Version May 2024
Note: Bosutinib is associated with a moderate or high emetic potential (Ref); nausea and vomiting may be managed with antiemetics and fluid replacement.
Chronic myeloid leukemia, Philadelphia chromosome-positive, chronic phase, newly diagnosed: Oral: 400 mg once daily; continue until disease progression or unacceptable toxicity (Ref).
Dose escalation : In clinical studies, dose escalation in increments of 100 mg once daily (to a maximum of 600 mg once daily) was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response (in the absence of ≥ grade 3 adverse reactions).
Chronic myeloid leukemia, Philadelphia chromosome-positive, chronic, accelerated, or blast phase, resistant or intolerant to prior therapy: Oral: 500 mg once daily; continue until disease progression or unacceptable toxicity (Ref).
Dose escalation : In clinical studies, dose escalation in increments of 100 mg once daily (to a maximum of 600 mg once daily) was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response (in the absence of ≥ grade 3 adverse reactions).
Missed doses: If a dose is missed beyond 12 hours, skip the dose and resume the usual dose the following day. If entire dose/contents of capsules prepared in applesauce or yogurt is not consumed, do not administer an additional dose; wait until the next day to resume dosing.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: Kidney function estimated using the Cockcroft-Gault equation.
Kidney impairment prior to treatment initiation:
Chronic myeloid leukemia, chronic phase, newly diagnosed:
CrCl >50 to 80 mL/minute: There are no dosage adjustments provided in manufacturer's labeling; however, no clinically significant effect on bosutinib pharmacokinetics was observed in mild kidney dysfunction.
CrCl 30 to 50 mL/minute: Reduce dose to 300 mg once daily.
CrCl <30 mL/minute: Reduce dose to 200 mg once daily.
Chronic myeloid leukemia, chronic, accelerated, or blast phase, resistant or intolerant to prior therapy:
CrCl >50 to 80 mL/minute: There are no dosage adjustments provided in manufacturer's labeling; however, no clinically significant effect on bosutinib pharmacokinetics was observed in mild kidney dysfunction.
CrCl 30 to 50 mL/minute: Reduce dose to 400 mg once daily.
CrCl <30 mL/minute: Reduce dose to 300 mg once daily.
Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Kidney toxicity during treatment: If declining kidney function occurs, reduce dose per adjustment recommendations for toxicity (withhold bosutinib until resolved, then consider resuming with the daily dose reduced by 100 mg; if clinically appropriate, may re-escalate dose to the starting dose).
Chronic myeloid leukemia, newly diagnosed (chronic phase) or resistant/intolerant to prior therapy (chronic, accelerated, or blast phase):
Hepatic impairment prior to treatment initiation:
Child-Turcotte-Pugh class A, B, or C: Reduce initial dose to 200 mg once daily.
Acute hepatotoxicity during treatment:
ALT or AST >5 times ULN: Withhold bosutinib 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.
Chronic myeloid leukemia, newly diagnosed (chronic phase) or resistant/intolerant to prior therapy (chronic, accelerated, or blast phase):
|
Adverse reaction |
Severity |
Bosutinib dosage modification |
|---|---|---|
|
a ASCO (Armenian 2017); ESC (Lyon 2022). | ||
|
Hematologic toxicity | ||
|
Neutropenia |
ANC <1,000/mm3 |
Withhold bosutinib until ANC ≥1,000/mm3. ANC recovery to ≥1,000/mm3 within 2 weeks following interruption: Resume bosutinib at same dose. ANC recovery to ≥1,000/mm3 after more than 2 weeks following interruption: Upon recovery, resume bosutinib with the daily dose reduced by 100 mg. Recurrent neutropenia (ANC <1,000/mm3): Withhold bosutinib until ANC ≥1,000/mm3. Upon recovery, resume bosutinib with the daily dose reduced by an additional 100 mg. |
|
Thrombocytopenia |
Platelets <50,000/mm3 |
Withhold bosutinib until platelets ≥50,000/mm3. Platelet recovery to ≥50,000/mm3 within 2 weeks following interruption: Resume bosutinib at same dose. Platelet recovery to ≥50,000/mm3 after more than 2 weeks following interruption: Upon recovery, resume bosutinib with the daily dose reduced by 100 mg. Recurrent thrombocytopenia (platelets <50,000/mm3): Withhold bosutinib until platelets ≥50,000/mm3. Upon recovery, resume bosutinib with the daily dose reduced by an additional 100 mg. |
|
Nonhematologic toxicity | ||
|
Diarrhea |
Grade 3 to 4 (≥7 stools/day increase over baseline/pretreatment) |
Manage with antidiarrheals and fluid replacement as clinically necessary. Withhold bosutinib until recovery to ≤ grade 1; may resume at 400 mg once daily. |
|
Hypertension |
Any (clinically significant) |
If indicated, initiate appropriate antihypertensive therapy to reduce the risk for cardiovascular complications.a |
|
Other treatment-related adverse events |
Moderate to severe |
Withhold bosutinib until resolved; consider resuming with the daily dose reduced by 100 mg; may re-escalate dose to the starting dose if clinically appropriate. Doses <300 mg daily have been used; however, efficacy has not been established. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults unless otherwise indicated.
>10%:
Cardiovascular: Chest pain (8% to 12%), edema (15% to 19%), hypertension (8% to 11%)
Dermatologic: Pruritus (7% to 12%), skin rash (children, adolescents, and adults: 40% to 49%, including drug reaction with eosinophilia and systemic symptoms, exfoliative dermatitis, fixed drug eruption, maculopapular rash)
Endocrine & metabolic: Decreased serum calcium (children and adolescents: 31%; adults: 45% to 55%), decreased serum phosphate (33% to 54%), decreased serum potassium (22% to 29%), decreased serum sodium (18% to 27%), hypermagnesemia (18% to 27%), increased serum glucose (children and adolescents: 41%; adults: 39% to 57%), increased serum potassium (19% to 25%), increased serum sodium (11% to 23%), increased uric acid (43% to 49%)
Gastrointestinal: Abdominal pain (children and adolescents: 73%; adults: 36% to 49%), constipation (children, adolescents, and adults: 13% to 20%), decreased appetite (children and adolescents: 27%; adults: 11% to 14%), diarrhea (children, adolescents, and adults: 75% to 85%, grades 3/4: 4% to 12%), increased serum amylase (children, adolescents, and adults: 27% to 32%), increased serum lipase (19% to 53%), nausea (children, adolescents, and adults: 37% to 49%, grades 3/4: 1% to 2%), vomiting (children and adolescents: 55%, grades 3/4: 6%; adults: 21% to 43%, grades 3/4: 1% to 3%)
Hematologic & oncologic: Decrease in absolute neutrophil count (42% to 66%, grades 3/4: 9% to 39%), decreased hemoglobin (children and adolescents: 31%, grades 3/4: 8%; adults: 89% to 97%, grades 3/4: 9% to 38%), decreased neutrophils (children and adolescents: 31%, grades 3/4: 12%), decreased platelet count (children and adolescents: 49%, grades 3/4: 18%; adults: 66% to 80%, grades 3/4: 14% to 57%), decreased white blood cell count (children, adolescents, and adults: 50% to 57%, grades 3/4: 4% to 27%), lymphocytopenia (children and adolescents: 29%, grades 3/4: 2%; adults: 79% to 84%, grades 3/4: 12% to 21%)
Hepatic: Hepatic impairment (children, adolescents, and adults: 21% to 45%), increased serum alanine aminotransferase (children, adolescents, and adults: 39% to 68%), increased serum alkaline phosphatase (39% to 41%), increased serum aspartate aminotransferase (children, adolescents, and adults: 37% to 56%), increased serum bilirubin (16% to 22%)
Infection: Influenza (3% to 11%)
Nervous system: Dizziness (11% to 14%), fatigue (children, adolescents, and adults: 27% to 37%, including asthenia), headache (children and adolescents: 35%; adults: 18% to 22%)
Neuromuscular & skeletal: Arthralgia (15% to 19%), back pain (8% to 14%), increased creatine phosphokinase in blood specimen (children and adolescents: 25%; adults: 36%)
Renal: Increased serum creatinine (children, adolescents, and adults: 87% to 95%)
Respiratory: Cough (11% to 24%), dyspnea (11% to 20%), pleural effusion (9% to 14%), pneumonia (10% to 18%), respiratory tract infection (children and adolescents: 12%; adults: 17% to 27%)
Miscellaneous: Fever (children, adolescents, and adults: 17% to 37%)
1% to 10%:
Cardiovascular: Angina pectoris (children and adolescents: 2%), coronary artery disease (serious: 3% to 4%), heart failure (2% to 5%), ischemic heart disease (5%), pericardial effusion (children and adolescents: grades 1/2: 2%; adults: grades 3/4: ≤4%), peripheral edema (children and adolescents: 2%), prolonged QT interval on ECG, right bundle branch block (children and adolescents: 2%), sinus tachycardia (children and adolescents: 2%), tachycardia (children and adolescents: 4%)
Endocrine & metabolic: Dehydration, fluid retention (grades 3/4: 1% to 6%), hypothyroidism
Gastrointestinal: Dysgeusia, gastritis, gastroenteritis (serious: 2%), gastrointestinal hemorrhage (including anal hemorrhage, rectal hemorrhage), pancreatitis (including acute pancreatitis, chronic pancreatitis, edematous pancreatitis, increased pancreatic enzymes)
Hypersensitivity: Facial edema (children and adolescents: 2%), hypersensitivity reaction
Nervous system: Pain
Neuromuscular & skeletal: Myalgia
Otic: Tinnitus
Renal: Acute kidney injury, kidney failure, kidney impairment
Respiratory: Bronchitis, pulmonary hypertension
<1%:
Cardiovascular: Pericarditis
Dermatologic: Erythema multiforme
Endocrine & metabolic: Hyperthyroidism
Hematologic & oncologic: Febrile neutropenia
Hypersensitivity: Anaphylactic shock
Respiratory: Acute pulmonary edema, interstitial lung disease, respiratory failure
Frequency not defined (any population):
Cardiovascular: Left ventricular dysfunction
Renal: Decreased estimated GFR (eGFR)
Respiratory: Pulmonary edema
Postmarketing (any population):
Dermatologic: Stevens-Johnson syndrome (Avila-Castano 2022)
Hematologic & oncologic: Thrombotic microangiopathy
Hypersensitivity to bosutinib or any component of the formulation.
Canadian labeling: Additional contraindications (not in the US labeling): History of long QT syndrome or with persistent QT interval >480 milliseconds; uncorrected hypokalemia or hypomagnesemia; hepatic impairment.
Concerns related to adverse effects:
• Bone marrow suppression: Anemia, neutropenia, and thrombocytopenia may occur.
• Cardiovascular toxicity: Bosutinib may cause cardiovascular toxicity, such as cardiac failure, left ventricular dysfunction, and cardiac ischemic events. Cardiac failure events occurred more commonly in previously treated patients versus those with newly diagnosed chronic myeloid leukemia (CML); events were also more frequent in patients with advanced age or risk factors (including a past medical history of cardiac failure). Cardiac ischemic events occurred more frequently in patients with coronary artery disease risk factors, including a history of diabetes, BMI >30, hypertension, and vascular disorders.
• Fluid retention/edema: Fluid retention, manifesting as pericardial effusion, pleural effusion, pulmonary edema and/or peripheral edema may occur; may be severe.
• GI toxicity: Diarrhea, nausea, vomiting, and abdominal pain may occur. For patients experiencing diarrhea (all grades), the median time to onset in patients with CML resistant or intolerant to prior therapy was 2 days; median duration (per event) was 2 days and the median number of diarrhea episodes per patient was 3 (range: 1 to 268). Similarly, the median time to onset for diarrhea (all grades) in patients with newly diagnosed CML was 4 days; the median duration per events was 3 days. GI hemorrhages have also been reported.
• Hepatotoxicity: Serum transaminase (ALT and/or AST) elevations have been reported. In patients with transaminase elevation, ~70% to 80% developed the transaminase elevation within the first 3 months of therapy. In a clinical study in patients with newly diagnosed chronic phase CML, the median time to onset of elevated ALT and AST was 29 and 56 days, respectively; the median duration was 19 and 15 days, respectively. In patients with CML resistant or intolerant to prior therapy, the mediation time to onset of ALT and AST elevation was 22 and 29 days, respectively, and the median duration (for each) was 21 days. Rare cases of drug-induced liver injury (without alternative etiologies) have been reported.
• Hypersensitivity: Hypersensitivity reactions have been reported, including anaphylaxis and anaphylactic shock (rare).
• Kidney toxicity: Declines in GFR throughout bosutinib treatment have been observed in clinical studies.
• QT prolongation: QTcF >500 milliseconds was observed rarely in clinical trials (Cortes 2012); patients with significant or uncontrolled cardiovascular disease (including prolonged QT interval at baseline) were not studied.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Bosulif: 50 mg, 100 mg
Tablet, Oral:
Bosulif: 100 mg, 400 mg, 500 mg
No
Capsules (Bosulif Oral)
50 mg (per each): $200.67
100 mg (per each): $200.67
Tablets (Bosulif Oral)
100 mg (per each): $200.67
400 mg (per each): $802.68
500 mg (per each): $802.68
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Bosulif: 100 mg, 500 mg
Bosutinib is associated with a moderate or high emetic potential (Ref); nausea and vomiting may be managed with antiemetics and hydration.
Oral:
Tablet: Administer with food. Swallow tablet whole; do not cut, crush, break, or chew.
Capsule: Administer with food; may be swallowed whole. For patients that are unable to swallow the whole capsule(s), the capsule may be opened, and the contents mixed with room temperature applesauce or yogurt (not a replacement for a full meal). Remove the required number of capsules from the container to prepare the dose; carefully open each capsule and add the entire content into the appropriate volume of applesauce or yogurt (which has been placed in a clean container) and mix. Immediately consume the full volume of the mixture; do not chew. Do not store mixture for later use; do not administer an additional dose if entire contents are not consumed.
|
Bosutinib dose |
Volume of applesauce or yogurt |
|---|---|
|
100 mg |
10 mL (2 teaspoons) |
|
200 mg |
20 mL (4 teaspoons) |
|
300 mg |
30 mL (6 teaspoons) |
|
400 mg |
35 mL (7 teaspoons) |
|
500 mg |
45 mL (9 teaspoons) |
|
600 mg |
50 mL (10 teaspoons) |
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Chronic myeloid leukemia:
Treatment of chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in adults and pediatric patients ≥1 year of age who are newly diagnosed or with resistance or intolerance to prior therapy.
Treatment of accelerated or blast phase Ph+ CML in adults with resistance or intolerance to prior therapy.
Bosutinib may be confused with bortezomib, bosentan, brigatinib, dasatinib, imatinib, nilotinib, PONATinib
This medication is in a class the Institute for Safe Medical Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Antacids: May decrease the serum concentration of Bosutinib. Management: Administer antacids more than 2 hours before or after bosutinib. Risk D: Consider therapy modification
Antithymocyte Globulin (Equine): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bitter Orange: May increase the serum concentration of Bosutinib. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Chikungunya Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Bosutinib. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Bosutinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Bosutinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Bosutinib. Risk X: Avoid combination
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Bosutinib. Management: Administer histamine H2 receptor antagonists (H2RAs) more than 2 hours before or after bosutinib. Risk D: Consider therapy modification
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease the serum concentration of Bosutinib. Management: Consider alternatives to proton pump inhibitors and potassium-competitive acid blockers, such as short-acting antacids or histamine-2 receptor antagonists. Administer alternative agents more than 2 hours before or after bosutinib. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Levoketoconazole: Bosutinib may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Mumps- Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Pomegranate: May increase the serum concentration of Bosutinib. Risk X: Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Star Fruit: May increase the serum concentration of Bosutinib. Risk X: Avoid combination
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Grapefruit juice may increase bosutinib plasma concentration. Management: Avoid grapefruit juice during bosutinib therapy.
Bosutinib Cmax and AUC increased by 1.8- and 1.7-fold, respectively, when bosutinib tablets were administered with a high-fat meal (800 to 1,000 calories with 150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories), compared to a fasted state. Bosutinib Cmax and AUC increased by 1.6- and 1.5-fold, respectively, when bosutinib capsules were administered with a high-fat meal, compared to a fasted state. Management: Administer with food.
Verify pregnancy status prior to initiating therapy in patients who could become pregnant. Patients who could become pregnant should use effective contraception (methods that result in <1% pregnancy rates) during bosutinib treatment and for 2 weeks after the last bosutinib dose.
Changes in menstrual patterns have been reported with tyrosine kinase inhibitor (TKI) therapy (Yu 2019).
Based on the mechanism of action, TKIs have the potential to adversely affect fertility by acting on receptors in the ovaries or testis; primarily when administered prior to puberty in males. Although there are cases showing difficulty conceiving, successful pregnancies have also been reported. Fertility data related to long term TKI use are limited. Recommendations are available for fertility preservation prior to TKI treatment (ASCO [Oktay 2018]; Madabhavi 2019; Rambhatla 2021).
Patients planning to become pregnant but currently receiving a TKI should minimize the risk of first trimester exposure (Rambhatla 2021). Discontinuing TKI therapy for chronic myeloid leukemia can be considered if the patient is eligible for a tumor-free remission, allowing a washout period before attempting to conceive (Baccarani 2019; ELN [Hochhaus 2020]; Madabhavi 2019). Because the time to conception can be highly variable, treatment may also be discontinued at the first positive pregnancy test, prior to organogenesis in select patients (Abruzzese 2020).
Outcome data following male use of bosutinib prior to conception are limited (Cortes 2020; Szakács 2020).
Outcome data following use of bosutinib during pregnancy are limited (Assi 2021; Cortes 2020). Based on data from animal reproduction studies and the mechanism of action, in utero exposure to bosutinib may cause fetal harm.
Treatment of chronic myeloid leukemia in pregnant patients should be individualized based on gestational age, hematologic parameters, and clinical condition at presentation. If pregnancy is detected in the first trimester in patients already on a tyrosine kinase inhibitor (TKI), treatment should be discontinued as soon as pregnancy is confirmed. Treatments other than a TKI are recommended in pregnant patients not eligible for a tumor-free remission. If a TKI is needed, use of agents other than bosutinib may be considered after the first trimester. Close maternal and fetal monitoring is recommended (Abruzzese 2020; BSH [Smith 2020]; ELN [Hochhaus 2020]; Madabhavi 2019).
The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team) approach (ESMO [Peccatori 2013]).
A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (877-635-4499).
It is not known if bosutinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 2 weeks after the last bosutinib dose. Patients diagnosed with chronic myeloid leukemia requiring a tyrosine kinase inhibitor may consider short-term breastfeeding for the first 2 to 5 days postpartum to provide the benefits of colostrum to the newborn prior to starting or restarting therapy (Abruzzese 2020; Madabhavi 2019).
CBC with differential (weekly during first month, then monthly thereafter, or as clinically indicated); hepatic enzymes (monthly for first 3 months and as clinically indicated; monitor more frequently with transaminase elevations); kidney function (at baseline and throughout therapy, particularly in patients with preexisting impairment or other risk factors for kidney dysfunction). Verify pregnancy status (prior to treatment initiation in patients who could become pregnant). Monitor for diarrhea episodes; fluid/edema status (eg, weight gain). Monitor for signs/symptoms of cardiac failure and cardiac ischemia. Monitor adherence.
Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking; repeat assessment every 3 months for the first year and then every 6 to 12 months thereafter (ASCO [Armenian 2017]; ESC [Lyon 2022]). ECG at baseline. Consider baseline echocardiography in all patients; repeat every 3 months for high- and very high-risk patients (ESC [Lyon 2022]).
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Bosutinib is a 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).
Onset:
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).
Absorption: Slow (Abbas 2012).
Distribution: Vd: 6,080 ± 1,230 L.
Protein binding: 94% to plasma proteins.
Metabolism: Hepatic via CYP3A4, primarily to inactive metabolites oxydechlorinated (M2) bosutinib and N-desmethylated (M5) bosutinib, also to bosutinib N-oxide (M6).
Bioavailability: 34% when administered with food.
Half-life elimination: 22.5 hours.
Time to peak: 6 hours (for a single 500 mg dose with food).
Excretion: Feces (~91%); urine (~3%).
Clearance (mean): 189 L/hour.
Altered kidney function: A single 200 mg dose was administered to subjects in a kidney impairment study; the AUC was increased 1.4-fold in patients with moderate impairment (CrCl 30 to 50 mL/minute) and 1.6-fold in patients with severe impairment (CrCl <30 mL/minute), compared to patients with normal kidney function.
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.
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