General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications:

Pronunciation:
boe-sue-ti nib

Trade Name(s)

• Bosulif

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

•  Chronic phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) that is newly diagnosed or resistant/intolerant to previous therapies.
•  Accelerated/blast phase Ph+ CML that is resistant/intolerant to previous therapies.

Action

Acts as a kinase inhibitor, specifically inhibiting the kinase that promotes CML.

Therapeutic Effect(s):

Decreased progression of CML.

Pharmacokinetics

Absorption: 34% absorbed following oral administration; absorption ↑ with high-fat meal.

Distribution: Extensively distributed to tissues.

Protein Binding: 96%

Metabolism and Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme; metabolites do not have antineoplastic activity.

Half-life: 22.5 hr

TIME/ACTION PROFILE (beneficial hematologic response)

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity
• OB:  Pregnancy;
• Lactation: Lactation.

Use Cautiously in:

• Renal impairment (↓ dose)
• Hepatic impairment (↓ dose)
• Rep:   Women of reproductive potential;
• Pedi:  Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: chest pain, HF, myocardial ischemia, pericardial effusion, pericarditis, peripheral edema, QT interval prolongation, tachycardia

Derm: itching, rash, acne, STEVENS-JOHNSON SYNDROME (SJS)

EENT: tinnitus

Endo: hypothyroidism

F and E: dehydration, hyperkalemia

GI: ↑ liver enzymes, abdominal pain, diarrhea, nausea, vomiting, gastritis, GI bleeding, HEPATOTOXICITY, pancreatitis

GU: ↓ fertility, renal impairment

Hemat: anemia, neutropenia, thrombocytopenia

Metabolic: ↓ appetite

MS: arthralgia, back pain, myalgia

Neuro: dizziness, fatigue, headache, dysgeusia

Resp: cough, pulmonary edema

Misc: fever, HYPERSENSITIVITY REACTIONS (including anaphylaxis)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Moderate or strong CYP3A4 inhibitors, including  aprepitant,  atazanavir,  ciprofloxacin,  clarithromycin,  conivaptan,  crizotinib,  darunavir,  diltiazem,  erythromycin,  fluconazole,  fosamprenavir,  imatinib,  itraconazole,  ketoconazole,  lopinavir/ritonavir,  nefazodone,  nelfinavir,  posaconazole,  ritonavir,  verapamil, and  voriconazole, may ↑ levels and risk of toxicity; avoid concurrent use.
•   Moderate or strong CYP3A4 inducers, including  bosentan,  carbamazepine,  efavirenz,  etravirine,  modafinil,  nafcillin,  phenobarbital,  phenytoin,  rifabutin, and  rifampin, may ↓ levels and effectiveness; avoid concurrent use.
•  Proton pump inhibitors, including  esomeprazole,  dexlansoprazole,  lansoprazole,  omeprazole,  pantoprazole, and  rabeprazole, may ↓ levels and effectiveness; avoid concurrent use. Consider using short-acting antacids or histamine-H₂  receptor blockers instead (these should be taken 2 hr before or after bosutinib).
• May ↑  digoxin  levels and risk of toxicity.

Drug-Natural Products:

 St. John's wort  may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage

Chronic Phase Ph+ CML Resistant/Intolerant to Previous Therapies

PO (Adults and Children  ≥1 yr and BSA ≥1.1 m2): 500 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved or maintained and there has been no occurrence of Grade ≥3 adverse reactions, consider ↑ dose in 100-mg/day increments up to max dose of 600 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA 0.9–<1.1 m2): 400 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 500 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA 0.75–<0.9 m2): 350 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 450 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA 0.63–<0.75 m2): 300 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 400 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA 0.55–<0.63 m2): 250 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 350 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA <0.55 m2): 200 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 300 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment 
PO (Adults and Children  ≥1 yr and BSA ≥1.1 m2): CCr 30–50 mL/min: 400 mg once daily;  CCr <30 mL/min: 300 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.9–<1.1 m2): CCr 30–50 mL/min: 300 mg once daily;  CCr <30 mL/min: 250 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.75–<0.9 m2): CCr 30–50 mL/min: 250 mg once daily;  CCr <30 mL/min: 200 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.63–<0.75 m2): CCr 30–50 mL/min: 200 mg once daily;  CCr <30 mL/min: 200 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.55–<0.63 m2): CCr 30–50 mL/min: 200 mg once daily;  CCr <30 mL/min: 150 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA <0.55 m2): CCr 30–50 mL/min: 150 mg once daily;  CCr <30 mL/min: 100 mg once daily.

Hepatic Impairment 
PO (Adults and Children  ≥1 yr and BSA ≥1.1 m2): Mild, moderate, or severe hepatic impairment: 200 mg once daily.

Hepatic Impairment 
(Children  ≥1 yr and BSA 0.9–<1.1 m2): Mild, moderate, or severe hepatic impairment: 200 mg once daily.

Hepatic Impairment 
(Children  ≥1 yr and BSA 0.63–<0.9 m2): Mild, moderate, or severe hepatic impairment: 150 mg once daily.

Hepatic Impairment 
(Children  ≥1 yr and BSA <0.63 m2): Mild, moderate, or severe hepatic impairment: 100 mg once daily.

Newly Diagnosed Chronic Phase Ph+ CML

PO (Adults and Children  ≥1 yr and BSA ≥1.1 m2): 400 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved or maintained and there has been no occurrence of Grade ≥3 adverse reactions, consider ↑ dose in 100-mg/day increments up to max dose of 600 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA 0.9–<1.1 m2): 300 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 400 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA 0.75–<0.9 m2): 250 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 350 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA 0.55–<0.75 m2): 200 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 300 mg once daily. Continue until disease progression or unacceptable toxicity.

PO (Children  ≥1 yr and BSA <0.55 m2): 150 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved after 3 mo, consider ↑ dose in 50-mg/day increments up to max dose of 250 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment 
(Adults and Children  ≥1 yr and BSA ≥1.1 m2): CCr 30–50 mL/min: 300 mg once daily;  CCr <30 mL/min: 200 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.9–<1.1 m2): CCr 30–50 mL/min: 200 mg once daily;  CCr <30 mL/min: 200 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.75–<0.9 m2): CCr 30–50 mL/min: 200 mg once daily;  CCr <30 mL/min: 150 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.63–<0.75 m2): CCr 30–50 mL/min: 150 mg once daily;  CCr <30 mL/min: 100 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA 0.55–<0.63 m2): CCr 30–50 mL/min: 150 mg once daily;  CCr <30 mL/min: 100 mg once daily.

Renal Impairment 
(Children  ≥1 yr and BSA <0.55 m2): CCr 30–50 mL/min: 100 mg once daily;  CCr <30 mL/min: 100 mg once daily.

Hepatic Impairment 
(Adults and Children  ≥1 yr and BSA ≥1.1 m2): Mild, moderate, or severe hepatic impairment: 200 mg once daily.

Hepatic Impairment 
(Children  ≥1 yr and BSA 0.9–<1.1 m2): Mild, moderate, or severe hepatic impairment: 150 mg once daily.

Hepatic Impairment 
(Children  ≥1 yr and BSA <0.9 m2): Mild, moderate, or severe hepatic impairment: 100 mg once daily.

Accelerated/Blast Phase Ph+ CML Resistant/Intolerant to Previous Therapies

PO (Adults): 500 mg once daily; if hematologic, cytogenetic, or molecular response is not achieved or maintained and there has been no occurrence of Grade ≥3 adverse reactions, consider ↑ dose in 100-mg/day increments up to max dose of 600 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment 
PO (Adults): CCr 30–50 mL/min: 400 mg once daily;  CCr <30 mL/min: 300 mg once daily.

Hepatic Impairment 
PO (Adults): Any degree of hepatic impairment: 200 mg once daily.

Availability (generic available)

Capsules: 50 mg, 100 mg

Tablets: 100 mg, 400 mg, 500 mg

Assessment

• Monitor for diarrhea, nausea, vomiting, and abdominal pain. Usually occurs within 4 days of therapy and lasts for about 3 days.  If Grade 3–4 diarrhea (↑ of ≥7 stools/day over baseline/pretreatment) occurs,  hold bosutinib until recovery to Grade ≤1.
• Assess for signs/symptoms fluid retention (swelling in hands, ankles, or feet; weight gain; shortness of breath; cough; chest pain). May manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. Interrupt, ↓ dose, or discontinue bosutinib as needed.
• Monitor for signs/symptoms of HF (dyspnea, peripheral edema, weight gain, rales/crackles, jugular venous distension) during therapy. Interrupt therapy, ↓ dose, or discontinue bosutinib as needed.
• Monitor for signs/symptoms of hypersensitivity reactions (rash, urticaria, pruritus, flushing, dizziness, vomiting, abdominal pain) and angioedema (swelling of throat, lips, tongue, face, dyspnea, wheezing, hoarseness).  If reaction occurs,  discontinue bosutinib and provide supportive care.
• Assess for rash or signs/symptoms of SJS periodically during therapy (fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis).  If skin reaction occurs, discontinue bosutinib and provide supportive care; may recur once treatment is stopped.
• Monitor for signs and symptoms of hepatotoxicity such as fatigue, nausea, upper abdominal pain, jaundice, scleral icterus, dark urine, or clay-colored stools.

Lab Test Considerations:

• Verify negative pregnancy test prior to starting therapy.
• Monitor CBC with differential weekly for 1st month, then monthly thereafter. May cause thrombocytopenia, anemia, and neutropenia.  If ANC <1,000 × 10⁶ /L or platelets <50,000 × 10⁶ /L,  hold bosutinib until ANC ≥1,000 × 10⁶ /L and platelets ≥50,000 × 10⁶ /L. Resume bosutinib at same dose if recovery occurs within 2 wk. If blood counts remain low for >2 wk, upon recovery, ↓ bosutinib dose by 100 mg (or by 50 mg in pediatric patients with BSA <1.1 m² ). If cytopenia recurs, ↓ bosutinib dose by an additional 100 mg (or by 50 mg in pediatric patients with BSA <1.1 m² ) upon recovery.
• Monitor hepatic function monthly for 1st 3 mo, then periodically during therapy as clinically indicated.  If liver transaminases >5 times upper limit of normal (ULN),  hold bosutinib until recovery to ≤2.5 times ULN and then resume at 400 mg once daily thereafter. If recovery takes >4 wk, discontinue bosutinib.  If liver transaminases ≥3 times ULN with bilirubin >2 times ULN and alkaline phosphatase <2 times ULN,  discontinue bosutinib.
• Monitor renal function prior to and periodically during therapy, especially in patients with pre-existing renal impairment and other risk factors.

Implementation

• During administration and when preparing or handling tablets, wear double chemotherapy gloves, protective gown, and hair and shoe covers; optimally prepare in a ventilated control device. Respiratory (N95) protection and eye/face protection is needed if there is risk of patient vomiting or spitting up. Single chemotherapy gloves are appropriate if handling and administering intact tablets from a unit-dose package. Health care providers who are actively trying to conceive, who are pregnant or may become pregnant, and who are breastfeeding should avoid handling bosutinib.
• PO Administer with food.  DNC: Swallow tablets and capsules whole; do not crush, break, or chew. Do not handle crushed or broken tablets.  For patients unable to swallow whole capsules, each capsule can be opened and the contents mixed with approximately 5 mL of applesauce or yogurt per 50 mg bosutinib. Patients should immediately consume the mixture without chewing. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal.

Patient/Family Teaching

• Explain the purpose and side effects of bosutinib. Instruct patient to take as directed. Take missed doses as soon as remembered if within 12 hr; if longer than 12 hr, skip dose and take usual prescribed dose on the following day. Do not stop taking bosutinib without consulting health care provider. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
• Advise patient to avoid grapefruit and grapefruit juice during therapy.
• Warn patient to report signs/symptoms and seek treatment for HF or fluid retention.
• Advise patient to immediately report signs/symptoms of hepatotoxicity.
• Instruct patient to notify health care provider or call 911 immediately to seek medical care if swelling of face, eyes, lips, or tongue or if difficulty swallowing or breathing occur.
• Advise patient to notify health care provider if fever, rash, diarrhea, nausea, vomiting, blood in stools, abdominal pain, or any signs of infection occur.
• Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications, especially St. John's wort.
• Rep:  May cause fetal harm. Advise women of reproductive potential to use effective contraception and to avoid breastfeeding during and for ≥2 wk after last dose of therapy. Advise patient to notify health care profvider immediately if pregnancy is suspected. May impair fertility in men and women.

Evaluation/Desired Outcomes

Decreased progression of CML.