6. |
| Excretion | Primarily fecal (approximately 85% of the administered dose), with renal excretion accounting for less than 1% as unchanged drug and 3% as metabolites. Biliary excretion is a significant route for elimination of unchanged drug and metabolites. |
| Half-life | The terminal elimination half-life is approximately 22.5 hours (range 15-34 hours) following a 500 mg oral dose. This supports once-daily dosing, with steady-state achieved within 15 days. |
| Protein binding | Highly bound to human plasma proteins (approximately 94-96%), primarily to albumin and alpha-1-acid glycoprotein. Binding is not concentration-dependent over the therapeutic range. |
| Volume of Distribution | The apparent volume of distribution (Vd/F) is approximately 5220 L (range 3100-9260 L), indicating extensive extravascular distribution. This large volume reflects extensive tissue binding and sequestration, with distribution into tissues such as liver, gastrointestinal tract, and bone marrow. |
| Bioavailability | Absolute oral bioavailability is approximately 34% (range 25-45%). Administration with a high-fat meal decreases Cmax by approximately 26% and AUC by 21% compared to fasting; therefore, bosutinib should be taken with food to reduce interpatient variability. |
| Onset of Action | Following oral administration, peak plasma concentrations are reached at approximately 4-6 hours (median Tmax). Clinical response (e.g., cytogenetic response in chronic myeloid leukemia) is typically assessed after 3 months of continuous therapy; earlier biochemical inhibition of Bcr-Abl occurs within hours. |
| Duration of Action | The duration of Bcr-Abl inhibition persists throughout the 24-hour dosing interval, consistent with the half-life. Once-daily dosing maintains continuous target suppression; dose interruptions or reductions may lead to loss of response within days to weeks. |
400 mg orally once daily with food.
| Dosage form | TABLET |
| Renal impairment | For CrCl 30-59 mL/min: 300 mg once daily. For CrCl <30 mL/min: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: 300 mg once daily. Child-Pugh C: not recommended. |
| Pediatric use | Pediatric safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended, but monitor renal function closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for BOSULIF (BOSULIF).
| Breastfeeding | No data on bosutinib in human milk or effects on breastfed infants. Due to potential for serious adverse reactions (e.g., hematologic toxicity, immunosuppression), breastfeeding is contraindicated during therapy and for at least 2 weeks after last dose. |
| Teratogenic Risk | Bosutinib is embryotoxic and fetotoxic in animal studies. There are no adequate human data. Risk cannot be excluded; avoid use in pregnancy unless benefit outweighs risk. First trimester exposure may cause congenital anomalies; second and third trimester exposure may cause fetal harm including growth restriction and developmental delay. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None known"]
| Precautions | ["Gastrointestinal toxicity: diarrhea, nausea, vomiting, and abdominal pain; manage with supportive care","Myelosuppression: thrombocytopenia, neutropenia, and anemia; monitor complete blood counts regularly","Hepatotoxicity: elevations in transaminases and bilirubin; monitor liver function tests","Cardiovascular events: including hypertension, arrhythmias, and heart failure; monitor blood pressure and cardiac function","Fluid retention: including pleural effusion, pericardial effusion, and edema; monitor for symptoms","Renal toxicity: monitor renal function","Pancreatitis: monitor pancreatic enzymes","Pulmonary toxicity: interstitial lung disease; discontinue if suspected","Fetal harm: can cause fetal harm; advise women of reproductive potential of effective contraception"] |
| Food/Dietary | Administer with food to reduce gastrointestinal upset. Avoid grapefruit and grapefruit juice as they inhibit CYP3A4 and may increase bosutinib levels. Avoid St. John's wort, a CYP3A4 inducer, which may decrease bosutinib efficacy. |
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| Fetal Monitoring | Monitor complete blood count (CBC) and hepatic function monthly. Assess fetal growth via ultrasound if pregnancy occurs. Monitor for maternal hypertension and proteinuria. Consider fetal echocardiography due to potential cardiotoxicity. |
| Fertility Effects | In animal studies, bosutinib impaired male and female fertility. In humans, effects on fertility are unknown but possible based on mechanism (inhibits tyrosine kinases involved in reproduction). May cause oligospermia, azoospermia, or amenorrhea. |
| Clinical Pearls | BOSULIF (bosutinib) is a tyrosine kinase inhibitor used for chronic myeloid leukemia. Monitor liver function tests closely as hepatotoxicity is common; dose reduction or interruption may be needed for elevated transaminases. Diarrhea is the most frequent adverse effect; manage with loperamide and hydration. Avoid concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin). Administer with food to reduce gastrointestinal irritation. |
| Patient Advice | Take BOSULIF exactly as prescribed, with food to decrease stomach upset. · Do not crush or chew tablets; swallow whole. · Report symptoms of liver problems (yellowing skin/eyes, dark urine, abdominal pain) or severe diarrhea immediately. · Avoid grapefruit and grapefruit juice during treatment. · Use effective contraception during treatment and for at least 2 weeks after the last dose. · Do not take antacids within 2 hours of BOSULIF. |