Usage
- Bosutinib is prescribed for the treatment of adult patients with:
- Newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
- CP, accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy.
- Pharmacological classification: Tyrosine kinase inhibitor (TKI), specifically a BCR-ABL TKI.
- Mechanism of action: Bosutinib inhibits the BCR-ABL tyrosine kinase, a protein that promotes the development and growth of CML cells. By blocking this protein, bosutinib helps to control the proliferation of leukemic cells.
Alternate Names
How It Works
- Pharmacodynamics: Bosutinib exerts its therapeutic effect by inhibiting the activity of BCR-ABL tyrosine kinase, thereby suppressing the growth and proliferation of CML cells. It also inhibits Src family kinases at clinically relevant concentrations.
- Pharmacokinetics:
- Absorption: Bosutinib reaches peak plasma concentrations (Cmax) approximately 4 hours after oral administration with food. Food intake significantly enhances absorption, increasing both Cmax and area under the curve (AUC).
- Metabolism: Primarily metabolized in the liver, mainly via CYP3A4.
- Elimination: Excreted primarily in feces, with a small portion eliminated in urine. The terminal half-life is approximately 35 hours, leading to once-daily dosing.
- Mode of action: Bosutinib competitively binds to the ATP-binding site of the BCR-ABL kinase, preventing phosphorylation of downstream signaling molecules and leading to inhibition of cell proliferation and apoptosis (programmed cell death) of CML cells.
- Receptor binding/Enzyme inhibition: Binds to and inhibits BCR-ABL tyrosine kinase and Src family kinases.
- Elimination pathways: Primarily hepatic metabolism via CYP3A4, followed by biliary and fecal excretion.
Dosage
Standard Dosage
Adults:
- Newly-diagnosed CP Ph+ CML: 400 mg orally once daily with food.
- CP, AP, or BP Ph+ CML resistant or intolerant to prior therapy: 500 mg orally once daily with food.
- Maximum dose: 600 mg once daily.
Children (≥1 year old):
- Newly-diagnosed CP Ph+ CML: 300 mg/m² orally once daily with food.
- CP Ph+ CML resistant or intolerant to prior therapy: 400 mg/m² orally once daily with food.
- Maximum dose: 600 mg once daily.
- BSA-based dosing: See sources for detailed BSA-based dosing recommendations.
- Capsules can be opened and mixed with applesauce or yogurt for patients who have difficulty swallowing capsules.
Special Cases:
- Elderly Patients: No specific dose adjustment is recommended, but caution is advised due to potential increased risk of adverse effects.
- Patients with Renal Impairment:
- Moderate (CrCl 30-50 mL/min): Dose adjustments are required; see sources for specifics based on CML phase and resistance/intolerance status.
- Severe (CrCl <30 mL/min): Dose adjustments are required; see sources for specifics based on CML phase and resistance/intolerance status.
- Patients with Hepatic Dysfunction (baseline impairment): Reduced starting dose of 200 mg orally once daily.
- Patients with Comorbid Conditions: Careful monitoring and potential dose adjustments may be needed depending on the comorbid condition(s).
Clinical Use Cases
Bosutinib’s indicated use is specifically for chronic myeloid leukemia. The dosages outlined above apply to the different phases and treatment history scenarios within CML. It is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
- Dose adjustments may be required based on individual patient response, tolerability, and the presence of toxicities (hematologic and non-hematologic). Refer to sources for specific dose adjustment recommendations based on toxicity grading and organ dysfunction.
Side Effects
Common Side Effects
Diarrhea, nausea, vomiting, abdominal pain, decreased appetite, rash, fatigue, thrombocytopenia, anemia, neutropenia, elevated liver enzymes (ALT, AST), headache, dizziness.
Rare but Serious Side Effects
Myocardial infarction, heart failure, QT interval prolongation, severe hepatotoxicity, pancreatitis, gastrointestinal bleeding and perforation, acute renal failure, anaphylaxis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.
Long-Term Effects
Potential long-term effects are largely unknown but may include secondary malignancies, cardiovascular complications, and chronic organ dysfunction.
Adverse Drug Reactions (ADR)
Clinically significant ADRs include severe myelosuppression, hepatotoxicity, gastrointestinal complications, cardiovascular events, and hypersensitivity reactions.
Contraindications
- Hypersensitivity to bosutinib.
Drug Interactions
- CYP3A4 Inhibitors: Avoid concomitant use of strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir). If co-administration is unavoidable, consider bosutinib dose interruption or reduction.
- CYP3A4 Inducers: Avoid concomitant use of strong or moderate CYP3A4 inducers (e.g., rifampin, phenytoin, St. John’s wort) as they decrease bosutinib exposure.
- Proton Pump Inhibitors (PPIs): Use with caution; PPIs reduce bosutinib absorption. Consider short-acting antacids or H2-receptor antagonists as alternatives.
- Drugs that prolong QT interval: Use with caution in patients taking drugs known to prolong the QT interval (e.g., amiodarone, quinidine).
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Not formally assigned a US FDA pregnancy category but use is not recommended due to potential for fetal harm.
- Fetal risks: Based on animal studies, bosutinib may cause fetal harm, including structural abnormalities, embryo-fetal death, and decreased fetal growth.
- Breastfeeding: Not recommended as it is unknown if bosutinib is excreted in human milk. Data from rat studies show excretion of bosutinib-derived radioactivity in milk.
Drug Profile Summary
- Mechanism of Action: BCR-ABL tyrosine kinase inhibitor.
- Side Effects: Diarrhea, nausea, myelosuppression, hepatotoxicity, rash, fatigue.
- Contraindications: Hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors/inducers, PPIs, QT-prolonging drugs.
- Pregnancy & Breastfeeding: Use is not recommended during pregnancy and breastfeeding.
- Dosage: See Dosage section above.
- Monitoring Parameters: Complete blood counts (CBC), liver function tests (LFTs), renal function, electrocardiogram (ECG) as clinically indicated.
Popular Combinations
No specific combinations are highlighted as “popular.” Treatment decisions, including combining bosutinib with other agents, must be individualized based on patient characteristics, disease stage, and treatment response.
Precautions
- General Precautions: Baseline assessment of liver function, renal function, and cardiac function. Monitor for myelosuppression and gastrointestinal toxicity.
- Specific Populations: See Dosage section above for considerations regarding pregnant/breastfeeding women, children, and the elderly.
- Lifestyle Considerations: Advise patients to avoid grapefruit and grapefruit juice, which can increase bosutinib exposure. Alcohol should be limited as it can exacerbate certain side effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Bosutinib?
A: See Dosage section above. Dosing depends on CML phase, prior treatment history, patient age, and comorbidities.
Q2: What are the most common side effects?
A: The most common side effects include diarrhea, nausea, vomiting, abdominal pain, myelosuppression (decreased blood cell counts), elevated liver enzymes, rash, and fatigue.
Q3: Are there any serious side effects I should be aware of?
A: Yes, rare but serious side effects include cardiovascular events (e.g., heart failure, myocardial infarction), severe hepatotoxicity, gastrointestinal bleeding/perforation, and hypersensitivity reactions.
Q4: What should I do if a patient experiences diarrhea while taking Bosutinib?
A: The management of diarrhea depends on the severity. For mild diarrhea, supportive care measures (e.g., hydration, antidiarrheal medications) may be sufficient. For moderate to severe diarrhea (Grade 2 or higher), bosutinib should be withheld until the diarrhea resolves, and the dose may need to be reduced upon re-initiation.
Q5: How should Bosutinib be administered?
A: Bosutinib should be administered orally once daily with food. Tablets should be swallowed whole and not crushed, broken, or chewed. Capsules can be opened and mixed with applesauce or yogurt if swallowing is difficult.
Q6: What are the key drug interactions with Bosutinib?
A: Significant drug interactions occur with strong/moderate CYP3A4 inhibitors and inducers, proton pump inhibitors (PPIs), and drugs that prolong the QT interval.
Q7: Can Bosutinib be used during pregnancy or breastfeeding?
A: Bosutinib is not recommended for use during pregnancy or breastfeeding due to the potential for fetal harm and unknown effects on infants.
Q8: What monitoring parameters are important for patients taking Bosutinib?
A: Monitor complete blood counts (CBCs), liver function tests (LFTs), renal function, and cardiac function (ECG if clinically indicated) regularly.
Q9: How are dose adjustments made for patients with renal or hepatic impairment?
A: Dose adjustments are necessary for patients with moderate to severe renal impairment and baseline hepatic dysfunction. Consult the Dosage section and available resources for specific recommendations.
Q10: What should I counsel patients on regarding lifestyle considerations while taking Bosutinib?
A: Advise patients to avoid grapefruit and its juice as they can increase bosutinib exposure. Alcohol consumption should be limited, and patients should be educated about signs and symptoms of adverse reactions.
Please remember that this information is current as of February 16, 2025, and may change with time. Always consult the latest prescribing information and clinical guidelines for the most up-to-date information.
