Note: Bosutinib is associated with a moderate or high emetic potential (ASCO [Hesketh 2020]; MASCC/ESMO [Roila 2016]); 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 (Cortes 2018).
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 (Cortes 2011).
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Preexisting impairment:
Chronic myeloid leukemia, chronic phase, newly diagnosed:
CrCl >50 to 80 mL/minute: There are no dosage adjustments provided in manufacturer's labeling, however, based on the pharmacokinetics, exposure is not altered and the need for dosage adjustment is not likely.
CrCl 30 to 50 mL/minute: 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, based on the pharmacokinetics, exposure is not altered and the need for dosage adjustment is not likely.
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).
Renal toxicity during treatment: If unable to tolerate initial dose, 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):
Preexisting impairment (mild, moderate, or severe): Child-Pugh class A, B, or C: Reduce initial dose to 200 mg once daily (this dose is predicted to result in an AUC similar to that of patients with normal hepatic function; however, there is no efficacy data for this dose in patients with chronic myeloid leukemia with hepatic impairment).
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.
Refer to adult dosing.
Chronic myeloid leukemia, newly diagnosed (chronic phase) or resistant/intolerant to prior therapy (chronic, accelerated, or blast phase):
Hematologic toxicity: ANC <1,000/mm3 or platelets <50,000/mm3: Withhold bosutinib until ANC ≥1,000/mm3 and platelets ≥50,000/mm3; if recovery occurs within 2 weeks, resume bosutinib at the same dose. If ANC and platelets remain low for >2 weeks, upon recovery, resume bosutinib with the daily dose reduced by 100 mg. If cytopenia recurs, withhold until recovery and resume bosutinib with the daily dose reduced by an additional 100 mg. Doses <300 mg daily have been used; however, efficacy has not been established.
Nonhematologic toxicity:
Diarrhea: Grade 3 or 4 (≥7 stools/day increase over baseline/pretreatment): Withhold bosutinib until recovery to ≤ grade 1; may resume at 400 mg once daily. Manage with antidiarrheals and fluid replacement as clinically necessary.
Other clinically significant nonhematologic toxicity, moderate or severe: Withhold bosutinib until resolved, then 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Bosulif: 100 mg, 400 mg, 500 mg
No
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 (ASCO [Hesketh 2020]; MASCC/ESMO [Roila 2016]); nausea and vomiting may be managed with antiemetics and hydration.
Oral: Administer with food. Swallow tablet whole; do not cut, crush, or break.
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 newly diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in adults.
Treatment of chronic, 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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Chest pain (8% to 12%), edema (15% to 19%), hypertension (8% to 11%)
Dermatologic: Pruritus (7% to 12%), skin rash (40% to 48%, including drug reaction with eosinophilia and systemic symptoms, exfoliative dermatitis, fixed drug eruption)
Endocrine & metabolic: Decreased serum calcium (45% to 55%), decreased serum potassium (22% to 29%), decreased serum sodium (18% to 27%), hypermagnesemia (18% to 27%), hypophosphatemia (33% to 54%), increased serum glucose (39% to 57%), increased serum potassium (19% to 25%), increased serum sodium (11% to 23%), increased uric acid (43% to 49%)
Gastrointestinal: Abdominal pain (36% to 49%), constipation (13% to 17%), decreased appetite (11% to 14%), diarrhea (75% to 85%), increased serum amylase (32%), increased serum lipase (19% to 53%), nausea (37% to 48%), vomiting (21% to 43%)
Hematologic & oncologic: Anemia (89% to 97%; grades 3/4: 9% to 38%), leukopenia (50% to 57%; grades 3/4: 6% to 27%), lymphocytopenia (79% to 84%; grades 3/4: 12% to 21%), neutropenia (42% to 66%; grades 3/4: 9% to 39%), thrombocytopenia (66% to 80%; grades 3/4: 14% to 57%)
Hepatic: Hepatic insufficiency (21% to 45%, including hepatitis, hepatotoxicity), increased serum alanine aminotransferase (39% to 68%), increased serum alkaline phosphatase (39% to 41%), increased serum aspartate aminotransferase (37% to 56%), increased serum bilirubin (16% to 22%)
Infection: Influenza (3% to 11%)
Nervous system: Dizziness (11% to 14%), fatigue (27% to 35%, including asthenia), headache (18% to 22%)
Neuromuscular & skeletal: Arthralgia (15% to 19%), back pain (8% to 14%), increased creatine phosphokinase in blood specimen (36%)
Renal: Increased serum creatinine (87% to 95%)
Respiratory: Cough (11% to 24%), dyspnea (11% to 20%), pleural effusion (9% to 14%), pneumonia (3% to 18%), respiratory tract infection (17% to 27%, including nasopharyngitis)
Miscellaneous: Fever (17% to 37%)
1% to 10%:
Cardiovascular: Cardiac failure (2% to 5%), coronary artery disease (3%), pericardial effusion, prolonged QT interval on ECG
Endocrine & metabolic: Dehydration, fluid retention (grade 3/4: 1% to 6%), hypothyroidism
Gastrointestinal: Dysgeusia, gastritis, gastroenteritis (2%), gastrointestinal hemorrhage (including anal hemorrhage, rectal hemorrhage), pancreatitis (including edematous pancreatitis, increased pancreatic enzymes, acute pancreatitis, and chronic pancreatitis)
Hypersensitivity: Hypersensitivity reaction
Nervous system: Pain
Neuromuscular & skeletal: Myalgia
Otic: Tinnitus
Renal: Acute kidney injury, renal failure syndrome, renal insufficiency
Respiratory: Bronchitis, pulmonary hypertension
<1%:
Cardiovascular: Pericarditis
Dermatologic: Erythema multiforme
Endocrine & metabolic: Hyperthyroidism
Hematologic & oncologic: Febrile neutropenia
Hepatic: Hepatic injury
Hypersensitivity: Anaphylactic shock
Respiratory: Acute pulmonary edema, respiratory failure
Frequency not defined:
Cardiovascular: Left ventricular dysfunction, peripheral edema
Renal: Decreased estimated GFR (eGFR)
Respiratory: Pulmonary edema
Postmarketing:
Dermatologic: Stevens-Johnson syndrome
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).
• 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.
• Renal toxicity: Declines in GFR throughout bosutinib treatment have been observed in clinical studies.
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
Antacids: May decrease the serum concentration of Bosutinib. Management: Administer antacids more than 2 hours before or after bosutinib. Risk D: Consider therapy modification
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Bitter Orange: May increase the serum concentration of Bosutinib. Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Bosutinib. Risk X: Avoid combination
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
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased 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
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 more than 2 hours before or after bosutinib. 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
Levoketoconazole: Bosutinib may enhance the QTc-prolonging effect of Levoketoconazole. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
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
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
St John's Wort: May decrease the serum concentration of Bosutinib. Risk X: Avoid combination
Star Fruit: May increase the serum concentration of Bosutinib. Risk X: Avoid combination
Grapefruit juice may increase bosutinib plasma concentration. Management: Avoid grapefruit juice during bosutinib therapy.
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 at least 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, bosutinib may cause fetal harm if administered during pregnancy.
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 at least 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 and platelets (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); renal function (at baseline and throughout therapy, particularly in patients with preexisting impairment or other risk factors for renal dysfunction). Verify pregnancy status (prior to treatment initiation in females of reproductive potential). Monitor for diarrhea episodes; fluid/edema status (eg, weight gain). Monitor for signs/symptoms of cardiac failure and cardiac ischemia. Monitor adherence.
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 to 27 hours (Cortes 2011).
Time to peak: 6 hours.
Excretion: Feces (~91%); urine (~3%).
Clearance (mean): ~64 L/hour.
Altered kidney function: A single 200 mg dose was administered to subjects in a renal 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 renal 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, compared to patients with normal hepatic function.
Tablets (Bosulif Oral)
100 mg (per each): $173.62
400 mg (per each): $694.47
500 mg (per each): $694.47
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.
