Bosutinib

Dosage Forms

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

Tablet, Oral:

Bosulif: 100 mg, 400 mg, 500 mg

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Absorption

Slow (Abbas 2012)

Distribution

V_d: 6,080 ± 1,230 L

Metabolism

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

Excretion

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

Onset of Action

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

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

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

Time to Peak

6 hours

Half-Life Elimination

22 to 27 hours (Cortes 2011)

Protein Binding

94% to plasma proteins

Use in Specific Populations

Special Populations: Renal Function Impairment

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.

Special Populations: Hepatic Function Impairment

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

Use: Labeled Indications

Chronic myelogenous leukemia: Treatment of newly-diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML); treatment of chronic, accelerated, or blast phase Ph+ CML in patients resistant or intolerant to prior therapy

Contraindications

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

Dosage and Administration

Dosing: Adult

Note: Bosutinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); nausea and vomiting may be managed with antiemetics and fluid replacement. In clinical studies of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML), 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).

Ph+ CML, newly-diagnosed chronic phase: Oral: 400 mg once daily; continue until disease progression or unacceptable toxicity (Cortes 2018)

Ph+ CML, resistant or intolerant to prior therapy: Oral: 500 mg once daily; continue until disease progression or unacceptable toxicity (Cortes 2011)

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Ph+ CML, newly diagnosed (chronic phase) or resistant/intolerant to prior therapy:

Hematologic toxicity: ANC <1,000/mm³ or platelets <50,000/mm³: Withhold treatment until ANC ≥1,000/mm³and platelets ≥50,000/mm³; if recovery occurs within 2 weeks, resume treatment at the same dose. If ANC and platelets remain low for >2 weeks, upon recovery, resume treatment with the daily dose reduced by 100 mg. If cytopenia recurs, withhold until recovery and resume treatment 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 treatment until recovery to ≤ grade 1; may resume at 400 mg once daily.

Other clinically significant nonhematologic toxicity, moderate or severe: Withhold treatment until resolved, then consider resuming with the daily dose reduced by 100 mg; may re-escalate dose to the starting dose if clinically appropriate.

Administration

Bosutinib is associated with a moderate emetic potential (Hesketh 2017; 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.

Storage

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

Drug Interactions

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

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

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

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

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

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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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. Consider therapy modification

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. 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. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

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. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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

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

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (17% to 20%), chest pain (7% to 12%)

Central nervous system: Fatigue (19% to 26%), headache (17% to 21%), dizziness (11% to 13%)

Dermatologic: Skin rash (34% to 42%), pruritus (7% to 12%)

Endocrine & metabolic: Hypophosphatemia (50% [Gambacorti-Passerini 2014]), hypokalemia (18% [Gambacorti-Passerini 2014])

Gastrointestinal: Diarrhea (70% to 85%), nausea (35% to 48%), vomiting (18% to 43%), abdominal pain (25% to 42%), increased serum lipase (13% to 38% [Cortes 2012; Gambacorti-Passerini 2014]), decreased appetite (10% to 14%)

Hematologic & oncologic: Thrombocytopenia (35% to 45%; grades 3/4: 14% to 39%), decrease in absolute neutrophil count (9% to 39%), anemia (19% to 38%; grades 3/4: 3% to 27%), neutropenia (11% to 22%; grades 3/4: 7% to 20%), leukopenia (10% to 15%; grades 3/4: 4% to 12%)

Hepatic: Increased serum alanine aminotransferase (18% to 31%), increased serum aspartate aminotransferase (11% to 23%)

Neuromuscular & skeletal: Arthralgia (11% to 17%), asthenia (10% to 13%), back pain (8% to 13%)

Respiratory: Respiratory tract infection (10% to 15%), cough (22%), dyspnea (12% to 20%), nasopharyngitis (6% to 13%), pleural effusion (9% to 12%)

Miscellaneous: Fever (13% to 37%)

1% to 10%:

Cardiovascular: Hypertension, pericardial effusion, prolonged Q-T interval on ECG

Central nervous system: Pain

Dermatologic: Urticaria

Endocrine & metabolic: Fluid retention (grade 3/4: 5%), dehydration, hyperkalemia, increased gamma-glutamyl transferase

Gastrointestinal: Dysgeusia, gastritis, gastrointestinal hemorrhage, increased serum amylase

Hematologic & oncologic: Febrile neutropenia

Hepatic: Abnormal hepatic function tests, hepatic injury, hepatic insufficiency, hepatotoxicity, increased serum bilirubin (grades ≥3: 1% to 3%)

Infection: Influenza (3% to 10%)

Neuromuscular & skeletal: Increased creatine phosphokinase, myalgia

Otic: Tinnitus

Renal: Increased serum creatinine (6% to 10%), acute renal failure, renal failure, renal insufficiency

Respiratory: Bronchitis, pneumonia

Frequency not defined: Genitourinary: Decreased estimated GFR (eGFR)

<1%, postmarketing, and/or case reports: Acute pancreatitis, acute pulmonary edema, anaphylactic shock, erythema multiforme, exfoliative dermatitis, fixed drug eruption, granulocytopenia, hypersensitivity reaction, pericarditis, pulmonary hypertension, respiratory failure, Stevens-Johnson syndrome, thrombotic microangiopathy

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Anemia, neutropenia, and thrombocytopenia may occur. May require treatment interruption, dose reduction, or discontinuation. Monitor blood counts weekly during first month, then monthly thereafter (or as clinically indicated).
• Fluid retention/edema: Fluid retention, manifesting as pericardial effusion, pleural effusion, pulmonary edema and/or peripheral edema may occur; may be severe. Monitor for fluid retention (eg, weight gain) and manage appropriately; may require treatment interruption, dose reduction, or discontinuation.
• GI toxicity: Diarrhea, nausea, vomiting, and abdominal pain may occur. Monitor; may require treatment interruption, dose reduction, discontinuation, or other management (eg, medications or fluids). 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); manage diarrhea with antidiarrheals and/or fluid replacement. Similarly, the median time to onset for diarrhea (all grades) in patients with newly-diagnosed CML was 3 days; the median duration per events was 3 days. Bosutinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); nausea and vomiting may be managed with antiemetics and fluid replacement. GI hemorrhages have also been reported.
• Hepatotoxicity: Serum transaminase (ALT and/or AST) elevations have been reported. In patients with transaminase elevation, ~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 32 and 43 days, respectively; the median duration was 20 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 35 and 33 days, respectively, and the median duration (for each) was 21 days. One case of drug-induced liver injury has been reported in a breast cancer clinical trial (not an approved indication); full recovery occurred after discontinuation. Monitor transaminases monthly for the first 3 months (and as clinically indicated; monitor more frequently if elevations occur). May require therapy interruption, dosage reduction, or therapy discontinuation.
• Hypersensitivity: Hypersensitivity reactions have been reported, including anaphylaxis and anaphylactic shock (rare).
• Pancreatitis: Acute pancreatitis has been reported (rare); use caution in patients with a prior history of pancreatitis.
• 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 glomerular filtration rates throughout bosutinib treatment have been observed in clinical studies; monitor renal function at baseline and during therapy, particularly in patients with preexisting impairment or other risk factors for renal dysfunction. Consider dosage adjustment in patients with renal dysfunction at baseline or with treatment emergent impairment.

Disease-related concerns:

• Hepatic impairment: Bosutinib exposure is increased in patients with hepatic impairment; dose reduction is recommended.
• Renal impairment: Bosutinib exposure is increased in patients with moderate or severe renal impairment. Consider dosage adjustment in patients with renal dysfunction at baseline or with treatment emergent impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Gastrointestinal medications: Proton pump inhibitors (PPIs) may decrease bosutinib effects; consider using short acting antacids or H₂ antagonists instead of PPIs. Separate administration of antacids or H₂ antagonists from bosutinib by at least 2 hours.

Monitoring Parameters

CBC with differential and platelets (weekly during first month, then monthly thereafter, or as clinically indicated); hepatic enzymes (monthly for first 3 months and as clinically indicated; monitor more frequently with transaminase elevations); renal function (at baseline and throughout therapy); pregnancy test (prior to treatment initiation in females of reproductive potential); diarrhea episodes; fluid/edema status (eg, weight gain). Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on data from animal reproduction studies and the mechanism of action, bosutinib may cause fetal harm if administered during pregnancy.

Verify pregnancy status in females of reproductive potential prior to initiating therapy. Females of reproductive potential 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.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

Frequently reported side effects of this drug

• Abdominal pain
• Nausea
• Vomiting
• Diarrhea
• Common cold symptoms
• Stuffy nose
• Sore throat
• Lack of appetite
• Dizziness
• Fatigue
• Headache
• Joint pain
• Back pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Passing a lot of urine
• Trouble breathing
• Weight gain
• Chest pain
• Swelling
• Severe loss of strength and energy
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.