bosutinib

General

Genetic Implications: Genetic Implications

Pronunciation:
boe-sue-ti nib


Trade Name(s)

  • Bosulif

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

  • Genetic implication Chronic/accelerated/blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) that it resistant/intolerant to previous therapies.
  • Newly diagnosed chronic phase Ph+ CML.

Action

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

Therapeutic Effect(s):

Decreased progression of CML.

Pharmacokinetics

Absorption: Absorbed following oral administration

Distribution: Unknown.

Protein Binding: 96%

Metabolism and Excretion: Mostly metabolized, mainly by the CYP3A4 enzyme system; metabolites do not have antineoplastic activity.

Half-life: 22.5 hr

TIME/ACTION PROFILE (beneficial hematologic response)

ROUTEONSETPEAKDURATION
POwithin 8–12 wk4–6 hr (blood level)9–18 mo or longer

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity;
  • Concurrent use of moderate to strong CYP3A4 inhibitors or inducers (may significantly alter drug effects);
  • OB:  Pregnancy (may cause fetal harm);
  • Lactation: Lactation.

Use Cautiously in:

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

Adverse Reactions/Side Effects

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

Derm: STEVENS-JOHNSON SYNDROME, itching, rash, acne

EENT: tinnitus

Endo: hypothyroidism

F and E: dehydration, hyperkalemia

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

GU: ↓ fertility, renal impairment

Hemat: anemia, neutropenia, thrombocytopenia

MS: arthralgia, back pain, myalgia

Neuro: dizziness, fatigue, headache, dysgeusia

Resp: cough, pulmonary edema

Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis), fever

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

Interactions

Drug-Drug

Drug-Natural Products:

Concurrent use with  St. John's wort  may ↓ blood levels and beneficial effects and should be avoided.

Drug-Food:

Grapefruit juice may ↑ blood levels and the risk of toxicity and should be avoided.

Route/Dosage

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

PO (Adults): 500 mg once daily, if complete hematologic response has not occurred by 8 wk, or complete cytologic response by 12 wk or there has been no occurrence of ≥Grade 3 adverse reactions, consider ↑ dose to 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.

Newly Diagnosis Ph+ CML

PO (Adults): 400 mg once daily, if complete hematologic response has not occurred by 8 wk, or complete cytologic response by 12 wk or there has been no occurrence of ≥Grade 3 adverse reactions, consider ↑ dose in 100–mg/day increments up to maximum dose of 600 mg once daily. Continue until disease progression or unacceptable toxicity.

Renal Impairment 
PO (Adults): CCr 30–50 mL/min– 300 mg once daily;  CCr <30 mL/min– 200 mg once daily.

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

Availability

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.  For Grade 3–4 diarrhea (↑ of ≥7 stools/day over baseline/pretreatment),  hold bosutinib until recovery to Grade ≤1.
  • Assess for signs and 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, reduce dose or discontinue bosutinib as necessary.

  • Monitor for signs of allergic reaction (rash, shortness of breath, respiratory tract infections, loss of appetite, headache, dizziness, back pain, joint pain, itching).

  • Assess patient for skin rash frequently during therapy. Discontinue bosutinib at first sign of rash; may be life-threatening. Stevens-Johnson syndrome may develop. Treat symptomatically; may recur once treatment is stopped.

  • Monitor for signs and symptoms of cardiac failure (shortness of breath; weight gain; swelling in hands, ankles or feet.) Interrupt therapy, reduce dose, or discontinue therapy as needed.

Lab Test Considerations:

Verify negative pregnancy test prior to starting therapy.

Monitor CBC weekly for first mo, then monthly thereafter. May cause thrombocytopenia, anemia, and neutropenia. If ANC <1000 × 106 /L or platelets <50,000 × 106 /L, withhold bosutinib until ANC ≥1000 × 106 /L and platelets ≥50,000 × 106 /L. Resume treatment with bosutinib at same dose if recovery occurs within 2 weeks. If blood counts remain low for >2 weeks, upon recovery, reduce dose by 100 mg and resume treatment. If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment.

  • Monitor hepatic function monthly for first 3 mo, then periodically during therapy as clinically indicated.  If ↑ liver transaminases >5 × institutional upper limit of normal (ULN) occur,  hold bosutinib until recovery to ≤2.5 × ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue bosutinib.  If transaminase ↑ ≥3 × ULN occur concurrently with bilirubin ↑ >2 × ULN and alkaline phosphatase <2 × ULN,  discontinue bosutinib.
  • Monitor renal function prior to and periodically during therapy, especially in patients with pre-existing renal dysfunction and other risk factors. May require dose adjustments.

Implementation

  • PO Administer once daily with food. In patients who do not reach complete hematological response by wk 8 or a complete cytogenetic response by wk 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily, consider dose escalation to 600 mg once daily with food.  DNC: Swallow tablets whole; do not crush, break or chew. Do not handle crushed or broken tablets. 

Patient/Family Teaching

  • Instruct patient to take bosutinib as directed. Take missed doses as soon as remembered if within 12 hours, if longer than 12 hrs skip dose and take usual prescribed dose on the following day. Do not stop taking bosutinib without consulting health care professional. 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.

  • Advise patient to immediately report fever, jaundice (skin or the white part of your eyes turns yellow or dark "tea color" urine), symptoms of infection, fluid retention, anaphylaxis, rash, unexpected bleeding or bruising, or blood in urine or stools occur. Advise patient to notify health care professional if diarrhea, nausea, vomiting, abdominal pain occur.

  • Inform patient to take medications that decrease stomach acid (antacids and H2  blockers) 2 hrs before or 2 hrs after bosutinib and to consult health care professional if taking a proton pump inhibitor (PPI).
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
  • Rep:  May cause fetal harm. Advise females of reproductive potential to use effective contraception and to avoid breastfeeding during and for at least 2 wk after last dose of therapy. Advise patient to notify health care professional immediately if pregnancy is suspected. May impair fertility in male and female patients.

Evaluation/Desired Outcomes

Decreased progression of CML.