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Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• 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.

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

• Decreased progression of CML.

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

Distribution: Extensively distributed to tissues.

Protein Binding: 96%.

Metabolism/Excretion: Mostly metabolized, mainly by the CYP3A4 isoenzyme; metabolites do not have antineoplastic activity.

Half-life: 22.5 hr.

(beneficial hematologic response)

Contraindicated in:

• Hypersensitivity
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

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

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.

Metab: ↓appetite.

MS: arthralgia, back pain, myalgia.

Neuro: dizziness, fatigue, headache, dysgeusia.

Resp: cough, pulmonary edema.
Misc: fever, (INCLUDING ANAPHYLAXIS)HYPERSENSITIVITY REACTIONS .

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, ↑ 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.

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 maximum 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 maximum 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 maximum 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 maximum 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 maximum 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 maximum dose of 300 mg once daily. Continue until disease progression or unacceptable toxicity.

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 maximum 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 maximum 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 maximum 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 maximum 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 maximum dose of 250 mg once daily. Continue until disease progression or unacceptable toxicity.

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 maximum dose of 600 mg once daily. Continue until disease progression or unacceptable toxicity.

• Capsules: 50 mg; 100 mg;
• Tablets: 100 mg; 400 mg; 500 mg;

• 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. SJS 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.

• 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 wk. If blood counts remain low for >2 wk, upon recovery, ↓ dose by 100 mg (or by 50 mg in pediatric patients with BSA <1.1 m²) and resume treatment. If cytopenia recurs, ↓ dose by an additional 100 mg (or by 50 mg in pediatric patients with BSA <1.1 m²) upon recovery and resume treatment.
  • Monitor hepatic function monthly for first 3 mo, then periodically during therapy as clinically indicated. If ↑ liver transaminases >5 times upper limit of normal (ULN) occur, hold bosutinib until recovery to 2.5 times ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 wk, discontinue bosutinib. If transaminase ↑3 times ULN occur concurrently 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. May require dose adjustments.

• PO: Administer once daily 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 applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal.

• Instruct patient to take bosutinib 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 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 the 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, or abdominal pain occur.
• Inform patient to take medications that ↓ stomach acid (antacids and H₂ blockers) 2 hr before or 2 hr after bosutinib and to consult health care professional if taking a proton pump inhibitor.
• 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.
• 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.

• Decreased progression of CML.

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