BOSULIF (Bosutinib) is a second-generation Tyrosine Kinase Inhibitor. It is used to treat CML (Chronic myeloid leukemia), a type of blood cancer that manifests in three stages:
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Chronic phase
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Accelerated phase, and
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Blast Crisis
The three phases can be differentiated based on the clinical features and the number of blasts in the bone marrow:
Stage |
Features |
Blasts in Bone Marrow |
Blasts in Peripheral Blood |
|
Chronic Phase |
|
<10% |
<5% |
|
Accelerated Phase |
|
10-19% |
5-10% |
|
Blast Phase |
|
>=20% |
>=20% |
BOSULIF (Bosutinib) Indications:
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Adults with CML who are tested positive for Philadelphia chromosome-positive (Ph+).
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It can be started at any stage of CML including chronic, accelerated, and blast phases.
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Like all other second-generation TKIs, BOSULIF (Bosutinib) can be used as a first-line of treatment in newly diagnosed as well as those who have not responded to Imatinib (Gleevec).
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However, patients who have mutations in the gene BCR/ABL/T315I may not respond well to the treatment.
BOSULIF (Bosutinib) Dosage and Administration:
Recommended Dosing:
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500 mg once daily with food for as long as the patient shows a response and does not develop significant side effects.
Missed Dose:
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If the time after missing the dose has been 12 hours or more, wait for the next dose. Avoid taking double doses.
Dose Escalation:
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Increase the dose to 600 mg once daily with food if:
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Complete hematological response (CHR) is not seen within 8 weeks, or
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Complete cytogenetic response (CCyR) is not seen within 12 weeks, and
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The patient is tolerating it without significant side effects (Grade 3 or higher)
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Dose adjustment in case side effects develop or organ impairment is observed:
Adverse Reaction |
Dose Adjustment |
|
Elevated liver transaminases |
|
|
Diarrhea (Grade 3-4) |
Withhold the treatment until recovery to Grade ≤1, then resume at 400 mg once daily. |
|
Other significant non-hematological toxicity |
Withhold the treatment until toxicity resolves, then resume at 400 mg once daily. |
|
Myelosuppression |
Stop the treatment if:
If counts recover within 2 weeks, start again at the same dose. If counts stay low for >2 weeks but eventually recover, lower the dose by 100 mg and restart. If counts drop again, repeat dose reduction. |
|
Concomitant use with CYP3A inhibitors |
Use caution with strong or moderate CYP3A inhibitors. |
|
Concomitant use with CYP3A inducers |
Avoid strong or moderate CYP3A inducers. |
|
Hepatic impairment |
The recommended dose is 200 mg daily. |
Strong and Moderate Enzyme Inducers and Inhibitors are given in the table below;
|
Strong CYP3A Inhibitors |
Moderate CYP3A Inhibitors |
|
|
|
Strong CYP3A Inducers |
Moderate CYP3A Inducers |
|
|
Contraindications to Bosutinib:
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Hypersensitivity reactions
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Anaphylaxis
Warnings And Precautions
Gastrointestinal Toxicity
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Severe diarrhea, nausea, vomiting, and abdominal pain may develop necessitating fluid replacement and antidiarrheal or antiemetic drugs.
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In addition, the treatment may need to be stopped or the dose reduced for a while until the symptoms improve.
Myelosuppression
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Cytopenias including thrombocytopenia, anemia, and neutropenia may develop.
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Monitoring counts for the first month on a weekly basis and then monthly is recommended.
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Stop the treatment, reduce the dose, or temporarily withhold it depending on how severe myelosuppression is.
Hepatic Toxicity
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Liver toxicity has been reported especially during the first three months of treatment initiation.
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Monitor LFTs monthly for the first three months or more frequently if baseline LFTs are above the normal ranges.
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The treatment may need to be stopped, the dose reduced, or temporarily withheld until liver toxicity improves.
Fluid Retention with BOSULIF:
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Fluid retention manifesting as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema may develop.
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Along with standard management of fluid retention such as diuretics, Bosutinib treatment may need to be stopped permanently or temporarily, or the dose reduced.
Embryofetal Toxicity:
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The drug is toxic to the fetus. Pregnancy should be avoided by recommending potent contraception.
Side effects of Bosutinib:
|
Side Effect |
Frequency |
|
Fluid retention |
Common |
|
Diarrhea |
Common |
|
Nausea |
Common |
|
Abdominal pain |
Common |
|
Rash |
Common |
|
Headache |
Common |
|
Fatigue |
Common |
|
Arthralgia |
Common |
|
Myalgia |
Common |
|
Vomiting |
Common |
|
Anemia |
Common |
|
Pyrexia |
Common |
|
Constipation |
Common |
|
Dyspnea |
Common |
|
Cough |
Common |
|
Upper respiratory tract infection |
Common |
|
Asthenia |
Common |
|
Peripheral edema |
Uncommon (3%) |
|
Pleural effusion |
Uncommon (3%) |
|
Pericardial effusion |
Uncommon (1%) |
|
Pulmonary edema |
Uncommon (1%) |
|
Increased blood creatinine levels |
Uncommon (1%) |
|
Rash, pruritic |
Uncommon (1%) |
|
QT prolongation |
Rare (<1%) |
|
Pancreatitis |
Rare (<1%) |
|
Hepatotoxicity |
Rare (<1%) |
|
Renal failure |
Rare (<1%) |
|
Stevens-Johnson syndrome |
Rare (<1%) |
|
Tumor lysis syndrome |
Rare (<1%) |
|
Hemorrhage |
Frequency not known |
|
Thrombocytopenia |
Frequency not known |
|
Neutropenia |
Frequency not known |
|
Leukopenia |
Frequency not known |
|
Febrile neutropenia |
Frequency not known |
|
Hypersensitivity reactions |
Frequency not known |
Bosutinib Drug Interactions:
|
Drugs that Increase Bosutinib Plasma Levels: |
Strong or moderate CYP3A or P-glycoprotein (P-gp) inhibitors |
|
Drugs That Decrease Bosutinib Plasma Levels: |
Strong or moderate CYP3A inducers Proton Pump Inhibitors (PPIs) |
|
Drugs That May Have Their Plasma Levels Affected by Bosutinib: |
Substrates of P-glycoprotein |
Use in specific Population:
|
Population |
Recommendation |
|
Pregnancy |
Pregnancy risk factor D. Can cause fetal harm. |
|
Nursing Mothers |
Excretion into breast milk is not known. Take a decision to either discontinue breastfeeding or the drug. |
|
Pediatric Use |
Not studied in children under 18 years of age. |
|
Geriatric Use |
Older people may be more sensitive to its side effects |
|
Hepatic Impairment |
Use a low dose (200 mg daily) in patients with any baseline hepatic impairment. |
|
Renal Impairment |
Renal impairment does not affect the drug levels. |
Mechanism of Action (MOA) of Bosutinib:
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Bosutinib is a 2nd generation tyrosine kinase inhibitor that works by blocking certain enzymes called kinases that help cancer cells grow and multiply
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Specifically, bosutinib targets the Bcr-Abl kinase, which is involved in the development of chronic myeloid leukemia (CML). It also blocks other kinases in the Src-family, including Src, Lyn, and Hck
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Bosutinib has been shown to inhibit many imatinib-resistant forms of Bcr-Abl, but not the T315I and V299L mutant cells.
|
Pharmacokinetics |
Data |
|
Absorption |
Time-to-peak: 4-6 hours |
|
Protein binding |
highly bound to plasma proteins (94-96%) It is a P-gp substrate and inhibitor in vitro |
|
Metabolism |
Primarily metabolized by CYP3A4 |
|
Elimination |
Terminal elimination half-life: 22.5 hours
|
Patient Counselling Information for BOSULIF
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Ask your patient to read FDA-Approved Patient Labelling.
Dosing and Administration
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Patients should take the drug as prescribed without altering, skipping, or doubling the dose.
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A missed dose should be taken immediately within 12 hours. In case more than 12 hours have passed, wait for your next dose.
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Take the drug with food without cutting, crushing, or chewing the tablet.
Gastrointestinal Problems
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Take medical advice if you develop diarrhea, nausea, vomiting, abdominal pain, or blood in your stools during the treatment.
Low Blood Cell Counts
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Monitor for signs of infection or bleeding and report to your doctor as Bosulif may cause marrow suppression.
Liver Problems
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Liver problems such as hepatitis can occur. Report to your doctor if you develop nausea, vomiting, upper abdominal pain, or jaundice.
Fluid Retention
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Report to your doctor if you develop swelling of the face or legs or notice easy fatiguability and shortness of breath as you may be developing fluid retention.
Other Adverse Reactions
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Respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, or pruritus, and anaphylaxis may occur which should all be reported.
Pregnancy and Breastfeeding
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BOSULIF can harm the fetus. Pregnancy should be avoided using effective contraception during the treatment and for 30 days after the last dose.
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Inform your doctor if you have missed your periods or are pregnant.
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Discontinue breastfeeding
Drug Interactions
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BOSULIF levels may be increased or decreased when used with OTC medications or herbal supplements, such as St. John's wort. Such interactions may alter the effects of BOSULIF.
Bosutinib International Brands:
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Bosulif
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