Dosing & Uses
Dosage Forms & Strengths
tablet
- 100mg
- 400mg
- 500mg
Chronic Myelogenous Leukemia
Newly-diagnosed chronic phase Philadelphia chromosome positive
- Indicated for newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML)
- 400 mg PO qDay with food
Chronic, accelerated, or blast phase Philadelphia chromosome positive
- Indicated for chronic, accelerated, or blast phase Ph+ CML in patients resistant to or intolerant to other therapies, including imatinib
- 500 mg PO qDay with food
Dose escalation
- Dose escalation allowed in patients with Ph+ CML who did not achieve or maintain a hematologic, cytogenetic, or molecular response and did not have ≥Grade 3 adverse reactions at the recommended starting dose
- May increase dose by 100-mg increments once daily; not to exceed 600 mg/day
Dosage Modifications
Renal impairment
- Hemodialysis: Safety and efficacy not established
- For patients who have declining renal function while on bosutinib who cannot tolerate the starting dose, follow dose adjustment recommendations for toxicity
- Newly diagnosed chronic phase Ph+ CML
- CrCl 30-50 mL/min: 300 mg PO qDay
- CrCl <30 mL/min: 200 mg PO qDay
- Chronic, accelerated, or blast phase Ph+ CML
- CrCl 30-50 mL/min: 400 mg PO qDay
- CrCl <30 mL/min: 300 mg PO qDay
Hepatic impairment
- Mild to severe (Child-Pugh A to C): 200 mg PO qDay
Hepatotoxicity
- Liver transaminases >5X ULN: Hold dosing until recovery to ≤2.5X ULN; resume at 400 mg qDay thereafter; discontinue if recovery takes longer than 4 weeks
- Liver transaminase elevations ≥3X ULN concurrently with bilirubin elevations >2X ULN and alkaline phosphatase <2X ULN (Hy’s law case definition): Discontinue treatment
Diarrhea
- Grade 3-4 diarrhea (≥7 stools/day over baseline/pretreatment): Hold dosing until recovery to Grade ≤1; may resume dose at 400 mg qDay
Other moderate or severe nonhematologic toxicities
- Withhold dose until toxicity resolved, and then consider reducing dose by 100 mg/day
- If clinically appropriate, consider re-escalating to the starting dose taken qDay
- Doses <300 mg/day have been used in patients; however, efficacy has not been established
Myelosuppression
- ANC <1000 x10^6/L or platelets <50,000 x10^6/L: Withhold dose until ANC ≥1000x10^6/L and platelets ≥50,000x10^6/L
- Resume treatment with same dose if recovery occurs within 2 weeks
- If blood counts remain low for >2 weeks, upon recovery, reduce dose by 100 mg and resume treatment
- If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment
- Doses <300 mg/day have been used in patients; however, efficacy has not been established
Coadministration with CYP3A and/or P-gp inhibitors
- Strong or moderate CYP3A and/or P-gp inhibitors: Avoid concomitant use; increase bosutinib plasma concentration expected and possible increased risk for toxicities
- Concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib Cmax 5.2-fold and AUC 8.6-fold compared to bosutinib alone
Coadministration with CYP3A inducers
- Strong or moderate CYP3A inducers: Avoid concomitant use; large reduction in exposure to bosutinib expected
- Coadministration with rifampin (strong inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to bosutinib alone
Coadministration with proton pump inhibitors
- PPI inhibitors: Avoid concomitant use
- As an alternative to PPIs, use short acting antacids or H2 blockers and separate dosing by more than 2 hours from bosutinib dose
Dosing Considerations
Newly-diagnosed chronic phase Ph+ CML
- Approved under accelerated approval based on molecular and cytogenetic response rates
- Continued approval for this indication may be contingent upon verification and confirmation of clinical benefit in an ongoing long term follow up trial
<18 years: Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10% (Chronic Phase CML)
Platelet count <50×10^9/L (26%)
Neutrophil count <1×10^9/L (16%)
Hemoglobin <80 g/L (13%)
SGPT/ALT >5X ULN (11%)
All grades
- Diarrhea (85%)
- Nausea (47%)
- Abdominal pain (42%)
- Rash (42%)
- Thrombocytopenia (40%)
- Vomiting (37%)
- Anemia (27%)
- Fatigue (26%)
- Pyrexia (23%)
- Cough (22%)
- Headache (21%)
- Increased ALT/AST (17-20%)
- Edema (20%)
- Neutropenia (18%)
- Arthralgia (17%)
Grade 3/4
- Thrombocytopenia (26%)
- Neutropenia (22%)
- Anemia (11%)
>10% (Advanced Phase CML)
Platelet count <50×10^9/L (57%)
Neutrophil count <1×10^9/L (39%)
Hemoglobin <80 g/L (38%)
All grades
- Diarrhea (76%)
- Nausea (48%)
- Abdominal pain (31%)
- Rash (38%)
- Thrombocytopenia (45%)
- Vomiting (43%)
- Anemia (38%)
- Pyrexia (37%)
- Cough (22%)
- Neutropenia (22%)
- Fatigue (21%)
- Dyspnea (20%)
- Headache (17%)
- Edema (17%)
- Respiratory tract infection (15%)
Grade 3/4
- Thrombocytopenia (39%)
- Anemia (27%)
- Neutropenia (20%)
- Leukopenia (12%)
1-10% (Chronic Phase CML)
Lipase >2X ULN (10%)
Phosphorus <0.6 mmol/L (7%)
SGOT/AST >5X ULN (5%)
Total bilirubin >3X ULN (1%)
1-10%
- Febrile neutropenia
- Pericardial effusion
- Tinnitus
- Gastritis
- Chest pain
- Pain
- Hepatotoxicity
- Abnormal hepatic function
- Drug hypersensitivity
- Pneumoniae, influenza, bronchitis, pleural effusion
- Electrocardiogram QT prolonged
- Increased blood CPK
- Increased blood creatinine, renal failure
- Hyperkalemia
- Dehydration
All grades
- Leukopenia (10%)
- Increased serum creatinine (10%)
- Influenza (10%) Chest pain (7%)
Grade 3/4
- Diarrhea (9%)
- Rash (9%)
- Increased ALT (8%)
- Leukopenia (4%)
- Vomiting (3%)
- Increased AST (3%)
- Fatigue (2%)
- Abdominal pain (2%)
- Asthenia (2%)
- Dyspnea (2%)
- Nausea (1%)
- Edema (1%)
1-10% (Advanced Phase CML)
SGPT/ALT >5X ULN (9%)
Lipase >2X ULN (9%)
Low Phosphorus <0.6 mmol/L (7%)
SGOT/AST >5X ULN (4%)
Total bilirubin >3X ULN (1%)
All grades
- Increased ALT (10%)
- Respiratory tract infection (10%)
- Pleural effusion (9%)
- Back pain (8%)
- Pruritus (7%)
- Nasopharyngitis (6%)
- Increased serum creatinine (6%)
- Influenza (3%)
Grade 3/4
- Abdominal pain (6%)
- Dyspnea (6%)
- Rash (5%)
- Increased ALT (5%)
- Diarrhea (4%)
- Pleural effusion (4%)
- Increased AST (3%)
- Vomiting (3%)
- Edema (2%)
- Nausea (2%)
- Back pain (1%)
- Influenza (1%)
<1% (Chronic Phase CML)
<1%
- Pericarditis
- Acute pancreatitis
- GI hemorrhage
- Liver injury
- Anaphylactic shock
- Acute pulmonary edema
- Respiratory failure
- Pulmonary hypertension
- Erythema multiforme
- Exfoliative rash
- Drug eruption
All grades
- Influenza
- Increased serum creatinine
- Pruritus
- Respiratory tract infection
- Decreased appetite
- Back pain
- Arthralgia
- Headache
- Pyrexia
<1% (Advanced Phase CML)
Asthenia
Dizziness
Increased serum creatinine
Postmarketing Reports
Hypertension
Steven's Johnson Syndrome
Thrombotic microangiopathy
Warnings
Contraindications
Hypersensitivity
Cautions
See Dosage Modifications regarding withholding, decreasing, or discontinuing bosutinib treatment with various toxicities
Diarrhea, nausea, vomiting, and abdominal pain may occur
Thrombocytopenia, anemia, and neutropenia occur with treatment; perform CBC weekly for first month and then monthly thereafter, or as clinically indicated
Fluid retention may occur and manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema
Decline in glomerular filtration rate reported in patients receiving therapy, which in turn increases bosutinib exposure in patients; use caution in patients with moderate renal impairment; dosage adjustment recommended
Fetal harm may occur when bosutinib is administered to a pregnant woman (see Pregnancy)
Hepatic toxicity
- Elevated ALT, AST, and/or bilirubin may occur; perform monthly hepatic enzyme tests for first 3 months during treatment, and then as clinically indicated
- Median time to onset of increased ALT and AST was 35 and 33 days; median duration for each was 21 days
- Perform hepatic enzyme tests monthly for the first 3 months of treatment and as clinically indicated; in patients with transaminase elevations, monitor liver enzymes more frequently
Drug interactions overview
- See Dosage Modifications
- Drugs that may increase bosutinib plasma levels: CYP3A or P-glycoprotein (P-gp) inhibitors
- Drugs that may decrease bosutinib plasma concentrations: CYP3A inducers, proton pump inhibitors
- Bosutinib altering plasma concentrations of drugs: Increases P-gp substrates
Pregnancy & Lactation
Pregnancy
No data are available in pregnant women to inform the drug-associated risk, however, fetal harm may occur when administered to pregnant women based on mechanism of action and findings from animal studies
Advise pregnant women of the potential risk to a fetus Females of reproductive potential should have a pregnancy test prior to initiating treatment with bosutinib
Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment and for at least 1 month after the last dose
Risk of infertility in females or males of reproductive potential has not been studied in humans; reduced fertility in females and males of reproductive potential may occur based on animal studies
Animal data
- In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib caused adverse developmental outcomes
- Bosutinib administration to rats prior to fertilization until gestation day (GD) 7 caused increased embryonic resorptions at maternal exposures (AUC) ~0.5 and 0.4 times the human exposure at recommended doses of 400 and 500 mg/day, respectively, and decreased implantations and reduced number of viable embryos at maternal exposures ~1.8 and 1.3 times the human exposure at recommended doses of 400 or 500 mg/day, respectively
- Administration of bosutinib to pregnant rabbits during organogenesis caused adverse developmental outcomes including fetal anomalies and reduced fetal body weights at maternal exposures (AUC) ~2.3 and 1.7 times the human exposure at the recommended doses of 400 or 500 mg/day
Lactation
Unknown whether distributed in breast milk; a decision should be made whether to discontinue nursing or to discontinue the drug
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Pharmacology
Mechanism of Action
Tyrosine kinase inhibitor; Inhibits Bcr-Abl kinase that promotes CML; also inhibits SRc-family kinases including Src, Lyn, and Hck
Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, but did not inhibit T315I and V299L mutant cells
Absorption
Absolute bioavailability: 34% (healthy volunteers with food)
Peak plasma time, 500 mg dose with food: 6 hr
Mean peak plasma concentration, doses 200-800 mg: 146 ng/mL; increased 1.8-fold with high fat meal
Mean AUC, doses 200-800 mg: 2720 ng•h/mL; increased 1.7-fold with high fat meal
Distribution
Protein Bound: 94(in vivo); 96% (ex vivo)
Vd: 6,080 L
P-gp substrate and inhibitor
Metabolism
Metabolized by in liver primarily by CYP3A4
Metabolites (inactive): Oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite
Elimination
Half-life: 22.5 hr (single oral dose); 35.5 hr (single 120-mg IV dose)
Clearance: 63.6 L/hr
Excretion: Feces (91.3%); urine (3%
Administration
Oral Administration
Take with food
Swallow table whole; do not chew, crush, or cut
Missed dose
- Missed dose >12 hr: Skip dose and take the usual prescribed dose on the following day
Storage
Tablets: Store at 68-77°F (20-25°C)
Images
Patient Handout
Formulary
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