Bosutinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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Overview
Bosutinib is a {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Chronic myelogenous leukemia
BOSULIF is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.
Recommended Dosing
- The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food. Continue treatment with BOSULIF until disease progression or patient intolerance.
- If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day.
Dose Escalation
- Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily.
Dose Adjustments for Non-Hematologic Adverse Reactions
- Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy's law case definition), discontinue BOSULIF.
- Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold BOSULIF until recovery to Grade less than or equal to 1. BOSULIF may be resumed at 400 mg once daily.
- For other clinically significant, moderate or severe non-hematological toxicity, withhold BOSULIF until the toxicity has resolved, then consider resuming BOSULIF at 400 mg once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to 500 mg once daily.
Dose Adjustments for Myelosuppression
- Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1).
table02
Concomitant Use With CYP3A Inhibitors
- Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected (strong CYP3A inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan. Moderate CYP3A inhibitors include fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin).
Concomitant Use With CYP3A Inducers
- Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected (strong CYP3A inducers include rifampin, phenytoin, carbamazepine, St. John's Wort, rifabutin and phenobarbital. Moderate CYP3A inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine).
Hepatic Impairment
- In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of BOSULIF is 200 mg daily. A daily dose of 200 mg in patients with hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 200 mg once daily in patients with hepatic impairment and CML.
Renal Impairment
- In patients with pre-existing severe renal impairment (CLcr less than 30 mL/min), the recommended dose of BOSULIF is 300 mg daily. A daily dose of 300 mg in patients with severe renal impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal renal function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 300 mg once daily in patients with severe renal impairment and CML.
Off-Label Use and Dosage (Adult)
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bosutinib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Bosutinib in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
- Developed by:
- Class of Recommendation:
- Strength of Evidence:
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Bosutinib in pediatric patients.
Non–Guideline-Supported Use
Condition1
- Dosing Information
- Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Bosutinib in pediatric patients.
Contraindications
- Hypersensitivity to BOSULIF. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients.
Warnings
Gastrointestinal Toxicity
- Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. In the single-arm Phase 1/2 clinical trial, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 1 day. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1–221). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary. =====Myelosuppression=====
- Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Patients with CML who are receiving BOSULIF should have a complete blood count performed weekly for the first month and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary.
Hepatic Toxicity
- One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) occurred in a trial of BOSULIF in combination with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of 1209 patients in BOSULIF clinical trials.
- In the 546 patients from the safety population, the incidence of ALT elevation was 17% and AST elevation was 14 %. Twenty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 30 and 33 days, respectively, and the median duration for each was 21 days.
- Perform monthly hepatic enzyme tests for the first three months of treatment with BOSULIF and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary.
Fluid Retention
Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema.
- In the single-arm Phase 1/2 clinical trial in 546 patients with CML treated with prior therapy, severe fluid retention was reported in 14 patients (3%). Specifically, 9 patients had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4 pleural and pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary edema, and 1 patient had a Grade 3 edema.
- Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary.
Precautions
- Description
Adverse Reactions
Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Gastrointestinal toxicity.
- Myelosuppression.
- Hepatic toxicity.
- Fluid retention.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Serious adverse reactions reported include anaphylactic shock [see CONTRAINDICATIONS (4)], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.
- Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase 1/2 safety population (n=546) were diarrhea (82%), nausea (46%), thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia (26%), and fatigue (24%).
Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML
- The single-arm Phase 1/2 clinical trial enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients. Within the safety population there were 287 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 24 months, and a median dose intensity of 484 mg/day. There were 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg/day. There were 76 patients with AP CML, and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months and 3 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively.
- Table 2 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase 1/2 CML safety population.
table03
- In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
- Table 3 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population.
table04
Additional Data from Multiple Clinical Trials
- The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from 870 patients with Ph+ leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.
Blood and Lymphatic System Disorders
- 1% and less than 10% - febrile neutropenia
Cardiac Disorders
- 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis
Ear and Labyrinth Disorders
- 1% and less than 10% - tinnitus
Gastrointestinal Disorders
- 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis, gastrointestinal hemorrhage
General Disorders and Administrative Site Conditions
- 1% and less than 10% - chest pain, pain
Hepatobiliary Disorders
- 1% and less than 10% - hepatotoxicity, abnormal hepatic function; 0.1% and less than 1% - liver injury
Immune System Disorders
- 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock
Infections and Infestations
- 1% and less than 10% - pneumonia, influenza, bronchitis
Investigations
- 1% and less than 10% - electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinine
Metabolism and Nutrition Disorder
- 1% and less than 10% - hyperkalemia, dehydration
Musculoskeletal and Connective Tissue Disorder
- 1% and less than 10% - myalgia
Nervous System Disorders
- 1% and less than 10% - dysgeusia
Renal and Urinary Disorders
- 1% and less than 10% - acute renal failure, renal failure
Respiratory, Thoracic and Mediastinal Disorders
- 1% and less than 10% - pleural effusion; 0.1% and less than 1% - acute pulmonary edema, respiratory failure, pulmonary hypertension.
Skin and Subcutaneous Disorders
- 1% and less than 10% - urticaria, pruritus, acne; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption
1 Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage 2 Chest pain includes the following preferred terms: chest pain, chest discomfort 3 Hepatotoxicity includes the following preferred terms: hepatotoxicity, toxic hepatitis, cytolytic hepatitis 4 Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder 5 Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Bosutinib in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Drug Interactions
- Drug
- Description
Use in Specific Populations
Pregnancy
Embryofetal Toxicity
- There are no adequate and well controlled studies of BOSULIF in pregnant women. BOSULIF can cause fetal harm when administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg/day. Females of reproductive potential should be advised to avoid pregnancy while being treated with BOSULIF. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus'
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bosutinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Bosutinib during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Bosutinib with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Bosutinib with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Bosutinib with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Bosutinib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Bosutinib with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Bosutinib in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Bosutinib in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Bosutinib in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Bosutinib in patients who are immunocompromised.
Administration and Monitoring
Administration
- Oral
- Intravenous
Monitoring
There is limited information regarding Monitoring of Bosutinib in the drug label.
- Description
IV Compatibility
There is limited information regarding IV Compatibility of Bosutinib in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
- Description
Management
- Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Bosutinib in the drug label.
Pharmacology
There is limited information regarding Bosutinib Pharmacology in the drug label.
Mechanism of Action
Structure
This image is provided by the National Library of Medicine.
Pharmacodynamics
There is limited information regarding Pharmacodynamics of Bosutinib in the drug label.
Pharmacokinetics
There is limited information regarding Pharmacokinetics of Bosutinib in the drug label.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Bosutinib in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Bosutinib in the drug label.
How Supplied
Storage
There is limited information regarding Bosutinib Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Patient Counseling Information of Bosutinib in the drug label.
Precautions with Alcohol
- Alcohol-Bosutinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- ®[1]
Look-Alike Drug Names
- A® — B®[2]
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
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