Advanced Breast Cancer: Learn about treatment options.

Bosulif

Generic Name: Bosutinib
Class: Antineoplastic Agents
Chemical Name: 4 - [(2,4 - Dichloro - 5 - methoxyphenyl)amino] - 6 - methoxy - 7 - [3 - (4 - methyl - 1 - piperazinyl)propoxy] - 3 - quinolinecarbonitrile
Molecular Formula: C26H29Cl2N5O3
CAS Number: 380843-75-4

Introduction

Antineoplastic agent; an inhibitor of multiple tyrosine kinases.1 7 8

Uses for Bosulif

Chronic Myelogenous Leukemia (CML)

Treatment of Philadelphia chromosome-positive (Ph+) CML in adults in the chronic, accelerated, or blast phase of the disease, after failure (secondary to resistance or intolerance) of prior therapy.1 7 18

Slideshow: 2013 Drug News Round-Up: Top 20 Stories

Designated an orphan drug by FDA for treatment of CML.6

Bosulif Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

  • Perform CBCs weekly for first month of therapy and monthly (or as clinically indicated) thereafter.1

  • Monitor liver function tests monthly for first 3 months of therapy and then as clinically indicated; more frequent monitoring recommended if increased ALT or AST concentrations occur.1

Administration

Oral Administration

Administer orally once daily with food;1 tolerability increased when taken with food.2

Swallow tablets whole; do not cut or crush.1 Avoid touching or handling crushed or broken tablets.1

Dosage

Available as bosutinib monohydrate; dosage expressed as anhydrous bosutinib.1

Adults

CML
Chronic, Accelerated, or Blast Phase
Oral

500 mg once daily.1 If complete hematologic or cytogenetic responses not achieved by 8 or 12 weeks, respectively, may increase dosage to 600 mg once daily in patients not experiencing grade 3 or worse adverse effects with starting dosage (500 mg daily).1

Continue treatment until evidence of disease progression or until no longer tolerated.1

If a dose is missed by >12 hours, take next dose at the regularly scheduled time.1 Do not double the dose to make up for the missed dose.1

Dosage Modification for Toxicity
Myelosuppression

Adjust dosage if neutropenia and/or thrombocytopenia (unrelated to underlying CML) occur.1

If ANC <1000/mm3 or platelet counts <50,000/mm3 occur, withhold bosutinib until recovery.1

Resume therapy at original starting dosage (500 mg once daily) if recovery occurs (i.e., ANC ≥1000/mm3 and platelet counts ≥50,000/mm3) within 2 weeks.1 If blood counts remain low for >2 weeks, resume therapy at a reduced dosage of 400 mg once daily.1

If neutropenia or thrombocytopenia recurs, withhold bosutinib until recovery.1 Upon resumption of therapy, reduce dosage to 300 mg once daily.1

Hepatotoxicity

For ALT and/or AST concentrations >5 times ULN, interrupt dosing until ALT and AST return to ≤2.5 times ULN; upon resumption of therapy, reduce dosage to 400 mg once daily.1 If recovery is delayed (>4 weeks), discontinue bosutinib.1

For ALT and/or AST concentrations ≥3 times ULN occurring concurrently with total bilirubin concentrations >2 times ULN and alkaline phosphatase concentrations <2 times ULN, discontinue bosutinib.1

Diarrhea

If grade 3 or 4 diarrhea (≥7 stools per day over baseline) occurs, interrupt dosing until diarrhea resolves to grade 1 or less; upon resumption of therapy, may reduce dosage to 400 mg once daily.1

Other Nonhematologic Effects

If other clinically important, moderate or severe nonhematologic toxicity occurs, interrupt dosing until resolution; upon resumption of therapy, reduce dosage to 400 mg once daily.1 If clinically appropriate, may re-escalate dosage to 500 mg once daily.1

Prescribing Limits

Adults

CML
Chronic, Accelerated, or Blast Phase
Oral

<300 mg daily not evaluated.1

Special Populations

Hepatic Impairment

Mild, moderate, or severe preexisting hepatic impairment: Reduce dosage to 200 mg once daily.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Severe preexisting renal impairment: Reduce dosage to 300 mg once daily.1 (See Renal Impairment under Cautions.)

Not studied in patients receiving hemodialysis.1

Geriatric Patients

Manufacturer makes no special dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Bosulif

Contraindications

  • Known hypersensitivity to bosutinib.1

Warnings/Precautions

GI Toxicity

Nausea, vomiting, and diarrhea may occur.1 Median time to onset of diarrhea was 2 days; median duration of each episode was 1 day in a clinical trial.1 Median number of episodes of diarrhea per patient was 3 episodes.1

If GI toxicity occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.1 (See Diarrhea under Dosage and Administration.)

Myelosuppression

Cytopenias (e.g., neutropenia, anemia, thrombocytopenia) reported.1

If myelosuppression occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be required.1 (See Myelosuppression under Dosage and Administration.)

Perform CBCs weekly during first month of therapy and monthly (or as clinically indicated) thereafter.1

Hepatic Toxicity

ALT or AST elevations reported, generally occurring early during therapy with median duration of 21 days.1

Drug-induced hepatic injury reported in a patient receiving bosutinib in combination with letrozole; hepatotoxicity occurred within the first week of therapy and resolved following discontinuance of bosutinib.1

Monitor liver function tests monthly for first 3 months of therapy and then as clinically indicated.1 More frequent monitoring recommended if ALT or AST elevations occur.1

If hepatic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.1 (See Hepatotoxicity under Dosage and Administration.)

Fluid Retention

Risk of fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, peripheral edema).1

Monitor and manage patients using current standards of care.1 Temporary interruption, dosage reduction, or discontinuance of therapy may be necessary.1 (See Other Nonhematologic Effects under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryotoxic and fetotoxic in animals.1 Avoid pregnancy during therapy.1 (See Advice to Patients.) If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Interactions with CYP3A Inhibitors and Inducers

Concomitant use with moderate or potent CYP3A inhibitors (e.g., ketoconazole) may substantially increase systemic exposure of bosutinib.1 Avoid concomitant use with moderate or potent CYP3A inhibitors.1 (See Interactions.)

Concomitant use with moderate or potent CYP3A inducers (e.g., rifampin) may substantially decrease systemic exposure of bosutinib.1 Avoid concomitant use with moderate or potent CYP3A inducers.1 (See Interactions.)

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety or efficacy in geriatric patients (≥65 years of age) compared with younger adults, but increased sensitivity cannot be ruled out.1 Limited data in patients ≥75 years of age.1

Hepatic Impairment

Prolonged elimination half-life and increased systemic exposure and peak plasma concentrations in patients with preexisting mild to severe hepatic impairment.1 3

Risk of QT interval prolongation increased in patients with hepatic impairment.3

Reduce dosage in patients with preexisting mild, moderate, or severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Increased systemic exposure in patients with preexisting moderate to severe renal impairment.1 3 (See Absorption: Special Populations, under Pharmacokinetics.)

Systemic exposure not affected by mild renal impairment.1

Reduce dosage in patients with preexisting severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,1 7 nausea,1 7 abdominal pain,1 vomiting,1 7 thrombocytopenia,1 7 anemia,1 fatigue,1 pyrexia,1 headache,1 cough,1 rash.1 7

Interactions for Bosulif

Metabolized principally by CYP3A4.1

Substrate and inhibitor of P-glycoprotein (P-gp).1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased serum concentrations of bosutinib).1 4 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.)

Moderate or potent CYP3A inducers: Possible pharmacokinetic interaction (decreased serum concentrations of bosutinib).1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.)

Substrates or Inhibitors of P-gp

P-gp substrates: Potential pharmacokinetic interaction (increased plasma substrate concentrations).1 (See Specific Drugs and Foods under Interactions.)

P-gp inhibitors: Potential pharmacokinetic interaction (increased plasma bosutinib concentrations).1 Avoid concomitant use.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased bosutinib concentrations1

Avoid concomitant use1

Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased bosutinib concentrations1 4

Ketoconazole: Increased bosutinib AUC and peak concentrations1 4

Avoid concomitant use1

Antimycobacterials, rifamycins (e.g., rifabutin, rifampin)

Possible decreased bosutinib concentrations1

Rifampin: Decreased bosutinib AUC and peak concentrations1

Avoid concomitant use1

Antiretroviral agents, HIV protease inhibitors (e.g., amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased bosutinib concentrations1

Avoid concomitant use1

Antiretroviral agents, nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz, etravirine)

Possible decreased bosutinib concentrations1

Avoid concomitant use1

Aprepitant

Possible increased bosutinib concentrations1

Avoid concomitant use1

Bosentan

Possible decreased bosutinib concentrations1

Avoid concomitant use1

Calcium-channel blockers (i.e., diltiazem, verapamil)

Possible increased bosutinib concentrations1

Avoid concomitant use1

Ciprofloxacin

Possible increased bosutinib concentrations1

Avoid concomitant use1

Conivaptan

Possible increased bosutinib concentrations1

Avoid concomitant use1

Crizotinib

Possible increased bosutinib concentrations1

Avoid concomitant use1

Digoxin

Potential for increased digoxin concentrations1

Grapefruit or grapefruit juice

Possible increased bosutinib concentrations1

Avoid concomitant use1

HCV protease inhibitors (e.g., boceprevir, telaprevir)

Possible increased bosutinib concentrations1

Avoid concomitant use1

Imatinib

Possible increased bosutinib concentrations1

Avoid concomitant use1

Macrolides (clarithromycin, erythromycin, telithromycin)

Possible increased bosutinib concentrations1

Avoid concomitant use1

Modafinil

Possible decreased bosutinib concentrations1

Avoid concomitant use1

Nafcillin

Possible decreased bosutinib concentrations1

Avoid concomitant use1

Nefazodone

Possible increased bosutinib concentrations1

Avoid concomitant use1

Proton-pump inhibitors

Lansoprazole: Decreased bosutinib AUC and peak concentrations1

Concomitant use not recommended1

Consider substituting H2-receptor antagonist or short-acting antacid (administered 2 hours before or after bosutinib dose) for proton-pump inhibitor1

St. John’s wort (Hypericum perforatum)

Possible decreased bosutinib concentrations1

Avoid concomitant use1

Bosulif Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 4–6 hours.1

Food

Oral administration with a high-fat meal increases peak plasma concentrations and AUC by 1.8- and 1.7-fold, respectively.1

Special Populations

Patients with hepatic impairment (Child-Pugh class A, B, or C): Peak concentrations increased by 2.4-, 2-, or 1.5-fold, respectively; AUCs increased by 2.3-, 2-, or 1.9-fold, respectively, compared with healthy individuals following a 200-mg dose.1

Systemic exposure following bosutinib 200 mg daily in patients with hepatic impairment expected to be similar to that observed in those with normal hepatic function receiving 500 mg daily; efficacy of bosutinib 200 mg daily in patients with hepatic impairment and CML unknown.1 (See Hepatic Impairment under Cautions.)

Patients with moderate (ClCr 30–50 mL/minute) or severe (ClCr <30 mL/minute) renal impairment: AUC increased by 35 or 60%, respectively, compared with healthy individuals following a 200-mg dose.1

Systemic exposure following bosutinib 300 mg daily in patients with severe renal impairment expected to be similar to that observed in those with normal renal function receiving 500 mg daily; efficacy of bosutinib 300 mg daily in patients with renal impairment and CML unknown.1 (See Renal Impairment under Cautions.)

Distribution

Extent

Not known whether distributed into milk.1

Plasma Protein Binding

94–96%.1

Elimination

Metabolism

Metabolized principally by CYP3A4 to 3 inactive metabolites, oxydechlorinated (M2), N-desmethylated (M5), and N-oxide (M6) derivatives. 1

Elimination Route

Eliminated in feces (91%) and urine (3%).1

Half-life

Mean terminal half-life: 22.5 hours.1

Special Populations

Patients with mild to severe hepatic impairment: Prolonged elimination half-life expected.3

Patients with renal impairment: Elimination half-life not affected.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits multiple tyrosine kinases (e.g., Bcr-Abl, Src family [Src, Lyn, Hck]);1 7 8 minimal inhibitory activity against c-Kit or platelet-derived growth factor (PDGF)-β.8 15 16 17 18

  • Inhibits Bcr-Abl tyrosine kinase (abnormal protein created by Ph+ abnormality in CML) that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues).9 10 11 12 13

  • Competitively and selectively inhibits Bcr-Abl tyrosine kinase, leading to inhibition of tyrosine phosphorylation of proteins involved in intracellular signal transduction.8 15 16

  • Inhibits most (16 of 18) imatinib-resistant Bcr-Abl kinase domain mutant forms except for T315I and V299L mutant cells.1 15 16

Advice to Patients

  • Importance of not altering the dosage or discontinuing therapy without first consulting clinician.1

  • If a dose is missed by >12 hours, take the next dose at the regularly scheduled time.1 Do not double the dose.1

  • Importance of advising patients to swallow bosutinib tablets whole and not to crush or cut the tablets.1 Importance of not touching or handling crushed or broken tablets.1

  • Importance of advising patients to take bosutinib tablets with food and not to drink grapefruit juice or consume grapefruit products while taking the drug.1

  • Risk of diarrhea, nausea, vomiting, abdominal pain, or bloody stools.1 Importance of promptly seeking medical attention if any of these symptoms occur.1

  • Risk of cytopenias.1 Importance of informing clinician if fever, easy bruising, or other signs and symptoms of infection or bleeding occur.1

  • Risk of liver function abnormalities.1 Importance of contacting clinician promptly if jaundice or dark urine occurs.1

  • Risk of fluid retention.1 Importance of contacting clinician promptly if swelling, weight gain, shortness of breath, coughing, or chest pain occurs.1

  • Necessity of advising women of childbearing potential to use an effective method of contraception while receiving bosutinib and for at least 30 days after discontinuance of therapy.1 Necessity of advising women to avoid pregnancy during therapy.1

    Importance of women informing clinicians if they become pregnant.1 Bosutinib may cause fetal harm.1 Advise pregnant women of risk to fetus.1

  • Necessity of advising women to avoid breast-feeding during therapy.1 Importance of women informing clinicians if they plan to breast-feed.1 If a woman wishes to resume breast-feeding following therapy, importance of advising the woman to discuss appropriate timing with clinician.1

  • Importance of informing patients of other important precautionary information.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Bosutinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

100 mg

Bosulif

Pfizer

500 mg

Bosulif

Pfizer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 21, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Bosulif (bosutinib) tablets prescribing information. New York, NY; 2013 Apr.

2. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 203341: Medical review(s). 2012 Jul 20. From FDA website.

3. Abbas R, Chalon S, Leister C et al. Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol. 2013; 71:123-32. [PubMed 23053269]

4. Abbas R, Hug BA, Leister C et al. Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy subjects. J Clin Pharmacol. 2011; 51:1721-7. [PubMed 21148045]

5. Abbas R, Leister C, El Gaaloul M et al. Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects. Clin Ther. 2012; 34:2011-9.e1. [PubMed 22884766]

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P. L. 97-414). Rockville, MD. From FDA website.

7. Cortes JE, Kantarjian HM, Brümmendorf TH et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011; 118:4567-76. [PubMed 21865346]

8. Abbas R, Hug BA, Leister C et al. A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol. 2012; 69:221-7. [PubMed 21691746]

9. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Investig. 2000; 105:3-7. [PubMed 10619854]

10. McGuire TR, Kazakoff PW. Chronic leukemias. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 4th ed. Stamford: Appleton and Lange; 1999:2169-80.

11. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344:1031-7. [IDIS 461596] [PubMed 11287972]

12. Anon. Gleevec (STI-571) for chronic myeloid leukemia. Med Lett Drugs Ther. 2001; 43:49-50. [PubMed 11402258]

13. Weisberg E, Griffin J. Mechanisms of resistance imatinib (STI-571) in preclinical models and in leukemia patients. Drug Resistance Updates. 2001; 4:22-8. [PubMed 11512149]

14. Donato NJ, Wu JY, Stapley J et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003; 101:690-8. [PubMed 12509383]

15. Boschelli F, Arndt K, Gambacorti-Passerini C. Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia. Eur J Cancer. 2010; 46:1781-9. [PubMed 20399641]

16. Keller-V Amsberg G, Brümmendorf TH. Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia. Expert Rev Anticancer Ther. 2012; 12:1121-7. [PubMed 23098112]

17. Remsing Rix LL, Rix U, Colinge J et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009; 23:477-85. [PubMed 19039322]

18. Khoury HJ, Cortes JE, Kantarjian HM et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012; 119:3403-12. [PubMed 22371878]

19. Pfizer Inc. New York, NY: Personal communication.

20. Li S. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008; 49:19-26. [PubMed 18203007]

22. Cortes J, Jabbour E, Kantarjian H et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood. 2007; 110:4005-11. [PubMed 17785585]

Advanced Breast Cancer: Learn about treatments to improve quality of life. Click Here

Close
Hide
(web3)