Bosutinib (Monograph)

Brand name: Bosulif
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple tyrosine kinases.

Uses for Bosutinib

Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia

Treatment of chronic phase Philadelphia chromosome-positive (Ph⁺) chronic myelogenous leukemia (CML) in adults and pediatric patients ≥1 year of age, newly diagnosed or resistant or intolerant to prior therapy.

Treatment of chronic, accelerated, or blast phase Ph⁺ CML in adults after failure (secondary to resistance or intolerance) of prior therapy.

Designated an orphan drug by FDA for treatment of CML.

First-line treatment of CML is a tyrosine kinase inhibitor (TKI) in most settings. Choice of TKI in first-line setting is individualized based on efficacy, tolerability, toxicity, and cost, particularly since adherence to therapy is life-long.

If treatment failure or resistance develops with first-line TKI therapy, second-line treatment requires changing to another TKI. If BCR-ABL1 resistance mutations occur with imatinib (the first generation TKI), second generation TKIs (dasatinib, nilotinib, bosutinib) are an option dependent upon the specific mutation present. If no BCR-ABL1 KD-mutations are present, there is no clear recommendation for any particular second generation TKI as all are effective.

Bosutinib Dosage and Administration

General

Pretreatment Screening

• Assess renal function at baseline.

• Verify pregnancy status in females of reproductive potential prior to initiation of therapy.

Patient Monitoring

• Monitor CBC weekly for the first month of therapy and monthly (or as clinically indicated) thereafter.

• Monitor liver function tests monthly for the first 3 months of therapy and then as clinically indicated; more frequent monitoring is recommended if increased aminotransferase concentrations occur.

• Monitor renal function during therapy, particularly in patients with preexisting renal impairment or risk factors for renal impairment.

• Monitor for signs and symptoms of cardiac failure or ischemia, fluid retention, or GI toxicity (e.g., diarrhea, nausea, vomiting, abdominal pain) and treat as clinically indicated.

Dispensing and Administration Precautions

Handling and Disposal

• Follow procedures for proper handling and disposal of antineoplastic drugs when preparing and administering bosutinib.

Administration

Oral Administration

Administer orally once daily with food as tablets or capsules; tolerability may be increased when taken with food.

If a dose is missed by >12 hours, take next dose at the regularly scheduled time. Do not double the dose to make up for the missed dose.

Swallow tablets whole; do not cut, break, chew, or crush. Avoid touching or handling crushed or broken tablets.

May swallow capsules whole. If patient is unable to swallow a whole capsule, open required number of capsules for dose and mix contents with room temperature applesauce or yogurt in a clean container (see Table 1). Immediately consume full mixture without chewing; do not store for later use. If entire mixture is not swallowed, do not administer an additional dose. Resume dosing on the next day.

Dosage

Available as bosutinib monohydrate; dosage expressed as anhydrous bosutinib.

Pediatric Patients

CML

Oral

Initial dosage (≥1 year of age): 300 mg/m² once daily.

In pediatric patients with BSA <1.1 m² and insufficient response after 3 months of therapy, consider increasing dosage in increments of 50 mg up to a maximum of 100 mg above starting dose.

Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m² can be performed similarly to adult 100 mg increment recommendations. Maximum dose in pediatric patients is 600 mg once daily. Therapy should be continued until disease progression or intolerance to therapy occurs.

Oral

Initial dosage (≥1 year of age): 400 mg/m² once daily. In pediatric patients with BSA <1.1 m² and insufficient response after 3 months of therapy, consider increasing dosage in increments of 50 mg up to a maximum of 100 mg above starting dose.

Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m² can be performed similarly to adult 100 mg increment recommendations. Maximum dose in pediatric patients is 600 mg once daily. Therapy should be continued until disease progression or intolerance to therapy occurs.

Dose Recommendations

Dose recommendations for pediatric patients with newly diagnosed chronic phase Ph⁺CML or with chronic phase Ph⁺CML with resistance or intolerance to prior therapy are presented in Table 2.

Maximum starting dose (corresponds to maximum starting dose for adult indication).

Adults

CML

Newly Diagnosed Chronic Phase CML.

Oral

400 mg once daily. If hematologic, cytogenetic, or molecular response not achieved, may increase dosage in increments of 100 mg once daily up to a maximum dosage of 600 mg once daily in patients not experiencing grade 3 or worse adverse effects with starting dosage (400 mg daily).

Continue treatment until evidence of disease progression or intolerance to therapy occurs.

Chronic, Accelerated, or Blast Phase CML Following Prior Treatment Failure

Oral

500 mg once daily. If hematologic, cytogenetic, or molecular response not achieved, may increase dosage in increments of 100 mg once daily up to a maximum dosage of 600 mg once daily in patients not experiencing grade 3 or worse adverse effects with starting dosage (500 mg daily).

Continue treatment until evidence of disease progression or intolerance to therapy occurs.

Dosage Modification for Toxicity

Myelosuppression

If ANC <1000/mm³ or platelet counts <50,000/mm³ (unrelated to underlying CML) occur, withhold bosutinib until recovery.

Resume therapy at original starting dosage if recovery occurs (i.e., ANC ≥1000/mm³ and platelet counts ≥50,000/mm³) within 2 weeks. If blood counts remain low for >2 weeks, reduce dose by 100 mg, or by 50 mg in pediatric patients with BSA <1.1 m², upon resumption of therapy.

If neutropenia or thrombocytopenia recurs, withhold bosutinib until recovery. Upon resumption of therapy, reduce dose by an additional 100 mg or by an additional 50 mg in pediatric patients with BSA <1.1 m². Efficacy of dosages <300 mg daily not established.

Hepatotoxicity

For ALT and/or AST concentrations >5 times ULN, interrupt dosing until ALT and AST return to ≤2.5 times ULN; resume therapy at 400 mg once daily. If recovery is delayed (>4 weeks), discontinue bosutinib.

For ALT and/or AST concentrations ≥3 times ULN occurring concurrently with total bilirubin concentrations >2 times ULN and alkaline phosphatase concentrations <2 times ULN, discontinue bosutinib.

Diarrhea

If grade 3 or 4 diarrhea (≥7 stools per day over baseline) occurs, interrupt dosing until diarrhea resolves to grade 1 or less; resume therapy at 400 mg once daily.

Other Nonhematologic Effects

If other clinically important, moderate or severe nonhematologic toxicity occurs, interrupt therapy until resolution; upon resumption of therapy, reduce dosage by 100 mg once daily. If clinically appropriate, may re-escalate dosage to the starting dosage.

In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however dose reduction increments may differ. For pediatric patients with BSA <1.1 m², reduce dose by 50 mg initially followed by additional 50 mg increment if adverse reactions persist. For pediatric patients with BSA ≥1.1 m², reduce dose similarly to adults.

Special Populations

Hepatic Impairment

Mild, moderate, or severe preexisting hepatic impairment (Child-Pugh class A, B, or C) in adults: Reduce dosage to 200 mg once daily.

Mild, moderate, or severe preexisting hepatic impairment (Child-Pugh class A, B, or C) in pediatric patients, manufacturer recommends the following initial doses based on indication for use and BSA group:

Newly Diagnosed Ph⁺Chronic Phase CML

• BSA <0.55 m²; 0.55 to <0.9 m²: 100 mg once daily

• BSA 0.9 to <1.1 m²: 150 mg once daily

• BSA ≥1.1 m²: 200 mg once daily

Chronic Phase CML Following Prior Treatment Failure

• BSA <0.55 m²; 0.55 to <0.63 m²: 100 mg once daily

• BSA 0.63 to <0.9 m²: 150 mg once daily

• BSA 0.9 to <1.1 m²; ≥1.1 m²: 200 mg once daily

Renal Impairment

Newly Diagnosed Chronic Phase CML

Cl_cr 30–50 mL/minute in adults: Reduce dosage to 300 mg daily.

Cl_cr <30 mL/minute in adults: Reduce dosage to 200 mg daily.

For pediatric patients with newly diagnosed chronic phase Ph⁺ CML and renal impairment, dosage adjustments are presented in Table 3.

Chronic, Accelerated, or Blast Phase CML

Cl_cr 30–50 mL/minute in adults: Reduce dosage to 400 mg daily.

Cl_cr <30 mL/minute in adults: Reduce dosage to 300 mg daily.

For pediatric patients with chronic phase Ph⁺CML following prior treatment failure and renal impairment, dosage adjustments are presented in Table 4.

Not studied in adult or pediatric patients receiving hemodialysis.

Geriatric Patients

Manufacturer makes no special dosage recommendations.

Cautions for Bosutinib

Contraindications

• Known hypersensitivity to bosutinib.

Warnings/Precautions

GI Toxicity

Nausea, vomiting, and diarrhea may occur.

Monitor for GI adverse effects and treat as clinically indicated with appropriate therapy (e.g., antidiarrheal, antiemetic, fluid replacement). If GI toxicity occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.

Myelosuppression

Cytopenias (e.g., neutropenia, anemia, thrombocytopenia) reported.

If myelosuppression occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be required.

Perform CBCs weekly during first month of therapy and monthly (or as clinically indicated) thereafter.

Hepatic Toxicity

ALT or AST elevations reported.

Monitor liver function tests monthly for first 3 months of therapy and then as clinically indicated. More frequent monitoring recommended if ALT or AST elevations occur.

If hepatic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.

Cardiovascular Toxicity

Cardiovascular toxicity, including cardiac failure, left ventricular dysfunction, and cardiac ischemic events, reported.

Cardiac failure occurs more frequently in patients with previously treated CML and in those with advanced age or risk factors for cardiac failure (e.g., previous history of cardiac failure).

Cardiac ischemic events more common in patients with risk factors for coronary artery disease (e.g., history of diabetes mellitus, BMI >30 kg/m², hypertension, vascular disorders).

Monitor for signs and symptoms of cardiac failure and cardiac ischemia and treat as clinically indicated. Temporary interruption of therapy, dosage reduction, or discontinuance of bosutinib may be necessary if cardiovascular toxicity occurs during therapy.

Fluid Retention

Risk of fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, peripheral edema).

Monitor and manage patients using current standards of care. Temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.

Renal Toxicity

Renal impairment reported.

Monitor renal function at baseline and during therapy with bosutinib; monitor patients with preexisting renal impairment or risk factors for renal impairment more closely. Consider dosage adjustment in patients with baseline and/or drug-induced renal impairment.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. No available data in pregnant patients, but embryotoxic, fetotoxic, and teratogenic effects observed in animals. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

Based on findings from animal studies and its mechanism of action, may cause fetal harm when administered to a pregnant patient.

If used during pregnancy or if the patient becomes pregnant while receiving the drug, inform patient of potential fetal hazard.

Lactation

Not known whether bosutinib or its metabolites distributes into human milk, affects the breast-fed child, or affects milk production. Detected in the milk of lactating rats.

Avoid breast-feeding during therapy and for 2 weeks after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to starting bosutinib therapy. Advise females of reproductive potential to use effective contraception during bosutinib therapy and for 2 weeks following the last dose of drug.

Pediatric Use

Safety and efficacy of bosutinib in pediatric patients ≥1 year of age with newly diagnosed chronic phase Ph⁺ CML or who had chronic phase Ph⁺ CML with prior treatment failure established.

Geriatric Use

No overall differences in safety or efficacy in geriatric patients (≥65 years of age) compared with younger adults, but increased sensitivity cannot be ruled out. Limited data in patients ≥75 years of age.

Hepatic Impairment

Prolonged elimination half-life and increased systemic exposure and peak plasma concentrations in patients with preexisting mild to severe hepatic impairment.

Risk of QT interval prolongation increased in patients with hepatic impairment.

Reduce dosage in patients with preexisting mild, moderate, or severe hepatic impairment.

Renal Impairment

Increased systemic exposure in patients with preexisting moderate to severe renal impairment.

Systemic exposure not affected by mild renal impairment. Not studied in patients receiving hemodialysis.

Reduce dosage in patients with preexisting moderate or severe renal impairment.

Common Adverse Effects

Adverse effects reported in ≥20% of adult and pediatric patients: Diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, respiratory tract infection, constipation.

Laboratory abnormalities reported in ≥20% of adult and pediatric patients: Increased S_cr concentrations, decreased hemoglobin concentrations, decreased lymphocyte count, decreased white blood cell count, decreased absolute neutrophil count, decreased platelet count, increased aminotransferase concentrations (ALT, AST), increased alkaline phosphatase concentrations, decreased calcium concentrations, decreased phosphorus concentrations, increased glucose concentrations, increased urate concentrations, increased lipase concentrations, increased creatine kinase (CK, creatine phosphokinase, CPK) concentrations, increased amylase concentrations.

Drug Interactions

Metabolized principally by CYP3A4.

May inhibit breast cancer resistance protein (BRCP) in the GI tract; low potential for inhibition of BRCP systemically.

Unlikely to inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, or OCT2 at clinically relevant concentrations.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of bosutinib). Avoid concomitant use.

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased serum concentrations of bosutinib). Avoid concomitant use.

Substrates of P-gp

No clinically significant difference in P-glycoprotein (P-gp) substrate pharmacokinetics observed when administered concomitantly with bosutinib.

Specific Drugs and Foods

Bosutinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 4–6 hours.

Absolute bioavailability following oral administration is 34%.

Food

Oral tablet administration with a high-fat meal increases peak plasma concentrations and AUC by 1.8- and 1.7-fold, respectively.

No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms at the same dose, under fed conditions.

No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of bosutinib capsule that was opened and the contents mixed with applesauce or yogurt immediately before use.

Special Populations

Patients with hepatic impairment (Child-Pugh class A, B, or C): Peak concentrations increased by 2.4-, 2-, or 1.5-fold, respectively; AUCs increased by 2.3-, 2-, or 1.9-fold, respectively, compared with healthy individuals following a 200-mg dose.

Systemic exposure following bosutinib 200 mg daily in patients with hepatic impairment expected to be similar to that observed in those with normal hepatic function receiving 500 mg daily; efficacy of bosutinib 200 mg daily in patients with hepatic impairment and CML unknown.

Patients with moderate (Cl_Cr 30–50 mL/minute) or severe (Cl_Cr <30 mL/minute) renal impairment: AUC increased by 1.4- or 1.6-fold, respectively, compared with healthy individuals following a 200-mg dose.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

94–96%.

Elimination

Metabolism

Metabolized principally by CYP3A4.

Elimination Route

Eliminated in feces (91.3%) and urine (3.3%).

Half-life

Mean terminal half-life: 22.5 hours.

Special Populations

Patients with mild to severe hepatic impairment: Prolonged elimination half-life expected.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Capsules

20–25°C (excursions permitted between 15–30°C).

Actions

• Inhibits multiple tyrosine kinases (e.g., Bcr-Abl, Src family [Src, Lyn, Hck]); minimal inhibitory activity against c-Kit or platelet-derived growth factor (PDGF)-β.

• Inhibits Bcr-Abl tyrosine kinase (abnormal protein created by Ph⁺ abnormality in CML) that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues).

• Competitively and selectively inhibits Bcr-Abl tyrosine kinase, leading to inhibition of tyrosine phosphorylation of proteins involved in intracellular signal transduction.

• Inhibits most (16 of 18) imatinib-resistant Bcr-Abl kinase domain mutant forms except for T315I and V299L mutant cells.

Advice to Patients

• Advise patients not to alter the dosage or discontinue therapy without first consulting a clinician.

• If a dose is missed by >12 hours, take the next dose at the regularly scheduled time. Do not double the dose.

• Advise patients to take bosutinib with food. Advise patients to swallow bosutinib tablets whole and not to crush, break, chew, or cut the tablets. Importance of not touching or handling crushed or broken tablets.

• Advise patients that bosutinib capsules may be swallowed whole. For patients that cannot swallow the whole capsule, the capsule can be opened and the contents mixed with applesauce or yogurt.

• Risk of diarrhea, nausea, vomiting, abdominal pain, or bloody stools. Advise patients to promptly seek medical attention if any of these symptoms occur.

• Risk of cytopenias. Inform a clinician if fever, easy bruising, or other signs and symptoms of infection or bleeding occur.

• Risk of liver function abnormalities. Contact a clinician promptly if jaundice occurs.

• Risk of cardiac problems. Inform patients to seek immediate medical attention if symptoms of cardiac failure or cardiac ischemia (e.g., shortness of breath, weight gain, fluid retention) occur.

• Risk of fluid retention. Contact a clinician promptly if swelling, weight gain, or shortness of breath occurs.

• Risk of renal impairment. Immediately report symptoms of frequent urination, polyuria, or oliguria to a clinician.

• Importance of females informing clinicians if they become pregnant. Advise pregnant females of risk to fetus. Advise females of reproductive potential to use an effective method of contraception while receiving bosutinib and for 2 weeks after discontinuance of therapy.

• Advise females to avoid breast-feeding during therapy and for 2 weeks after discontinuance of therapy.

• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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