Bosutinib (Monograph)

Brand name: Bosulif
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile
Molecular formula: C₂₆H₂₉Cl₂N₅O₃
CAS number: 380843-75-4

Medically reviewed by Drugs.com on Jul 25, 2022. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple tyrosine kinases.

Uses for Bosutinib

Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (CML)

Treatment of newly diagnosed Philadelphia chromosome-positive (Ph⁺) chronic myelogenous leukemia (CML) in adults in the chronic phase of the disease.

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

Some experts recommend dasatinib, imatinib, or nilotinib for the first-line treatment of chronic phase CML; selection of the tyrosine kinase inhibitor should be based on patient preference and factors such as age, comorbidities, and expected tolerability of therapy. If treatment failure occurs, an alternative tyrosine kinase inhibitor (e.g., bosutinib, dasatinib, imatinib, nilotinib, ponatinib) or stem cell transplantation may be considered.

Designated an orphan drug by FDA for treatment of CML.

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 complete blood cell counts (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

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

Administration

Oral Administration

Administer orally once daily with food; 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, or crush. Avoid touching or handling crushed or broken tablets.

Dosage

Available as bosutinib monohydrate; dosage expressed as anhydrous bosutinib.

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 upon resumption of therapy.

If neutropenia or thrombocytopenia recurs, withhold bosutinib until recovery. Upon resumption of therapy, reduce dose by an additional 100 mg. 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.

Prescribing Limits

Adults

CML

Newly Diagnosed Chronic Phase CML

Oral

<300 mg daily not evaluated. Maximum dosage is 600 mg daily.

Chronic, Accelerated, or Blast Phase Following Prior Treatment Failure

Oral

<300 mg daily not evaluated. Maximum dosage is 600 mg daily.

Special Populations

Hepatic Impairment

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

Renal Impairment

Newly Diagnosed Chronic Phase CML

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

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

Not studied in patients receiving hemodialysis.

Chronic, Accelerated, or Blast Phase CML

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

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

Not studied in 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. In patients with newly diagnosed Ph⁺ CML, median time to onset of diarrhea was 4 days; median duration of each episode was 3 days in a clinical trial. In patients with previously treated CML, median time to onset of diarrhea was 2 days; median duration of each episode was 2 days in a clinical trial. Median number of episodes of diarrhea per patient was 3 episodes.

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, generally occurring early during therapy with median duration of 15–21 days.

Drug-induced hepatic injury without other etiology reported in 2 patients.

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 Effects

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. (See Females and Males of Reproductive Potential under Cautions.) 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 not 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%: Diarrhea, rash, nausea, abdominal pain, vomiting, fatigue, hepatic dysfunction, respiratory tract infection, pyrexia, headache.

Laboratory abnormalities reported in ≥20%: 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.

Interactions for Bosutinib

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

Drug or Food	Interaction	Comments
Aprepitant	Possible increased bosutinib concentrations and systemic exposure	Avoid concomitant use
Dabigatran	No clinically significant impact on pharmacokinetics of dabigatran
Grapefruit or grapefruit juice	Possible increased bosutinib concentrations	Avoid concomitant use
Ketoconazole	Increased bosutinib AUC and peak concentrations	Avoid concomitant use
Proton-pump inhibitors	Lansoprazole: Decreased bosutinib AUC and peak concentrations	Concomitant use not recommended Consider substituting H₂-receptor antagonist or short-acting antacid (administered 2 hours before or after bosutinib dose) for proton-pump inhibitor
Rifampin	Decreased bosutinib AUC and peak concentrations	Avoid concomitant use

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

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 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).

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

Importance of not altering the dosage or discontinuing therapy without first consulting clinician.
If a dose is missed by >12 hours, take the next dose at the regularly scheduled time. Do not double the dose.
Importance of advising patients to swallow bosutinib tablets whole and not to crush, break, or cut the tablets. Importance of not touching or handling crushed or broken tablets.
Importance of advising patients to take bosutinib tablets with food and not to drink grapefruit juice or consume grapefruit products while taking the drug.
Risk of diarrhea, nausea, vomiting, abdominal pain, or bloody stools. Importance of promptly seeking medical attention if any of these symptoms occur.
Risk of cytopenias. Importance of informing clinician if fever, easy bruising, or other signs and symptoms of infection or bleeding occur.
Risk of liver function abnormalities. Importance of contacting clinician promptly if jaundice occurs.
Risk of cardiac problems. Importance of seeking 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. Importance of contacting clinician promptly if swelling, weight gain, or shortness of breath occurs.
Risk of renal impairment. Importance of immediately reporting symptoms of frequent urination, polyuria, or oliguria to a clinician.
Necessity of advising females of reproductive potential to use an effective method of contraception while receiving bosutinib and for at least 2 weeks after discontinuance of therapy. Necessity of advising females to avoid pregnancy during therapy.
Importance of females informing clinicians if they become pregnant. Bosutinib may cause fetal harm. Advise pregnant females of risk to fetus.
Necessity of advising females to avoid breast-feeding during therapy and for at least 2 weeks after discontinuance of therapy.
Importance of informing patients of other important precautionary information.
Importance of informing 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.

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.