Bosutinib, an inhibitor of multiple tyrosine kinases, is an antineoplastic agent.1, 7, 8
Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia
Bosutinib is used for the treatment of chronic phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adults and pediatric patients 1 year of age and older who are newly diagnosed or resistant or intolerant to prior therapy.1, 23 Bosutinib is also used for the treatment of chronic, accelerated, or blast phase Ph+ CML in adults after failure (secondary to resistance or intolerance) of prior therapy.1, 7, 18, 24, 25, 26, 27 Bosutinib is designated an orphan drug by FDA for use in the treatment of CML.6
Treatment of Newly Diagnosed Chronic Phase CML in Adults
Bosutinib is used for the treatment of newly diagnosed Ph+ CML in adults who are in the chronic phase of the disease.1 This indication is based principally on the results of an open-label, randomized, multicenter trial (BFORE trial).1, 23 In this study, 487 patients with Ph+ CML harboring b2a2 and/or b3a2 transcripts at baseline with Bcr-Abl gene copies >0 were randomized (stratified by Sokal score and geographical region) in a 1:1 ratio to receive bosutinib 400 mg once daily or imatinib 400 mg once daily.1, 23 The median treatment duration was 55.1 months in the bosutinib group and 55 months in the imatinib group.1 The median age of patients was 53 years, and distribution of Sokal scores in the bosutinib and imatinib groups was similar (35 and 39% were low risk, 44 and 38% were intermediate risk, and 22 and 22% were high risk in the bosutinib and imatinib groups, respectively).1
The primary efficacy end point was major molecular response at 12 months (48 weeks), defined as ≤0.1% Bcr-Abl ratio on international scale (corresponding to ≥3 log reduction from standardized baseline) with a minimum of 3000 Abl transcripts as assessed by the central laboratory.1, 23 Complete cytogenetic response was also assessed at 12 months; complete cytogenetic response was defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases derived from bone marrow aspirate, or major molecular response if adequate cytogenetic assessment was unavailable.1 At 12 months, 78 and 72% of patients receiving bosutinib and imatinib, respectively, were still receiving the assigned treatment.1 The major molecular response rate at 12 months was 47 and 37% in patients receiving bosutinib and those receiving imatinib, respectively.1 The complete cytogenetic response rate at 12 months was 77 and 66% in bosutinib- and imatinib-treated patients, respectively.1 By month 60 (week 240), the rates of major molecular response were 74 and 66% in the bosutinib and imatinib groups, respectively.1 Median time to major molecular response was 9 months in patients receiving bosutinib and 11.9 months in patients receiving imatinib.1 Transformation to acute phase or blast phase occurred in 2 and 3% of bosutinib- and imatinib-treated patients, respectively, after 60 months of follow-up.1
Treatment of Chronic, Accelerated, or Blast Phase CML Following Prior Treatment Failure in Adults
Bosutinib is used for the treatment of chronic, accelerated, or blast phase Ph+ CML in adults after failure (secondary to resistance or intolerance) of prior therapy.1, 7, 18, 24, 25, 26, 27
This indication is based principally on the results of an open-label, single-arm, multicenter, phase 1/phase 2 study in adults with chronic, accelerated, or blast phase CML following therapy with either imatinib alone or imatinib followed by dasatinib and/or nilotinib; patients were intolerant of or had disease that was resistant to imatinib.1 In this study, 546 patients received bosutinib 500 mg once daily (increased to 600 mg daily if complete hematologic or cytogenetic response was not achieved by week 8 or 12, respectively).1, 2, 19 The median duration of therapy with bosutinib was 26 months in patients with chronic phase CML previously treated with only imatinib; patients previously treated with imatinib followed by dasatinib and/or nilotinib received therapy with bosutinib for a median duration of 9 months.1 The median duration of therapy with bosutinib in patients previously treated with at least imatinib who were in the accelerated or blast phase of the disease was 10 or 3 months, respectively.1
The primary efficacy end point of this study was major cytogenetic response (defined as elimination or substantial reduction [by at least 65%] of Ph+ hematopoietic cells19 ) at 24 weeks.1, 2, 19 In this study, resistance to imatinib was defined as failure to achieve or maintain any hematologic improvement within 4 weeks of therapy; or failure to achieve a complete hematologic response by 3 months, a cytogenetic response by 6 months, or a major cytogenetic response by 12 months; or disease progression after a previous cytogenetic or hematologic response; or evidence of the genetic mutation in the Bcr-Abl gene associated with imatinib resistance.1 Imatinib intolerance was defined as inability to tolerate imatinib because of toxicity, or disease progression with imatinib and inability to receive a higher dosage because of toxicity.1 Definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib.1 Major cytogenetic response was achieved at 24 weeks in 40.1% of patients in chronic phase CML who were previously treated with imatinib alone and in 25.9% of those previously treated with imatinib followed by dasatinib or nilotinib.1 Major cytogenetic response was achieved at any time during the study in 59.5% of patients in chronic phase CML who were previously treated with imatinib alone and 40.2% of those previously treated with imatinib followed by dasatinib or nilotinib.1 In an exploratory analysis, treatment with bosutinib resulted in confirmed complete hematologic responses at 48 weeks in 30.6 or 16.7% of patients in accelerated or blast phase CML, respectively.1 Overall hematologic response at 48 weeks was observed in 56.9 or 28.3% of patients in accelerated or blast phase CML, respectively.1 Long-term follow-up data was based on a minimum of 60 months for patients with chronic phase CML previously treated with imatinib alone, and a minimum of 48 months for patients with chronic phase CML previously treated with imatinib and at least one other tyrosine kinase inhibitor, patients with accelerated phase CML, and patients with blast phase CML.1, 24, 25, 26 Median duration of major cytogenetic response was not reached in patients with chronic phase CML previously treated with imatinib alone or in those with chronic phase CML previously treated with imatinib and at least one other tyrosine kinase inhibitor.1 Among patients with chronic phase CML previously treated with imatinib alone, 65.4 and 42.9% had a major cytogenetic response lasting at least 18 and 54 months, respectively.1 Among patients with chronic phase CML previously treated with imatinib and at least one other tyrosine kinase inhibitor, 64.4 and 35.6% had a major cytogenetic response lasting at least 9 and 42 months, respectively.1 Twenty of the 403 patients with chronic phase CML at baseline had disease transformation to accelerated or blast phase during bosutinib therapy, and 3 of 79 patients with accelerated phase CML at baseline had disease transformation to blast phase CML during bosutinib therapy.1
A single-arm, open-label, phase 4 study (BYOND) confirmed the results of the initial approval trial in patients with chronic or advanced Ph+ CML who had failed previous tyrosine kinase inhibitor therapy.27 In this trial, the cumulative confirmed major cytogenetic response rate at 1 year was 75.8% among patients with chronic phase CML who had received 1 or 2 prior tyrosine kinase inhibitors and 62.2% in those with chronic phase CML who had received 3 prior tyrosine kinase inhibitors.27
Bosutinib is used for the treatment of chronic phase Ph+ CML in pediatric patients 1 year of age and older who are newly diagnosed or resistant or intolerant to prior therapy.1 This indication is based primarily on the results of a multicenter, non-randomized, open-label study (BCHILD).1
The BCHILD study enrolled 28 patients with chronic phase Ph+ CML with resistance or intolerance to prior therapy and 21 patients with newly diagnosed chronic phase Ph+ CML.1 Patients in the prior treatment failure group received bosutinib at doses of 300 to 400 mg/m2 orally once daily and those in the newly diagnosed group were administered bosutinib 300 mg/m2 orally once daily.1 Efficacy outcomes included complete cytogenetic response, major cytogenetic response, and major molecular response.1
Patients with newly diagnosed chronic phase Ph+ CML had a median age of 14 years (range, 5 to 17 years); 68% were male; 81% were white and 14% were Black/African American.1 In the chronic phase Ph+ CML with resistance or intolerance to prior therapy group, the median age was 11.5 years (range, 1 to 17 years); 57% were male; 43% were white, 7% were Black/African American, and 14% were Asian.1
The major and complete cytogenetic responses among newly diagnosed patients were 76.2% and 71.4%, respectively.1 The major molecular response was 28.6%.1 The median duration of follow-up was 14.2 months (range, 1.1 to 26.3 months) in this group.1 For patients in the prior treatment failure group, the major and complete cytogenetic responses were 82.1% and 78.6%, respectively.1 The major molecular response was 50.0%.1 Among 14 patients who achieved major molecular response, 2 lost this response after 13.6 months and 24.7 months on treatment, respectively .1 The median duration of follow-up for overall survival was 23.2 months (range, 1.0 to 61.5 months) in this patient group.1
Most adult patients with chronic phase CML can expect a normal life expectancy.35 With the exception of newly diagnosed cases during pregnancy, first-line treatment of CML is a tyrosine kinase inhibitor (TKI).35 The choice of TKI in the first-line setting is individualized based on efficacy, tolerability, toxicity, and cost, particularly since adherence to therapy is life-long.35
If treatment failure or resistance develops with first-line TKI therapy, second-line treatment requires changing to another TKI with investigation of potential BCR-ABL1 KD-mutations.35 If intolerance or treatment-related complications related to the initial TKI occurs, the decision to change to another TKI is partly subjective and dependent upon the patient, clinician, supportive care options, and level of response.35
If BCR-ABL1 resistance mutations occur with imatinib (the first generation TKI), second generation TKIs (dasatinib, nilotinib, bosutinib) are an option dependent upon the specific mutation.35 If there are no BCR-ABL1 KD-mutations present, there is no clear recommendation for any particular second generation TKI as all are effective.35 Choice of TKI is almost entirely patient-related and depends on age, comorbidities, toxicity of the initial TKI, and other factors.35
Dispensing and Administration Precautions
Bosutinib is administered orally once daily with food;1 tolerability of the drug may be increased when taken with food.2 Bosutinib is available as tablets and capsules.1
Swallow tablets whole.1 Tablets should not be crushed, broken, chewed, or cut.1 Touching or handling of crushed or broken tablets should be avoided.1
Capsules may be swallowed whole.1 If a patient is unable to swallow a whole capsule, the required number of capsules for the dose can be opened and contents mixed with room temperature applesauce or yogurt in a clean container (see Table 1).1 Patients should immediately consume the full mixture without chewing; do not store for later use.1 If the entire mixture is not swallowed, do not administer an additional dose.1 Resume dosing on the next day.1
Dose (mg) | Volume of Applesauce or Yogurt |
|---|---|
100 | 10 mL (2 teaspoons) |
150 | 15 mL (3 teaspoons) |
200 | 20 mL (4 teaspoons) |
250 | 25 mL (5 teaspoons) |
300 | 30 mL (6 teaspoons) |
350 | 30 mL (6 teaspoons) |
400 | 35 mL (7 teaspoons) |
450 | 40 mL (8 teaspoons) |
500 | 45 mL (9 teaspoons) |
550 | 45 mL (9 teaspoons) |
600 | 50 mL (10 teaspoons) |
If a dose of bosutinib is missed by more than 12 hours, the dose should be omitted, and the next dose should be taken at the regularly scheduled time.1 Do not double the dose to make up for the missed dose.1
Store bosutinib tablets and capsules at 20-25°C (excursions permitted between 15-30°C).1
Bosutinib is commercially available as the monohydrate; dosage is expressed in terms of anhydrous bosutinib.1
Treatment of Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia
The recommended initial adult dosage of bosutinib for the treatment of newly-diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) is 400 mg once daily.1 In clinical studies, patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response could increase the dosage in increments of 100 mg once daily up to a maximum dosage of 600 mg once daily if they did not experience grade 3 or higher adverse effects while receiving the original starting dosage (400 mg daily).1 Therapy should be continued until disease progression or intolerance to therapy occurs.1
Treatment of Chronic, Accelerated, or Blast Phase CML Following Prior Treatment Failure
The recommended initial adult dosage of bosutinib for the treatment of Ph+ chronic, accelerated, or blast phase CML following prior treatment failure is 500 mg once daily.1 In clinical studies, patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response could increase the dosage in increments of 100 mg once daily up to a maximum dosage of 600 mg once daily if they did not experience grade 3 or higher adverse effects while receiving the original starting dosage (500 mg daily).1 Therapy should be continued until disease progression or intolerance to therapy occurs.1
Treatment of Newly Diagnosed Chronic Phase CML
The recommended initial pediatric (≥1 year of age) dosage of bosutinib for the treatment of newly-diagnosed chronic phase Ph+ CML is 300 mg/m2 once daily.1 In pediatric patients with a body surface area (BSA) <1.1 m2and an insufficient response after 3 months of therapy, consider increasing the dosage in increments of 50 mg up to a maximum of 100 mg above the starting dose.1 Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m2 can be performed similarly to adult 100 mg increment recommendations.1 The maximum dose in pediatric patients is 600 mg once daily.1 Therapy should be continued until disease progression or intolerance to therapy occurs.1
Treatment of Chronic Phase CML Following Prior Treatment Failure
The recommended initial pediatric (≥1 year of age) dosage of bosutinib for the treatment of chronic phase Ph+ CML following prior treatment failure is 400 mg/m2 once daily.1 In pediatric patients with BSA <1.1 m2and an insufficient response after 3 months of therapy, consider increasing the dosage in increments of 50 mg up to a maximum of 100 mg above the starting dose.1 Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m2 can be performed similarly to adult 100 mg increment recommendations.1 The maximum dose in pediatric patients is 600 mg once daily.1 Therapy should be continued until disease progression or intolerance to therapy occurs.1
Dose recommendations for pediatric patients with newly diagnosed chronic phase Ph+ CML or with chronic phase Ph+ CML with resistance or intolerance to prior therapy are presented in Table 2.1
Body Surface Area (m2) | Newly Diagnosed Recommended Dose (Once Daily) | Resistant or Intolerant Recommended Dose (Once Daily) |
|---|---|---|
<0.55 | 150 mg | 200 mg |
0.55 to <0.63 | 200 mg | 250 mg |
0.63 to <0.75 | 200 mg | 300 mg |
0.75 to <0.9 | 250 mg | 350 mg |
0.9 to <1.1 | 300 mg | 400 mg |
≥1.1 | 400 mga | 500 mga |
aMaximum starting dose (corresponds to maximum starting dose for adult indication).
Dosage Modification for Toxicity
In patients who experience neutropenia (i.e., absolute neutrophil counts [ANC] less than 1000/mm3) or thrombocytopenia (i.e., platelet counts less than 50,000/mm3) unrelated to the underlying CML, therapy with bosutinib should be withheld until ANC reaches or exceeds 1000/mm3 and platelet counts reach or exceed 50,000/mm3.1 Bosutinib therapy may then be resumed at the original starting dosage if recovery occurs within 2 weeks; if recovery is delayed (exceeding 2 weeks), the dose of bosutinib should be reduced by 100 mg (e.g., a dose of 500 mg reduced to 400 mg), or by 50 mg in pediatric patients with BSA <1.1 m2, upon resumption of therapy.1 If neutropenia or thrombocytopenia recurs, withhold bosutinib therapy until recovery, then reduce the dose by an additional 100 mg or by an additional 50 mg in pediatric patients with BSA <1.1 m2 upon resumption of therapy.1 Dosages less than 300 mg daily have been used, but efficacy has not been established.1
In patients who exhibit increases in serum aminotransferase concentrations (ALT or AST exceeding 5 times the upper limit of normal [ULN]), therapy with bosutinib should be withheld until serum aminotransferase concentrations decrease to no more than 2.5 times the ULN.1 Bosutinib therapy may then be resumed at a dosage of 400 mg once daily.1 If recovery is delayed (exceeding 4 weeks), discontinue treatment with bosutinib.1
In patients who exhibit increases in aminotransferase concentrations (ALT or AST 3 or more times the ULN) concurrently with total bilirubin concentrations exceeding 2 times the ULN and alkaline phosphatase concentrations less than 2 times the ULN, discontinue treatment with bosutinib.1
In patients with grade 3 or 4 diarrhea (7 or more stools per day over baseline), withhold therapy with bosutinib until diarrhea resolves to no more than grade 1.1 Bosutinib therapy may then be resumed at a dosage of 400 mg once daily.1
In patients who exhibit other clinically important, moderate or severe nonhematologic toxicity, therapy with bosutinib should be withheld until the toxicity has resolved.1 Bosutinib therapy may then be resumed at a dosage reduced by 100 mg once daily.1 If clinically appropriate, bosutinib may be re-escalated to the original starting dosage.1
In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however dose reduction increments may differ.1 For pediatric patients with BSA <1.1 m2, reduce dose by 50 mg initially followed by additional 50 mg increment if the adverse reactions persist.1 For pediatric patients with BSA ≥1.1 m2, reduce dose similarly to adults.1
For adult patients with mild to severe preexisting hepatic impairment (Child-Pugh class A, B, or C), the manufacturer recommends a bosutinib dosage of 200 mg daily.1
For pediatric patients with mild to severe preexisting hepatic impairment (Child-Pugh class A, B, or C), the manufacturer recommends the following initial doses based on indication for use and BSA group:
Newly Diagnosed Ph+ Chronic Phase CML
For adult patients with creatinine clearance 30-50 mL/minute, the recommended dosage of bosutinib is 300 mg daily.1
For adult patients with creatinine clearance <30 mL/minute, the recommended dosage of bosutinib is 200 mg daily.1
For pediatric patients with newly diagnosed chronic phase Ph+ CML and renal impairment, dosage adjustments are presented in Table 3.
BSA Band (m2) | Creatinine Clearance: 30-50 mL/min | Creatinine Clearance: <30 mL/min |
|---|---|---|
<0.55 | 100 mg once daily | 100 mg once daily |
0.55 to <0.63 | 150 mg once daily | 100 mg once daily |
0.63 to <0.75 | 150 mg once daily | 100 mg once daily |
0.75 to <0.9 | 200 mg once daily | 150 mg once daily |
0.9 to <1.1 | 200 mg once daily | 200 mg once daily |
≥1.1 | 300 mg once daily | 200 mg once daily |
Chronic, Accelerated, or Blast Phase Ph+ CML Following Prior Treatment Failure
For adult patients with creatinine clearance 30-50 mL/minute, the recommended dosage of bosutinib is 400 mg daily.1
For adult patients with creatinine clearance <30 mL/minute, the recommended dosage of bosutinib is 300 mg daily.1
For pediatric patients with chronic phase Ph+CML following prior treatment failure and renal impairment, dosage adjustments are presented in Table 4.
BSA Band (m2) | Creatinine Clearance: 30-50 mL/min | Creatinine Clearance: <30 mL/min |
|---|---|---|
<0.55 | 150 mg once daily | 100 mg once daily |
0.55 to <0.63 | 200 mg once daily | 150 mg once daily |
0.63 to <0.75 | 200 mg once daily | 200 mg once daily |
0.75 to <0.9 | 250 mg once daily | 200 mg once daily |
0.9 to <1.1 | 300 mg once daily | 250 mg once daily |
≥1.1 | 400 mg once daily | 300 mg once daily |
Bosutinib has not been studied in adult or pediatric patients receiving hemodialysis.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Nausea, vomiting, abdominal pain, and diarrhea occur frequently in patients receiving bosutinib.1 In a randomized clinical trial in adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), the median time to onset of diarrhea was 4 days and the median duration of each episode of diarrhea was 3 days.1 In a single-arm study of adult patients with CML who were resistant or intolerant to prior therapy, the median time to onset of diarrhea was 2 days and the median duration of each episode of diarrhea was 2 days.1 Among patients who experienced diarrhea, the median number of episodes of diarrhea per patient during therapy with bosutinib was 3 (range: 1-268 episodes).1
Among pediatric patients with newly-diagnosed chronic phase Ph+ CML or who had chronic phase Ph+ CML with prior treatment failure, the median time to onset for diarrhea (all grades) was 2 days and the duration was 2 days.1 For those who experienced diarrhea, the median number of episodes per patient during treatment with bosutinib was 2 (range, 1 to 198).1
Monitor patients for GI adverse effects and treat as clinically indicated with appropriate therapy (e.g., antidiarrheal, antiemetic, fluid replacement).1 Temporary interruption, dosage reduction, or discontinuance of bosutinib may be necessary if GI toxicity occurs during therapy with the drug.1
Cytopenias, including thrombocytopenia, anemia, and neutropenia, have been reported in patients receiving bosutinib.1, 7 Complete blood cell (CBC) counts should be monitored weekly for the first month of therapy and monthly thereafter, or as clinically indicated.1
Temporary interruption, dosage reduction, or discontinuance of bosutinib may be necessary if myelosuppression occurs during therapy with the drug.1
Elevations in aminotransferase (ALT or AST) concentrations have occurred in patients receiving bosutinib.1
In clinical trials, 2 of 1711 bosutinib-treated adult patients developed drug-induced hepatic injury without other etiology.1 In a randomized clinical trial evaluating adult patients with newly diagnosed CML, increased serum ALT and AST concentrations occurred in 68.3 and 56% of patients, respectively; increased aminotransferase concentrations occurred within the first 3 months of bosutinib therapy in 73% of these patients.1 The median time to onset of increased ALT and AST concentrations was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively.1 In a single-arm study evaluating bosutinib in adult patients with CML who were resistant or intolerant to prior therapy, ALT and AST elevations occurred in 53.3 and 46.7% of patients, respectively; increased aminotransferase concentrations occurred within the first 3 months of bosutinib therapy in 81% of these patients.1 The median time to onset of increased ALT and AST concentrations was 22 and 29 days, respectively, and the median duration was 21 days for both ALT and AST elevations.1
Among pediatric patients with newly diagnosed chronic phase Ph+ CML or who had chronic phase Ph+ CML with prior treatment failure, the incidence of increased ALT and AST from baseline was 59% and 51%, respectively.1 Most cases of increased transaminases occurred early in treatment; 84% of patients experienced initial increases within the first 3 months of treatment.1 The median time to onset for increased ALT and AST was 22 and 15 days, respectively.1 The median duration for grade 3 or 4 increased ALT or AST was 26 and 12 days, respectively.1
Liver function tests should be monitored monthly for the first 3 months of therapy and then as clinically indicated.1 More frequent monitoring is recommended if elevations in aminotransferase concentrations occur.1 Temporary interruption, dosage reduction, or discontinuance of bosutinib may be necessary if hepatic toxicity occurs during therapy with the drug.1
Cardiovascular toxicity, including cardiac failure, left ventricular dysfunction, and cardiac ischemic events, has been reported with bosutinib.1 In a randomized study of adult patients with newly diagnosed CML, cardiac failure occurred in 1.9% of patients receiving bosutinib and 0.8% of patients receiving imatinib.1 Cardiac ischemic events occurred in 4.9 and 0.8% of bosutinib- and imatinib-treated patients, respectively.1 In a single-arm study of patients with CML who were resistant or intolerant to prior therapy, rates of cardiac failure and cardiac ischemic events were 5.3 and 4.9%, respectively.1
Cardiac failure occurred more frequently in adult patients with previously treated CML and in those with advanced age or risk factors for cardiac failure (e.g., previous history of cardiac failure).1 Cardiac ischemic events were more common in patients with risk factors for coronary artery disease (e.g., history of diabetes mellitus, body mass index >30 kg/m2, hypertension, vascular disorders).1
Among pediatric patients with newly diagnosed chronic phase Ph+ CML or who had chronic phase Ph+ CML with prior treatment failure, 4 (8%) patients had grade 1-2 cardiac events, including tachycardia (n=2), angina pectoris, right bundle branch block, and sinus tachycardia (n=1 each).1
Monitor patients for signs and symptoms of cardiac failure and cardiac ischemia and treat as clinically indicated.1 Temporary interruption of therapy, dosage reduction, or discontinuance of bosutinib may be necessary if cardiovascular toxicity occurs during therapy.1
Fluid retention has occurred in patients receiving bosutinib and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema.1 In a randomized trial evaluating bosutinib in 268 adult patients with newly diagnosed CML, 1.1% of patients experienced grade 3 fluid retention, 1 patient experienced grade 3 pericardial effusion, and 2 patients experienced grade 3 pleural effusion.1 In a single-arm study of 546 adult patients with CML who were resistant or intolerant to prior therapy, grade 3 or 4 fluid retention was reported in 6% of patients.1 Some patients experienced more than 1 fluid retention event; 24 patients had grade 3 or 4 pleural effusions, 9 patients had grade 3 or 4 pericardial effusions, and 6 patients had grade 3 edema.1
Among pediatric patients with newly diagnosed chronic phase Ph+ CML or who had chronic phase Ph+ CML with prior treatment failure, grade 1-2 pericardial effusion, peripheral edema, and face edema were seen in 1 patient each.1
If fluid retention occurs, patients should be monitored and managed according to current standards of care.1 Temporary interruption, dosage reduction, or discontinuance of bosutinib therapy may be necessary.1
Renal impairment has been reported during bosutinib therapy.1 In patients with normal baseline renal function who received bosutinib therapy for a median duration of 24 months, mild, mild to moderate, moderate to severe, or severe renal impairment occurred in 62.6, 9.5, 4.4, or 0.6% of patients, respectively; kidney failure was reported in 0.9% of bosutinib-treated patients.1 In patients with mild renal impairment at baseline who received bosutinib therapy for a median duration of 24 months, mild to moderate, moderate to severe, or severe renal impairment occurred in 40.3, 14.3, or 3.9% of patients, respectively; kidney failure was reported in 0.9% of bosutinib-treated patients.1 In patients with mild to moderate renal impairment at baseline who received bosutinib therapy for a median duration of 24 months, moderate to severe or severe renal impairment occurred in 48.2 or 17.5% of patients, respectively; kidney failure was reported in 0.7% of bosutinib-treated patients.1 In patients with moderate to severe renal dysfunction at baseline who received bosutinib therapy for a median duration of 24 months, severe renal dysfunction occurred in 57.6% of patients and kidney failure occurred in 12.1% of patients.1
Among pediatric patients with a normal estimated glomerular filtration rate (eGFR) at baseline and newly diagnosed chronic phase Ph+ CML or chronic phase Ph+ CML with prior treatment failure, 45% shifted to a maximum of mild renal impairment, and 40% of patients who had mild eGFR at baseline shifted to a maximum of moderate renal impairment during treatment.1
Monitor renal function at baseline and during therapy with bosutinib; patients with preexisting renal impairment or risk factors for renal impairment should be monitored more closely.1 Consider dosage adjustment in patients with baseline and/or drug-induced renal impairment.1
Fetal/Neonatal Morbidity and Mortality
Bosutinib may cause fetal harm when administered to pregnant patients; there are no available data in pregnant patients to inform the drug-associated risk, but bosutinib was associated with structural abnormalities, embryofetal mortality, and alterations in growth when administered to pregnant rats and rabbits during the period of organogenesis.1 Pregnancy should be avoided during therapy.1 If used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Based on findings from animal studies and its mechanism of action, bosutinib may cause fetal harm when administered to a pregnant patient.1 If used during pregnancy or if the patient becomes pregnant while receiving the drug, inform the patient of the potential fetal hazard.1
No data are available regarding the presence of bosutinib or its metabolites in human milk, its effects on a breast-fed child, or its effects on milk production.1 However, bosutinib is present in the milk of lactating rats.1 Breast-feeding during bosutinib treatment is not recommended due to the potential for serious adverse reactions; breast-feeding should be avoided during bosutinib therapy and for 2 weeks following the last bosutinib dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to starting bosutinib therapy.1 Advise females of reproductive potential to use effective contraception during bosutinib therapy and for 2 weeks following the last dose of the drug.1
Safety and efficacy of bosutinib in pediatric patients ≥1 year of age with newly diagnosed chronic phase Ph+ CML or who had chronic phase Ph+ CML with prior treatment failure has been established.1 .1 Use of bosutinib for these indications is based on data from a clinical study that included pediatric patients with newly diagnosed chronic phase Ph+ CML in the following age groups: 1 to <6 years of age (2 patients), 6 to <12 years of age (3 patients), and 12 to <17 years of age (10 patients).1 The study also included pediatric patients with chronic phase Ph+ CML with prior treatment failure in the following age groups: 1 to <6 years of age (4 patients), 6 to <12 years of age (10 patients), and 12 to <17 years of age (10 patients).
In clinical trials evaluating bosutinib in patients with Ph+ CML who were resistant or intolerant to prior therapy, 20% of patients were ≥65 years of age and 4% were ≥75 years of age.1 In clinical trials evaluating bosutinib for newly diagnosed CML, 20% of patients were ≥65 years of age and 5% were ≥75 years of age.1 No overall differences in safety or efficacy were observed between geriatric and younger adults.1 However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.1
Following oral administration of a single 200-mg dose of bosutinib with food, peak plasma concentrations of bosutinib were increased by 2.4-, 2-, or 1.5-fold in patients with preexisting mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, respectively, compared with healthy individuals with normal hepatic function.1, 3 In the same study, systemic exposure of bosutinib was increased by 2.3-, 2-, and 1.9-fold, respectively.1, 3 Systemic exposure following administration of bosutinib 200 mg daily in patients with hepatic impairment is expected to be similar to that observed in those with normal hepatic function receiving bosutinib 500 mg once daily; however, efficacy of bosutinib 200 mg once daily in patients with hepatic impairment and CML is unknown.1 In addition, the elimination half-life of bosutinib was prolonged in patients with preexisting mild to severe hepatic impairment compared with healthy individuals with normal hepatic function.3 The incidence of QT interval prolongation (i.e., QT interval corrected for rate [QTc] exceeding 450 msec or increased by more than 30 msec compared with baseline) increased with declining hepatic function; QTc interval prolongation was observed in all patients with severe (Child-Pugh class C) hepatic impairment enrolled in the study.3 Dosage adjustment is required in patients with preexisting mild, moderate, or severe hepatic impairment.1
Following oral administration of a single 200-mg dose of bosutinib with food, systemic exposure of bosutinib was increased by 1.4- or 1.6-fold in patients with preexisting moderate (creatinine clearance 30-50 mL/minute) or severe (creatinine clearance less than 30 mL/minute) renal impairment, respectively, compared with healthy individuals with normal renal function.1 Systemic exposure of bosutinib was not affected by mild (creatinine clearance 51-80 mL/minute) renal impairment.1 Bosutinib has not been studied in patients receiving hemodialysis.1 Dosage adjustment is required in patients with preexisting moderate or severe renal impairment.1
Adverse effects reported in 20% or more of adult and pediatric patients receiving bosutinib include diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, respiratory tract infection, and constipation.1
Laboratory abnormalities reported in 20% or more of adult and pediatric patients receiving bosutinib include increased serum creatinine 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, and increased amylase concentrations.1
Bosutinib is principally metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1
Bosutinib may inhibit breast cancer resistance protein (BRCP) in the GI tract but has a low potential to inhibit BRCP systemically.1 Bosutinib is also 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.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Concomitant use of bosutinib with moderate or potent inhibitors of CYP3A may result in increased systemic exposure of bosutinib and possible bosutinib toxicity.1, 4 When the potent CYP3A inhibitor ketoconazole (400 mg once daily for 5 days) was administered concomitantly with bosutinib (single 100-mg dose) under fasting conditions, peak plasma concentrations and systemic exposure of bosutinib were increased 5.2- and 8.6-fold, respectively;1, 4 however, in another study, adverse effects generally were mild in severity when a single bosutinib dose ranging from 100-600 mg was administered with ketoconazole (400 mg once daily for 5 days).5 When bosutinib (single 500-mg dose) was administered concomitantly with the moderate CYP3A inhibitor aprepitant (125 mg with food), aprepitant increased peak plasma concentrations and systemic exposure of bosutinib by 1.5- and 2-fold, respectively.1
Concomitant use of bosutinib with moderate or potent inhibitors of CYP3A should be avoided.1
Concomitant use of bosutinib with potent inducers of CYP3A may decrease bosutinib exposure.1 When the potent CYP3A inducer rifampin (600 mg once daily) was administered concomitantly with bosutinib (single 500-mg dose) with meals, peak plasma concentrations and systemic exposure of bosutinib were decreased by 86 and 94%, respectively.1
Concomitant use of bosutinib with potent inducers of CYP3A should be avoided.1
Substrates of P-glycoprotein Transport Systems
When a single 500-mg dose of bosutinib was administered concomitantly with the P-glycoprotein (P-gp) substrate dabigatran etexilate mesylate (150-mg dose), no clinically significant difference in dabigatran pharmacokinetics was observed.1
Drugs that Prolong the QT Interval
When bosutinib (single 500-mg dose) was administered concomitantly with ketoconazole, clinically important changes in the QTc interval were not observed.1
When bosutinib (single 400-mg dose) was administered in combination with lansoprazole (multiple 60-mg doses) under fasting conditions, peak plasma concentrations and AUC of bosutinib were reduced by 46 and 26%, respectively.1 Concomitant use of bosutinib and proton-pump inhibitors is not recommended.1 Instead, use of histamine H2-receptor antagonists or short-acting antacids, administered at least 2 hours before or after a dose of bosutinib, should be considered.1
Bosutinib, an inhibitor of multiple tyrosine kinases (including Bcr-Abl and the Src family [Src, Lyn, Hck]), is an antineoplastic agent;1, 7, 8 the drug has minimal inhibitory activity against c-Kit or platelet-derived growth factor (PDGF)-β.8, 15, 16, 17, 18
The Philadelphia chromosome, characteristic of chronic myelogenous leukemia (CML), is created by a reciprocal translocation between chromosomes 9 and 22.9, 10, 11, 12, 13 Translocation between these chromosomes results in production of an abnormal protein (Bcr-Abl tyrosine kinase) that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues);9, 10, 13 phosphorylation of tyrosine residues on growth factor receptors is thought to be important in stimulating cell proliferation and inhibiting cell death (apoptosis).10, 15 Bosutinib competitively and selectively inhibits Bcr-Abl tyrosine kinase, thereby inhibiting tyrosine phosphorylation of proteins involved in Bcr-Abl signal transduction.8, 15, 16 In vitro studies show the drug inhibits the growth of leukemic cell lines expressing Bcr-Abl.16
Clinical resistance to imatinib in CML has been attributed to several mechanisms, but point mutations in the Bcr-Abl kinase domain appear to be the most common, occurring in 30-90% of patients who develop resistance.22 In preclinical studies in cell-line models, bosutinib inhibited most (16 of 18) imatinib-resistant Bcr-Abl kinase domain mutant forms except for T315I and V299L mutant cells.1, 15, 16 Data from preclinical and clinical studies also implicate signaling pathways involving the Src family kinases (Lyn, Hck) in imatinib resistance.14, 20
Bosutinib is 94-96% bound to plasma proteins in vitro.1 In a dose escalation study, bosutinib exhibited linear and dose proportional pharmacokinetics under fed conditions;8 AUC and peak plasma concentrations of the drug are dose proportional over the bosutinib dosage range of 200-800 mg.1 The median time to peak plasma concentrations of bosutinib is 6 hours, and the absolute bioavailability of the drug is 34%.1 Administration of bosutinib tablets with a high-fat meal resulted in increases in systemic exposure and peak plasma concentrations of 1.7- and 1.8-fold, respectively.1 No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet or capsule dosage forms at the same dose, under fed conditions.1 Bosutinib is extensively metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by the isoenzyme 3A4 to inactive metabolites.1 Following administration of a single radiolabeled dose of bosutinib, 91.3% of the dose was recovered in feces and 3.3% was recovered in urine.1 Following administration of single 500-mg doses of bosutinib with food, the elimination half-life of bosutinib was 22.5 hours.1 No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of bosutinib capsule that was opened and the contents mixed with applesauce or yogurt immediately before use.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Pfizer. Bosulif® (bosutinib) tablets prescribing information. New York, NY; 2023 Sep. [Web]
2. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 203341: Medical review(s). 2012 Jul 20. From FDA website. [Web]
3. Abbas R, Chalon S, Leister C et al. Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol . 2013; 71:123-32. [PubMed 23053269]
4. Abbas R, Hug BA, Leister C et al. Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy subjects. J Clin Pharmacol . 2011; 51:1721-7. [PubMed 21148045]
5. Abbas R, Leister C, El Gaaloul M et al. Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects. Clin Ther . 2012; 34:2011-9.e1. [PubMed 22884766]
6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P. L. 97-414). Rockville, MD. From FDA website. [Web]
7. Cortes JE, Kantarjian HM, Brümmendorf TH et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood . 2011; 118:4567-76. [PubMed 21865346]
8. Abbas R, Hug BA, Leister C et al. A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol . 2012; 69:221-7. [PubMed 21691746]
9. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Investig . 2000; 105:3-7. [PubMed 10619854]
10. Kiel PJ, Grove M. Chronic leukemias. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: a pathophysiologic approach. 11th ed. McGraw Hill; 2020. Accessed 2022 March 23.
11. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med . 2001; 344:1031-7. [PubMed 11287972]
12. Anon. Gleevec (STI-571) for chronic myeloid leukemia. Med Lett Drugs Ther . 2001; 43:49-50. [PubMed 11402258]
13. Weisberg E, Griffin J. Mechanisms of resistance imatinib (STI-571) in preclinical models and in leukemia patients. Drug Resistance Updates . 2001; 4:22-8. [PubMed 11512149]
14. Donato NJ, Wu JY, Stapley J et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood . 2003; 101:690-8. [PubMed 12509383]
15. Boschelli F, Arndt K, Gambacorti-Passerini C. Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia. Eur J Cancer . 2010; 46:1781-9. [PubMed 20399641]
16. Keller-V Amsberg G, Brümmendorf TH. Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia. Expert Rev Anticancer Ther . 2012; 12:1121-7. [PubMed 23098112]
17. Remsing Rix LL, Rix U, Colinge J et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia . 2009; 23:477-85. [PubMed 19039322]
18. Khoury HJ, Cortes JE, Kantarjian HM et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood . 2012; 119:3403-12. [PubMed 22371878]
19. Pfizer Inc. New York, NY: Personal communication.
20. Li S. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma . 2008; 49:19-26. [PubMed 18203007]
22. Cortes J, Jabbour E, Kantarjian H et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood . 2007; 110:4005-11. [PubMed 17785585]
23. Cortes JE, Gambacorti-Passerini C, Deininger MW et al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol . 2018; 36:231-237. [PubMed 29091516]
24. Gambacorti-Passerini C, Cortes JE, Lipton JH et al. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica . 2018; 103:1298-1307. [PubMed 29773593]
25. Cortes JE, Khoury HJ, Kantarjian HM et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol . 2016; 91:1206-1214. [PubMed 27531525]
26. Gambacorti-Passerini C, Kantarjian HM, Kim DW et al. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol . 2015; 90:755-68. [PubMed 26040495]
27. Hochhaus A, Gambacorti-Passerini C, Abboud C et al. Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study. Leukemia . 2020; 34:2125-2137. [PubMed 32572189]
35. Hochhaus A, Baccarini M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966-84.