Bosutinib is a kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5­methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3•H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure: Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly. BOSULIF® (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “100” on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “500” on the other. Each 100 mg BOSULIF tablet contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib; each 500 mg BOSULIF tablet contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib. The following inactive ingredients are included in the tablets: microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet).

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The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Gastrointestinal toxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Myelosuppression [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Hepatic toxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
• Fluid retention [see WARNINGS AND PRECAUTIONS].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Serious adverse reactions reported include anaphylactic shock [see CONTRAINDICATIONS], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash. Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase ½ safety population (n=546) were diarrhea (82%), nausea (46%), thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia (26%), and fatigue (24%). Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML The single-arm Phase ½ clinical trial enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. The safety population (received at least 1 dose of BOSULIF) included 546 CML patients. Within the safety population there were 287 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 24 months, and a median dose intensity of 484 mg/day. There were 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg/day. There were 76 patients with AP CML, and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months and 3 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively. Table 2 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase ½ CML safety population. Table 2: Adverse Reactions (10% or greater) in patients with CML
System Organ Class Preferred Term CP CML
N=406
n (%) AdvP CML
N=140
n (%) All CP and AdvP CML
N=546
n (%) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal Disorders   Diarrhea 342 (84) 38 (9) 107 (76) 7 (5) 449 (82) 45 (8)   Nausea 186 (46) 5 (1) 66 (47) 3 (2) 252 (46) 8 (1)   Abdominal Paina 162 (40) 6 (1) 41 (29) 7 (5) 203 (37) 13 (2)   Vomiting 152 (37) 12 (3) 59 (42) 5 (4) 211 (39) 17 (3) Blood and Lymphatic System Disorders   Thrombocytopenia 163 (40) 105 (26) 59 (42) 52 (37) 222 (41) 157 (29)   Anemia 94 (23) 35 (9) 52 (37) 37 (26) 146 (27) 72 (13)   Neutropenia 65 (16) 43 (11) 26 (19) 25 (18) 91 (17) 68 (12) General Disorders and Administrative Site Conditions   Fatigueb 104 (26) 6 (1) 28 (20) 6 (4) 132 (24) 12 (2)   Pyrexia    90 (22) 2 ( < 1) 51 (36) 4 (3) 141 (26) 6 (1)   Edemac 56 (14) 1 ( < 1) 19 (14) 1 (1) 75 (14) 2 ( < 1)   Asthenia 45 (11) 5 (1) 14 (10) 1 (1) 59 (11) 6 (1) Infections and Infestations   Respiratory tract infectiond 49 (12) 2 ( < 1) 14 (10) 0 63 (12) 2 ( < 1)   Nasopharyngitis 47 (12) 0 7 (5) 0 54 (10) 0 Investigations   Alanine aminotransferase increased 81 (20) 30 (7) 14(10) 7(5) 95(17) 37(7)   Aspartate aminotransferase increased 64 (16) 15 (4) 15(11) 4 (3) 79(14) 19(3) Metabolism and nutrition disorder   Decreased appetite 53 (13) 3 (1) 19 (14) 0 72 (13) 3 (1) Musculoskeletal and Connective Tissue Disorder   Arthralgia 58 (14) 2 ( < 1) 18 (13) 0 76 (14) 2 ( < 1)   Back pain 49 (12) 3 (1) 10 (7) 2 (1) 59 (11) 5 (1) Nervous System Disorders   Headache 82 (20) 3 (1) 25 (18) 6 (4) 107 (20) 9 (2)   Dizziness 39 (10) 0 18 (13) 1 (1) 57 (10) 1 ( < 1) Respiratory, Thoracic and Mediastinal Disorders   Dyspnea 41 (10) 4 (1) 26 (19) 8 (6) 67 (12) 12 (2)   Cough 80(20) 0 30(21) 0 110(20) 0 Skin and Subcutaneous Disorders   Rashe 140 (34) 32 (8) 49 (35) 6 (4) 189 (35) 38 (7)   Pruritus 43 (11) 3 (1) 11 (8) 0 54 (10) 3 (1) CP CML = Chronic Phase CML; AdvP CML = Advanced Phase CML (includes patients with Accelerated Phase and Blast Phase CML)
aAbdominal pain includes the following preferred terms: Abdominal pain, Abdominal pain upper, Abdominal pain lower, Abdominal tenderness, Gastrointestinal pain, Abdominal discomfort
bFatigue includes the following preferred terms: Fatigue, Malaise
cEdema includes the following preferred terms: Edema, Edema peripheral, Localized edema, Face edema
dRespiratory tract infection includes the following preferred terms: Respiratory tract infection, Upper respiratory tract infection, Lower respiratory tract infection, Viral upper respiratory tract infection, Respiratory tract infection viral
eRash includes the following preferred terms: Rash, Rash macular, Rash pruritic, Rash generalized, Rash papular, Rash maculo-papular In the single-arm Phase ½ clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 3 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase ½ CML safety population. Table 3: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities In the Phase ½ Clinical Study, Safety Population
  CP CML
N=406
n (%) AdvP CML
N=140
n (%) All CP and AdvP CML
N=546
n (%) Hematology Parameters   Platelet Count (Low) less than 50×109/L 102 (25) 80 (57) 182 (33)   Absolute Neutrophil Count less than 1×109/L 74 (18) 52 (37) 126 (23)   Hemoglobin (Low) less than 80 g/L 53 (13) 49 (35) 102 (19) Biochemistry Parameters   SGPT/ALT greater than 5.0×ULN 39 (10) 8 (6) 47 (9)   SGOT/AST greater than 5.0×ULN 17 (4) 4 (3) 21 (4)   Lipase greater than 2×ULN 33 (8) 4 (3) 37 (7)   Phosphorus (Low) less than 0.6 mmol/L 30 (7) 10 (7) 40 (7)   Total Bilirubin greater than 3.0×ULN 3 (1) 2 (1) 5 (1) Additional Data from Multiple Clinical Trials The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from 870 patients with Ph+ leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Blood and Lymphatic System Disorders: 1% and less than 10% -febrile neutropenia Cardiac Disorders: 1% and less than 10% -pericardial effusion; 0.1% and less than 1% -pericarditis Ear and Labyrinth Disorders: 1% and less than 10% -tinnitus Gastrointestinal Disorders: 1% and less than 10% -gastritis; 0.1% and less than 1% -acute pancreatitis, gastrointestinal hemorrhagea General Disorders and Administrative Site Conditions: 1% and less than 10% -chest painb, pain Hepatobiliary Disorders: 1% and less than 10% -hepatotoxicityc, abnormal hepatic functiond; 0.1% and less than 1% -liver injury Immune System Disorders: 1% and less than 10% -drug hypersensitivity; 0.1% and less than 1% -anaphylactic shock Infections and Infestations: 1% and less than 10% -pneumoniae, influenza, bronchitis Investigations: 1% and less than 10% -electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinine Metabolism and Nutrition Disorder: 1% and less than 10% -hyperkalemia, dehydration Musculoskeletal and Connective Tissue Disorder: 1% and less than 10% -myalgia Nervous System Disorders: 1% and less than 10% -dysgeusia Renal and Urinary Disorders: 1% and less than 10% -acute renal failure, renal failure Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% -pleural effusion; 0.1% and less than 1% -acute pulmonary edema, respiratory failure, pulmonary hypertension Skin and Subcutaneous Disorders: 1% and less than 10% -urticaria, pruritus, acne; 0.1% and less than 1% -erythema multiforme, exfoliative rash, drug eruption aGastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage
bChest pain includes the following preferred terms: chest pain, chest discomfort
cHepatotoxicity includes the following preferred terms: hepatotoxicity, toxic hepatitis, cytolytic hepatitis
dAbnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder
ePneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia Read the Bosulif (bosutinib tablets) Side Effects Center for a complete guide to possible side effectsLearn More »

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Recommended Dosing The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food. Continue treatment with BOSULIF until disease progression or patient intolerance. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dose Escalation Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily. Dose Adjustments for Non-Hematologic Adverse Reactions Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy's law case definition), discontinue BOSULIF [see WARNINGS AND PRECAUTIONS]. Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold BOSULIF until recovery to Grade less than or equal to 1. BOSULIF may be resumed at 400 mg once daily [see WARNINGS AND PRECAUTIONS]. For other clinically significant, moderate or severe non-hematological toxicity, withhold BOSULIF until the toxicity has resolved, then consider resuming BOSULIF at 400 mg once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to 500 mg once daily. Dose Adjustments for Myelosuppression Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1). Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia
ANCa less than 1000x106/L
or
Platelets less than 50,000x106/L Withhold BOSULIF until ANC greater than or equal to1000x106/L and platelets greater than or equal to 50,000x106/L.
Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks. If blood counts remain low for greater than 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.
Doses less than 300 mg/day have not been evaluated. aAbsolute Neutrophil Count Concomitant Use With CYP3A Inhibitors Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected (strong CYP3A inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan. Moderate CYP3A inhibitors include fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin) [see DRUG INTERACTIONS]. Concomitant Use With CYP3A Inducers Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected (strong CYP3A inducers include rifampin, phenytoin, carbamazepine, St. John's Wort, rifabutin and phenobarbital. Moderate CYP3A inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine) [see DRUG INTERACTIONS]. Hepatic Impairment In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of BOSULIF is 200 mg daily. A daily dose of 200 mg in patients with hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 200 mg once daily in patients with hepatic impairment and CML [see Use in Special Populations and CLINICAL PHARMACOLOGY]. Renal Impairment In patients with pre-existing severe renal impairment (CLcr less than 30 mL/min), the recommended dose of BOSULIF is 300 mg daily. A daily dose of 300 mg in patients with severe renal impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal renal function receiving 500 mg daily. However, there are no clinical data for efficacy at the dose of 300 mg once daily in patients with severe renal impairment and CML [see Use in Special Populations and CLINICAL PHARMACOLOGY].

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Drugs That May Increase Bosutinib Plasma Concentrations CYP3A or P-glycoprotein (P-gp) inhibitors: Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected [see DOSAGE AND ADMINISTRATION]. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib Cmax 5.2-fold and AUC 8.6-fold compared to BOSULIF alone [see CLINICAL PHARMACOLOGY]. Drugs That May Decrease Bosutinib Plasma Concentrations CYP3A Inducers Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected [see DOSAGE AND ADMINISTRATION]. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant rifampin (strong CYP3A inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to BOSULIF alone [see CLINICAL PHARMACOLOGY]. Proton Pump Inhibitors In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant lansoprazole (PPI) decreased bosutinib Cmax by 46% and AUC by 26% compared to BOSULIF alone [see CLINICAL PHARMACOLOGY]. Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours. Drugs That May Have Their Plasma Concentrations Altered By Bosutinib Substrates of P-glycoprotein An in vitro study suggests that BOSULIF may have the potential to increase the plasma concentrations of drugs that are P-gp substrates, such as digoxin [see CLINICAL PHARMACOLOGY]. Read the Bosulif Drug Interactions Center for a complete guide to possible interactions Learn More »

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BOSULIF is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.

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Hypersensitivity to BOSULIF. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients. Last reviewed on RxList: 10/17/2013
This monograph has been modified to include the generic and brand name in many instances.

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Experience with BOSULIF overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment.

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Dosage Forms And Strengths 100 mg tablets: yellow, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “100” on the other. 500 mg tablets: red, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “500” on the other. Storage And Handling BOSULIF (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “100” on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with “Pfizer” on one side and “500” on the other. BOSULIF (bosutinib) tablets are available in the following packaging configurations (Table 8): Table 8: Tablet Presentations
BOSULIF Tablets Package Configuration Tablet Strength (mg) NDC Tablet Description 120 tablets per bottle 100 mg 0069-0135-01 Yellow, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “100” on the other. 30 tablets per bottle 500 mg 0069-0136-01 Red, oval, biconvex, film-coated tablets, debossed “Pfizer” on one side and “500” on the other. 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) [see USP Controlled Room 10 Temperature]. Handling and Disposal Procedures for proper disposal of anticancer drugs should be considered. Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs. Distributed by: Pfizer Labs, Division of Pfizer Inc, NY, NY 10017. Revised: 2013 Last reviewed on RxList: 10/17/2013
This monograph has been modified to include the generic and brand name in many instances.

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Gastrointestinal Toxicity Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. In the single-arm Phase ½ clinical trial, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 1 day. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-221). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. Myelosuppression Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Patients with CML who are receiving BOSULIF should have a complete blood count performed weekly for the first month and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. Hepatic Toxicity One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) occurred in a trial of BOSULIF in combination with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of 1209 patients in BOSULIF clinical trials. In the 546 patients from the safety population, the incidence of ALT elevation was 17% and AST elevation was 14 %. Twenty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 30 and 33 days, respectively, and the median duration for each was 21 days. Perform monthly hepatic enzyme tests for the first three months of treatment with BOSULIF and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. Fluid Retention Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. In the single-arm Phase ½ clinical trial in 546 patients with CML treated with prior therapy, severe fluid retention was reported in 14 patients (3%). Specifically, 9 patients had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4 pleural and pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary edema, and 1 patient had a Grade 3 edema. Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. Embryofetal Toxicity There are no adequate and well controlled studies of BOSULIF in pregnant women. BOSULIF can cause fetal harm when administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg/day. Females of reproductive potential should be advised to avoid pregnancy while being treated with BOSULIF. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION).

• Dosing and Administration
  Instruct patients to take BOSULIF exactly as prescribed, not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor. If patients miss a dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. A double dose should not be taken to make up for any missed dose. Advise patients to take BOSULIF withfood. Patients should be advised: “Do not crush or cut tablet. Do not touch or handle crushed or broken tablets.”
• Gastrointestinal Problems
  Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with BOSULIF and to seek medical attention promptly for these symptoms.
• Low Blood Cell Counts
  Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising.
• Liver Problems
  Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice.
• Fluid Retention
  Advise patients of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention promptly if these symptoms arise.
• Other Adverse Reactions
  Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, or pruritus with BOSULIF and to seek medical attention if symptoms are significant. There is a possibility of anaphylactic shock.
• Pregnancy and Breast-feeding
  Advise patients that BOSULIF can cause fetal harm when administered to a pregnant woman. Advise women of the potential hazard to the fetus and to avoid becoming pregnant. If BOSULIF is used during pregnancy, or if the patient becomes pregnant while taking BOSULIF, the patient should be apprised of the potential hazard to the fetus. Because a potential risk to the nursing infant cannot be excluded, women that are taking BOSULIF should not breast-feed or provide breast milk to infants.
  Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after completing treatment with BOSULIF. Instruct patients to contact their physicians immediately if they become pregnant during treatment. Advise patients not to take BOSULIF treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician.
• Drug Interactions
  Advise patients that BOSULIF and certain other medicines, including over the counter medications or herbal supplements (such as St. John's wort) can interact with each other and may alter the effects of BOSULIF [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility A 2-year carcinogenicity study was conducted orally in rats at bosutinib doses up to 25 mg/kg/day in males and 15 mg/kg/day in females. The exposures achieved at the high dose were approximately 1.5-to 3-fold the human exposure (based on AUC) at the bosutinib dose of 500 mg/day. The study was negative for carcinogenic findings. Bosutinib was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice. In a rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately equal to that in humans at the 500 mg/day dose of bosutinib. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (40% of the human exposure), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (1.4 times the human exposure). Use In Specific Populations Pregnancy Pregnancy Category D [see WARNINGS AND PRECAUTIONS] Based on its mechanism of action and findings in animals, BOSULIF can cause fetal harm when administered to a pregnant woman. Studies in animals showed reproductive toxicities. If BOSULIF is used during pregnancy, or if the patient becomes pregnant while taking BOSULIF, the patient should be apprised of the potential hazard to the fetus. Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, 3 and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. In a study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10 and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and two fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 4 times those in humans at the 500 mg/day dose of bosutinib. Nursing Mothers It is not known whether bosutinib is excreted in human milk. Bosutinib and/or its metabolites were excreted in the milk of lactating rats. Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BOSULIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established. Geriatric Use In the Phase ½ clinical trial of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment. In a dedicated hepatic impairment trial, the exposure to bosutinib increased (Cmax increased 1.5-to 2.3-fold and the AUC increased 1.9-to 2.4-fold) in patients with hepatic impairment (Child-Pugh classes A, B, and C; N=18) compared to matched healthy volunteers (N=9) [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY]. Renal Impairment Reduce the BOSULIF dose in patients with CLcr less than 30 mL/min at baseline. For patients with CLcr 30 to 50 mL who cannot tolerate a 500 mg dose, follow dose adjustment recommendations for toxicity. In a dedicated renal impairment trial, compared to volunteers with normal renal function, the exposure (AUC) of bosutinib increased by 60% and 35% in subjects with CLcr less than 30 mL/min and CLcr 30 to 50 mL/min, respectively [see DOSING AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. BOSULIF has not been studied in patients undergoing hemodialysis. Last reviewed on RxList: 10/17/2013
This monograph has been modified to include the generic and brand name in many instances.

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