Dosing & Uses
Dosage Forms & Strengths
Chronic Myelogenous Leukemia
Indicated for chronic, accelerated, or blast phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in patients resistant to or intolerant to other therapies, including imatinib
500 mg PO qDay with food
May increase dose to 600 mg qDay if complete hematological response is not achieved by week 8 or a complete cytogenetic response by week 12; dose escalation only if adverse reactions grade 2 or lower and patient taking 500 mg/day dose
- Pre-existing severe renal impairment (CrCl <30 mL/min): 300 mg PO qDay
- For patients with CrCl 30-50 mL/min who cannot tolerate a 400 mg dose, follow dose adjustment recommendations for toxicity In a dedicated renal impairment trial, compared to volunteers with normal renal function, the exposure (AUC) of bosutinib increased by 60% and 35% in subjects with CrCL <30 mL/min and CrCL 30-50 mL/min, respectively
- Pre-existing mild, moderate, and severe hepatic impairment: 200 mg PO qDay
- 200 mg/day in hepatic impairment is predicted to result in AUC similar to 500 mg/day in normal hepatic function; however, there are no clinical data for efficacy of 200 mg/day in patients with hepatic impairment and CML
- If liver transaminases greater than 5 xULN occur, hold dosing until recovery to ≤2.5 x ULN and resume at 400 mg qDay thereafter; discontinue if recovery takes longer than 4 weeks
- Discontinue if transaminase elevations ≥3 xULN occur concurrently with bilirubin elevations >2 xULN and alkaline phosphatase <2 x ULN (Hy’s law case definition)
- NCI CTCAE 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 nonhematologic toxicities
- Withhold dose until toxicity resolved, and then consider resuming at 400 mg qDay
- If clinically appropriate, consider re-escalating the dose to 500 mg qDay
- 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 greater than 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 not been evaluated
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
Take with food
Swallow table whole, do not chew, crush, or cut
Medications that neutralize stomach acid (eg, H2 antagonists, antacids) may be taken 2 hr before or after bosutinib
Bosutinib displays pH-dependent aqueous solubility, avoid PPIs because of long-term gastric acid suppression
<18 years: Safety and efficacy not established
Serious - Use Alternative
Significant - Monitor Closely
Thrombocytopenia, all grades (41%)
Abdominal pain (37%)
Thrombocytopenia, grades 3/4 (33%)
Increased ALT (17%)
Increased AST (14%)
Decreased appetite (13%)
Respiratory tract infection (12%)
Back pain (11%)
SGPT/ALT >5 xULN (9%)
Lipase >2 xULN (7%)
Phosphorus <0.6 mmol/L (7%)
SGOT/AST >5 xULN (4%)
Total bilirubin >3 xULN (1%)
Anormal hepatic function
Pneumoniae, influenza, bronchitis
Electrocardiogram QT prolonged
Increased blood CPK
Increased blood creatinine
Acute pulmonary edema
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
Elevated ALT, AST, and/or bilirubin may occur; perform monthly hepatic enzyme tests for first 3 months during treatment, and then as clinically indicated
Fluid retention may occur and manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema
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
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
Hepatic impairment increases exposure to bosutinib in patients with hepatic impairment; consider decreasing the dose
Use caution in patients with a prior history of pancreatitis; acute pancreatitis reported with use
Monitor closely patients at risk for bleeding episodes (eg, coagulation disorders); bleeding events reported
Bone fracture and mineral abnormalities, including hypophosphatemia reported; monitor patients with severe osteoporosis or endocrine disease, including hyperparathyroidism; monitor bone density and/or mineral abnormalities
Pregnancy & Lactation
Pregnancy Category: D; Based on mechanism of action and findings in animals, can cause fetal harm when administered to a pregnant woman
Lactation: Unknown whether distributed in breast milk; a decision should be made whether to discontinue nursing or to discontinue the drug
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.
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
Absolute bioavailability: 34% (healthy volunteers with food)
Peak Plasma Time: 4-6 hr
Peak Plasma Concentration: 200 ng/mL (with food at day15); increased 1.8-fold with high fat meal
AUC: 3650 ng•h/mL (with food at day 15); increased 1.7-fold with high fat meal
Protein Bound: 94-96%
Vd: 6,080 L
P-gp substrate and inhibitor
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
Half-life (terminal phase): 22.5 hr
Total body clearance: 189 L/hr
Excretion: 91.3% feces; 3% urine
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