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
- Continue until disease progression or unacceptable toxicity
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
- Continue until disease progression or unacceptable toxicity
Dose escalation
- Consider escalating dose 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 initial dose
- May increase dose by 100-mg/day increments; 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
- There are no clinical data for efficacy at 200-mg/day
Hepatotoxicity
- AST/ALT>5X ULN: Hold until recovery to ≤2.5X ULN; resume at 400 mg qDay thereafter; discontinue if recovery takes >4 weeks
- AST/ALT ≥3X ULN concurrently with bilirubin elevations >2X ULN and alkaline phosphatase <2X ULN (Hy’s law case definition): Discontinue treatment
Diarrhea
- Grade 3-4 (≥7 stools/day over baseline/pretreatment): Hold until recovery to Grade ≤1; may resume dose at 400 mg qDay
Other moderate or severe nonhematologic toxicities
- Withhold until toxicity resolved, and then consider reducing dose by 100 mg/day
- If clinically appropriate, consider re-escalating to the initial dose taken once daily
- Doses <300 mg/day have been used in patients; however, efficacy has not been established
Myelosuppression
- ANC <1000 x 106/L or platelets <50,000 x 106/L: Withhold until ANC ≥1000 x106/L and platelets ≥50,000 x106/L
- Resume at same dose if recovery occurs within 2 weeks
- If blood cell counts remain low for >2 weeks, reduce dose by 100 mg upon recovery 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
Dosing Considerations
Verify pregnancy status in females of reproductive potential prior to initiation
<18 years: Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Newly diagnosed CP CML
-
All grades
- Creatinine increased (94%)
- Hemoglobin decreased (89%)
- Lymphocyte count decreased (84%)
- Diarrhea (75%)
- Platelet count decreased (68%)
- Serum glutamic-pyruvic transaminase (SGPT)/ALT increased (68%)
- Glucose increased (57%)
- Serum glutamic-oxaloacetic transaminase (SGOT)/AST increased (56%)
- Calcium decreased (55%)
- Phosphorus decreased (54%)
- Lipase increased (53%)
- WBC decreased (50%)
- Hepatic dysfunction (45%)
- ANC decreased (42%)
- Alkaline phosphatase increased (41%)
- Rash (40%)
- Abdominal pain (39%)
- Nausea (37%)
- Creatine kinase increased (36%)
- Fatigue (33%)
- Amylase increased (32%)
- Respiratory tract infection (27%)
- Headache (22%)
- Vomiting (21%)
- Arthralgia (18%)
- Pyrexia (17%)
- Edema (15%)
- Constipation (13%)
- Back pain (12%)
- Pruritus (11%)
- Cough (11%)
- Dyspnea (11%)
- Decreased appetite (11%)
-
Grade 3 or 4
- SGPT/ALT increased (26%)
- Hepatic dysfunction (27%)
- Lipase increased (19%)
- Platelet count (14%)
- SGOT/AST increased (13%)
- Lymphocyte count (12%)
- Pruritus (11%)
- Hypertension (11%)
Imatinib-resistant or -intolerant Ph+ CP, AP, and BP CML
-
All grades
- Hemoglobin decreased (89-97%)
- Creatinine increased (87-95%)
- Diarrhea (76-85%)
- Lymphocyte decreased (79-82%)
- Platelet count decreased (66-80%)
- ANC decreased (50-66%)
- SGPT/ALT increased (39-58%)
- WBC decreased (51-57%)
- Calcium decreased (45-55%)
- SGOT/AST increased (37-50%)
- Abdominal pain (36-49%)
- Urate increased (43-46%)
- Rash (42-48%)
- Nausea (47-48%)
- Vomiting (38-43%)
- Glucose increased (39-42%)
- Phosphorus decreased (33-41%)
- Alkaline phosphatase increased (39%)
- Fatigue (27-35%)
- Lipase increased (19-32%)
- Hepatic dysfunction (21-29%)
- Potassium decreased (22-29%)
- Magnesium increased (18-27%)
- Respiratory tract infection (17-27%)
- Potassium increased (19-25%)
- Pyrexia (25-37%)
- Cough (224%)
- Sodium decreased (18-27%)
- Sodium increased (11-23%)
- Total bilirubin increased (16-22%)
- Headache (18-21%)
- Dyspnea (12-20%)
- Edema (17-19%)
- Arthralgia (15-19%)
- Pneumonia (10-18%)
- Constipation (15-17%)
- Decreased appetite (14%)
- Pleural effusion (9-14%)
- Dizziness (11-14%)
- Back pain (8-14%)
- Chest pain (8-12%)
- Pruritis (7-12%)
- Hypertension (8-11%)
- Influenza (3-11%)
-
Grade 3 or 4
- Platelet count decreased (26-57%)
- ANC decreased (16-39%)
- Hemoglobin decreased (13-38%)
- WBC decreased (7-27%)
- Lymphocyte (14-21%)
- Lipase increased (6-12%)
- Pneumonia (4-12%)
- Hepatic dysfunction (10-11%)
- SGPT/ALT increased (6-11%)
1-10%
Pulmonary hypertension
Acute kidney injury
Renal impairment
Renal failure
Dysgeusia
Myalgia
Dehydration
Electrocardiogram QT prolonged
Bronchitis
Drug hypersensitivity
Pain
Gastritis
Pancreatitis
Gastrointestinal hemorrhage
Hypothyroidism
Tinnitus
Pericardial effusion
Newly diagnosed CP CML
-
Grade 3 or 4
- Diarrhea (9%)
- ANC decreased (9%)
- Hemoglobin decreased (9%)
- Phosphorus decreased (9%)
- WBC decreased (6%)
- Hypertension (5%)
- Amylase increased (3.4%)
- Glucose increased (3%)
- Creatinine kinase increased (3%)
- Rash (2%)
- Abdominal pain (2%)
- Calcium decreased (1.5%)
- Creatinine increased (1.1%)
- Vomiting (1%)
- Dyspnea (1%)
- Arthralgia (1%)
- Headache (1%)
- Respiratory tract infection (1%)
- Pyrexia (1%)
- Fatigue (1%)
Imatinib-resistant or -intolerant Ph+ CP, AP, and BP CML
-
All grades
- Chest pain (8%)
-
Grade 3 or 4
- Diarrhea (4-10%)
- Rash (5-9%)
- Phosphorus decreased (7-8%)
- Abdominal pain (2-7%)
- Fatigue (3-6%)
- SGOT/AST increased (3.5-5%)
- Pleural effusion (4%)
- Vomiting (3%)
- Hypertension (3%)
- Pyrexia (1-3%)
- Total bilirubin increased (0.7-2.8%)
- Dyspnea (2%)
- Nausea (1-2%)
- Chest pain (1%)
- Headache (1%)
- Back pain (1%)
- Decreased appetite (<1%)
- Constipation (<1%)
- Edema (<1%)
- Influenza (<1%)
- Pruritis (<1%)
- Respiratory tract infection (<1%)
- Arthralgia (<1%)
<1%
Febrile neutropenia
Pericarditis
Hyperthyroidism
Acute pulmonary edema (eg, acute pulmonary edema, pulmonary edema)
Erythema multiforme
Newly diagnosed CP CML
-
Grade 3 or 4
- Decreased appetite
- Back pain
- Pruritis
Postmarketing Reports
Thrombotic microangiopathy
Stevens Johnson syndrome
Warnings
Contraindications
Hypersensitivity
Cautions
Diarrhea, nausea, vomiting, and abdominal pain may occur; monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement
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
Cardiac failure and left ventricular dysfunction have been reported in patients taking; monitor for signs and symptoms consistent with cardiac failure and treat as clinically indicated; interrupt, dose reduce, or discontinue as necessary
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 administered to pregnant females
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 interaction overview
- CYP3A4 substrate
-
Strong or moderate CYP3A4 inhibitors
- Avoid coadministration
- Strong or moderate CYP3A4 inhibitors increase bosutinib Cmax and AUC, which may increase the risk of toxicities
-
Strong CYP3A4 inducers
- Avoid coadministration
- Strong CYP3A4 inducers decrease bosutinib Cmax and AUC, which may reduce efficacy
-
Proton pump inhibitors (PPI)
- Use short-acting antacids or H2-blockers as an alternant; separate dosing by >2 hr from bosutinib dosing
- PPIs decrease bosutinib Cmax and AUC, which may reduce efficacy
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
Verify pregnancy status in females of reproductive potential prior to starting treatment
Animal data
- In rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryofetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at a 500-mg/day dose
- Advise pregnant women of the potential risk to a fetus
Contraception
- Based on findings from animal studies, fetal harm may occur when administered to pregnant females
- Females of reproductive potential: Use effective contraception during treatment and for at least 2 weeks after the last dose
Infertility
- Risk of infertility in females or males of reproductive potential has not been studied in humans
- Based on findings from animal studies, reduced fertility may occur in females and males of reproductive potential
Lactation
No data are available regarding presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production
Bosutinib is present in the milk of lactating rats
Owing to the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose
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
Peak plasma concentration
- Multiple 400-mg doses: 146 ng/mL
- Multiple 500-mg doses: 200 ng/mL
AUC
- Multiple 400-mg doses: 2720 ng•hr/mL
- Multiple 500-mg doses: 3650 ng•hr/mL
Effect of food
- Bosutinib administered with a high-fat meal (800-1000 total calories) increased Cmax by 1.8-fold and increased AUC by 1.7-fold
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
- Single 120-mg IV: 33.5 hr
- Single oral dose: 22.5 hr
Clearance
- Single 120-mg IV: 63.6 L/hr
- Single oral dose: 189 L/hr
Excretion: Feces (91.3%); urine (3%)
Administration
Oral Administration
Take with food
Swallow tablet whole; do not chew, crush, or cut
Consider procedures for proper disposal of drug
Avoid touching or handling crushed or broken tablets
Take antacids or H2-blockers at least 2 hr before or 2 hr after bosutinib
Missed dose
- Missed dose >12 hr: Skip dose and take the usual prescribed dose on the following day: do not take 2 doses at one time
Storage
Tablets: Store at 20-25ºC (68-7ºF)
Discard any unused products or waste materials in accordance with local requirements, or drug take back programs
Images
Patient Handout
Formulary
Adding plans allows you to compare formulary status to other drugs in the same class.
To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.
Adding plans allows you to:
- View the formulary and any restrictions for each plan.
- Manage and view all your plans together – even plans in different states.
- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.
