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Bosutinib

Pronunciation

(boe SUE ti nib)

Index Terms

  • Bosutinib Monohydrate
  • SKI-606

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Bosulif: 100 mg, 500 mg

Brand Names: U.S.

  • Bosulif

Pharmacologic Category

  • Antineoplastic Agent, BCR-ABL Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

BCR-ABL tyrosine kinase inhibitor (TKI); inhibits BCR-ABL kinase that promotes CML. Also inhibits SRC family (including SRC, LYN, and HCK). Bosutinib has minimal activity against c-KIT and platelet-derived growth factor receptor (PDGFR), which are nonspecific targets associated with toxicity in other TKIs (Cortes 2012). Bosutinib has activity in 16 of 18 imatinib-resistant BCR-ABL mutations, with the exceptions of the T315I and V299L mutants (Cortes 2011).

Absorption

Slow (Abbas 2012)

Distribution

Vd: 6,080 ± 1,230 L

Metabolism

Hepatic via CYP3A4, primarily to inactive metabolites oxydechlorinated (M2) bosutinib and N-desmethylated (M5) bosutinib, also to bosutinib N-oxide (M6)

Excretion

Feces (~91%); urine (3%)

Onset of Action

Median time to complete hematologic response (in responders): 2 weeks (Cortes 2011)

Median time to major cytogenetic response (in responders): 12.3 weeks (Cortes 2011)

Median time to first complete cytogenic response: 12.9 weeks (Cortes 2012)

Time to Peak

4 to 6 hours

Half-Life Elimination

22 to 27 hours (Cortes 2011)

Protein Binding

94% to plasma proteins

Special Populations: Renal Function Impairment

A single 200 mg dose was administered to subjects in a renal impairment study; the AUC was increased 35% in patients with moderate impairment (CrCl 30 to 50 mL/minute) and 60% in patients with severe impairment (CrCl <30 mL/minute) compared to patients with normal renal function.

Special Populations: Hepatic Function Impairment

In a hepatic impairment study (in patients with Child-Pugh classes A, B, and C administered a single 200 mg dose), the Cmax of bosutinib increased 2.4-, 2-, and 1.5- fold, respectively, and the AUC increased 2.3-, 2-, and 1.9-fold, respectively, compared to patients with normal hepatic function.

Use: Labeled Indications

Chronic myelogenous leukemia (CML):

US labeling: Treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) CML in patients resistant or intolerant to prior therapy

Canadian labeling: Treatment of chronic, accelerated or blast phase Philadelphia chromosome-positive (Ph+) CML in patients resistant or intolerant to prior therapy and for whom subsequent treatment with imatinib, nilotinib, and dasatinib is not appropriate

Contraindications

Hypersensitivity to bosutinib or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): History of long QT syndrome or with persistent QT interval >480 milliseconds; uncorrected hypokalemia or hypomagnesemia; hepatic impairment

Dosing: Adult

Note: Bosutinib is associated with a moderate emetic potential (MASCC 2016); nausea and vomiting may be managed with antiemetics and fluid replacement.

Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+CML): Oral: 500 mg once daily; continue until disease progression or unacceptable toxicity. Note: If complete hematologic response is not achieved by week 8 or complete cytogenetic response is not achieved by week 12, in the absence of grade 3 or higher adverse reactions, consider increasing the dose from 500 mg once daily to 600 mg once daily.

Missed doses: If a dose is missed beyond 12 hours, skip the dose and resume the usual dose the following day

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Preexisting impairment:

CrCl >50 to 80 mL/minute: There are no dosage adjustments provided in manufacturer’s labeling, however, based on the pharmacokinetics, exposure is not altered and the need for dosage adjustment is not likely.

CrCl 30 to 50 mL/minute: Initial: 400 mg once daily.

CrCl <30 mL/minute: Reduce dose to 300 mg once daily (this dose is predicted to result in an AUC similar to that of patients with normal renal function, however, there is no efficacy data for this dose in CML patients with renal impairment).

Renal toxicity during treatment: If unable to tolerate initial dose, reduce dose per adjustment recommendations for toxicity (withhold treatment until resolved, then consider resuming at 400 mg once daily; if clinically appropriate, may re-escalate dose to 500 mg once daily).

Hemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Preexisting impairment (mild, moderate, or severe):

US labeling: Child-Pugh class A, B, or C: Reduce initial dose to 200 mg once daily (this dose is predicted to result in an AUC similar to that of patients with normal hepatic function, however, there is no efficacy data for this dose in CML patients with hepatic impairment).

Canadian labeling: Use is contraindicated in hepatic impairment.

Hepatotoxicity during treatment:

ALT or AST >5 times ULN: Withhold treatment until recovery to ≤2.5 times ULN and resume at 400 mg once daily thereafter. If recovery to ≤2.5 times ULN takes >4 weeks: Discontinue bosutinib.

ALT or AST ≥3 times ULN in conjunction with bilirubin elevation >2 times ULN and alkaline phosphatase <2 times ULN: Discontinue bosutinib.

Dosing: Adjustment for Toxicity

Hematologic toxicity: ANC <1000/mm3 or platelets <50,000/mm3: Withhold treatment until ANC ≥1000/mm3 and platelets ≥50,000/mm3; if recovery occurs within 2 weeks, resume treatment at the same dose. If ANC and platelets remain low for >2 weeks, upon recovery, resume treatment with the dose reduced by 100 mg. If cytopenia recurs, withhold until recovery and resume treatment with the dose reduced by an additional 100 mg. Doses <300 mg daily have not been evaluated.

Nonhematologic toxicity:

Diarrhea: Grade 3 or 4 (≥7 stools/day increase over baseline): Withhold treatment until recovery to ≤ grade 1; may resume at 400 mg once daily.

Other clinically significant nonhematologic toxicity, moderate or severe: Withhold treatment until resolved, then consider resuming at 400 mg once daily; may re-escalate dose to 500 mg once daily if clinically appropriate.

Administration

Bosutinib is associated with a moderate emetic potential (MASCC 2016); nausea and vomiting may be managed with antiemetics and hydration.

Administer with food. Swallow tablet whole; do not crush or break. Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of an intact tablet (NIOSH 2014).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Antacids: May decrease the serum concentration of Bosutinib. Management: Administer antacids more than 2 hours before or after bosutinib. Consider therapy modification

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bitter Orange: May increase the serum concentration of Bosutinib. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Bosutinib. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Bosutinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Bosutinib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Bosutinib. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

H2-Antagonists: May decrease the serum concentration of Bosutinib. Management: Administer histamine H2 receptor antagonists more than 2 hours before or after bosutinib. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Bosutinib. Avoid combination

Pomegranate: May increase the serum concentration of Bosutinib. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Bosutinib. Management: Consider alternatives to proton pump inhibitors, such as antacids or H2 receptor antagonists. Administer alternative agents more than 2 hours before or after bosutinib. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Bosutinib. Avoid combination

Star Fruit: May increase the serum concentration of Bosutinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (14%; grades 3/4: <1%)

Cardiovascular: Edema (14%; grades 3/4: <1%)

Central nervous system: Fatigue (20% to 26%), headache (18% to 20%), dizziness (10% to 13%)

Dermatologic: Skin rash (34% to 35%), pruritus (8% to 11%)

Endocrine & metabolic: Hypophosphatemia (50% [Gambacorti–Passerini 2014]; grades 3/4: 7%), hypokalemia (18%; grades 3/4: 2% [Gambacorti-Passerini 2014])

Gastrointestinal: Diarrhea (76% to 84%; grades 3/4: 5% to 9%), nausea (46% to 47%; grades 3/4: 1% to 2%), vomiting (37% to 42%; grades 3/4: 3% to 4%), abdominal pain (29% to 40%; grades 3/4: 1% to 5%), increase serum lipase (15% to 38%; grades 3/4: 3% to 9% [Cortes 2012, Gambacorti–Passerini 2014]), decreased appetite (13% to 14%)

Hematologic & oncologic: Thrombocytopenia (40% to 42%; grades 3/4: 26% to 37%), anemia (23% to 37%; grades 3/4: 9% to 26%), neutropenia (16% to 19%; grades 3/4: 11% to 18%)

Hepatic: Increased serum ALT (10% to 20%; grades 3/4: 5% to 7%), increased serum AST (11% to 16%; grades 3/4: 3% to 4%)

Neuromuscular & skeletal: Arthralgia (13% to 14%), back pain (7% to 12%), weakness (10% to 11%)

Respiratory: Cough (20% to 21%), dyspnea (10% to 19%), respiratory tract infection (10% to 12%), nasopharyngitis (5% to 12%)

Miscellaneous: Fever (22% to 36%)

1% to 10%:

Cardiovascular: Pericardial effusion (grades 3/4: <1%), chest pain, prolonged Q-T interval on ECG

Central nervous system: Pain

Dermatologic: Acne vulgaris, urticaria

Endocrine & metabolic: Dehydration, hyperkalemia

Gastrointestinal: Dysgeusia, gastritis

Hematologic & oncologic: Febrile neutropenia

Hepatic: Hepatic insufficiency, hepatotoxicity, increased serum bilirubin

Hypersensitivity: Hypersensitivity reaction

Infection: Influenza

Neuromuscular & skeletal: Increased creatine phosphokinase, myalgia

Otic: Tinnitus

Renal: Increased serum creatinine, renal failure

Respiratory: Bronchitis, pleural effusion, pneumonia

<1% (Limited to important or life-threatening): Anaphylactic shock, erythema multiforme, exfoliative dermatitis, gastrointestinal hemorrhage, pancreatitis, pericarditis, pulmonary edema, pulmonary hypertension, respiratory failure

Warnings/Precautions

Concerns related to adverse effects:

• Bone density changes: Bone fracture and mineral abnormalities (eg, hypophosphatemia) has been reported (Bosulif Canadian product monograph 2014); monitor patients with severe osteoporosis or endocrine disease (eg, hyperparathyroidism) for mineral abnormalities and/or changes in bone density.

• Bone marrow suppression: Anemia, neutropenia, and thrombocytopenia may occur. May require treatment interruption, dose reduction, or discontinuation. Monitor blood counts weekly during first month, then monthly thereafter (or as clinically indicated).

• Fluid retention/edema: Fluid retention, manifesting as pericardial effusion, pleural effusion, pulmonary edema and/or peripheral edema may occur; may be severe. Monitor for fluid retention (eg, weight gain) and manage appropriately; may require treatment interruption, dose reduction, or discontinuation.

• Gastrointestinal toxicity: Diarrhea, nausea, vomiting, and abdominal pain may occur. Monitor; may require treatment interruption, dose reduction, or discontinuation. For patients experiencing diarrhea (all grades), the median time to onset was 2 days; median duration (per event) was 1 day; manage diarrhea with antidiarrheals and/or fluid replacement. Bosutinib is associated with a moderate emetic potential (MASCC 2016); nausea and vomiting may be managed with antiemetics and fluid replacement.

• Hemorrhage: Bleeding events (eg, GI, ophthalmic, pericardial, cerebral, vaginal) have been reported; monitor closely, particularly in patients at risk for bleeding episodes (eg, patients with decreased platelets or coagulation disorders).

• Pancreatitis: Acute pancreatitis has been reported; use caution in patients with a prior history of pancreatitis. The Canadian labeling recommends interruption of therapy in patients with elevated amylase/lipase accompanied by abdominal symptoms and evaluation to rule out pancreatitis.

• QT prolongation: QTcF >500 milliseconds was observed rarely (≤0.8%) in clinical trials (Abbas 2012; Cortes 2012); patients with significant or uncontrolled cardiovascular disease (including prolonged QT interval at baseline) were not studied. The Canadian labeling recommends obtaining an ECG (baseline and as clinically indicated thereafter), correction of preexisting hypokalemia and/or hypomagnesemia and periodic monitoring of serum potassium and magnesium.

Disease-related concerns:

• Hepatic impairment: Bosutinib exposure is increased in patients with hepatic impairment; dose reduction is recommended (Canadian labeling contraindicates use in patients with hepatic impairment at baseline). Hepatotoxicity has been reported during treatment; dose reductions may be necessary. Monitor liver function. ALT and AST elevations may occur, usually with an onset in the first 3 months of treatment (median onset was ~30 to 33 days; median duration was 21 days). One case of drug-induced liver injury has been reported; full recovery occurred after discontinuation.

• Hypersensitivity: Hypersensitivity reactions have been reported, including anaphylaxis and anaphylactic shock (rare).

• Renal impairment: Bosutinib exposure is increased in patients with moderate or severe renal impairment. Declines in glomerular filtration rates throughout bosutinib treatment have been observed in clinical studies; monitor renal function at baseline and during therapy, particularly in patients with preexisting impairment or other risk factors for renal dysfunction. Consider dosage adjustment in patients with renal dysfunction at baseline or with treatment emergent impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Gastrointestinal medications: Proton pump inhibitors (PPIs) may decrease bosutinib effects; consider using short acting antacids or H2 antagonists instead of PPIs. Separate administration of antacids or H2 antagonists from bosutinib by at least 2 hours.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Monitoring Parameters

CBC with differential and platelets (weekly during first month, then monthly thereafter, or as clinically indicated); hepatic enzymes (monthly for first 3 months or as clinically indicated; monitor more frequently with transaminase elevations); renal function (at baseline and throughout therapy); diarrhea episodes; fluid/edema status (eg, weight gain)

Canadian labeling: Additional recommendations (not in US labeling): ECG (baseline then as clinically indicated); serum electrolytes and lipase/amylase (baseline, frequently during treatment, and as clinically indicated); bone density (patients with severe osteoporosis or endocrine disease)

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, bosutinib may cause fetal harm if administered in pregnancy. Females of reproductive potential should use effective contraception during bosutinib treatment and for at least 30 days after completion of treatment. The Canadian labeling suggests that semen from male patients (including those who have undergone successful vasectomy) receiving bosutinib may pose a risk to a developing fetus and recommends that male patients use effective contraception while receiving treatment, during any treatment interruptions, and for at least 4 weeks after discontinuation of treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, dizziness, abdominal pain, nausea, vomiting, diarrhea, rhinitis, pharyngitis, lack of appetite, joint pain, or back pain. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), polyuria, shortness of breath, weight gain, angina, edema, severe loss of strength and energy, or signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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