HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`BOSULIF safely and effectively. See full prescribing information for
`BOSULIF
`
`BOSULIF® (bosutinib) tablets, for oral use
`Initial U.S. Approval: 2012
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`Dosage and Administration, Renal Impairment (2.8)
`4/2013
`
`----------------------------INDICATIONS AND USAGE--------------------------
` BOSULIF is a kinase inhibitor indicated for the treatment of adult patients
`with chronic, accelerated, or blast phase Ph+ chronic myelogenous
`leukemia (CML) with resistance or intolerance to prior therapy. (1)
`
`----------------------DOSAGE AND ADMINISTRATION----------------------
` Recommended Dose: 500 mg orally once daily with food. (2.1)
` Consider dose escalation to 600 mg daily in patients who do not reach
`complete hematologic response by week 8 or complete cytogenetic
`response by week 12 and do not have Grade 3 or greater adverse reactions.
`(2.2)
` Adjust dosage for hematologic and non-hematologic toxicity. (2.3, 2.4)
` Adjust dosage for hepatic and renal impairment. (2.7, 2.8)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`Tablets: 100 mg and 500 mg. (3)
`
`-------------------------------CONTRAINDICATIONS----------------------------
`Hypersensitivity to BOSULIF. (4)
`
` Myelosuppression: Monitor blood counts and manage as necessary. (2.4,
`5.2)
` Hepatic toxicity: Monitor liver enzymes at least monthly for the first three
`months and as needed. Withhold, dose reduce, or discontinue BOSULIF.
`(2.3,5.3)
` Fluid retention: Monitor patients and manage using standard of care
`treatment. Withhold, dose reduce, or discontinue BOSULIF. (2.3,5.4)
` Embryofetal toxicity: May cause fetal harm. Females of reproductive
`potential should avoid becoming pregnant while being treated with
`BOSULIF. (5.5)
`
`------------------------------ADVERSE REACTIONS------------------------------
` Most common adverse reactions (incidence greater than 20%) are diarrhea,
`nausea,
`thrombocytopenia, vomiting, abdominal pain, rash, anemia,
`pyrexia, and fatigue. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`CYP3A Inhibitors and Inducers: Avoid concurrent use of BOSULIF with
`strong or moderate CYP3A inhibitors and inducers. (2.5, 2.6, 7.1, 7.2)
`
`Proton Pump Inhibitors: May decrease bosutinib drug levels. Consider short-
`acting antacids in place of proton pump inhibitors. (7.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`Revised: x/2013
`
`----------------------WARNINGS AND PRECAUTIONS------------------------
` Gastrointestinal toxicity: Monitor and manage as necessary. Withhold,
`dose reduce, or discontinue BOSULIF. (2.3,5.1)
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`2
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`16.3 Handling and Disposal
`PATIENT COUNSELING INFORMATION
`
`17
`
`* Sections or subsections omitted from the Full Prescribing Information
`are not listed.
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Dose Escalation
`2.3 Dose Adjustments for Non-Hematologic Adverse Reactions
`2.4 Dose Adjustments for Myelosuppression
`2.5 Concomitant Use With CYP3A Inhibitors
`2.6 Concomitant Use With CYP3A Inducers
`2.7 Hepatic Impairment
`2.8 Renal Impairment
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Gastrointestinal Toxicity
`5.2 Myelosuppression
`5.3 Hepatic Toxicity
`5.4 Fluid Retention
`5.5 Embryofetal Toxicity
`ADVERSE REACTIONS
`6.1
`Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP),
`Accelerated Phase (AP), and Blast Phase (BP) CML
`6.2 Additional Data from Multiple Clinical Trials
`DRUG INTERACTIONS
`7.1 Drugs That May Increase Bosutinib Plasma Concentrations
`7.2 Drugs That May Decrease Bosutinib Plasma Concentrations
`7.3 Drugs That May Have Their Plasma Concentration Altered By
`Bosutinib
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`
`6
`
`7
`
`8
`
`Reference ID: 3381509
`
`1
`
`

`

`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`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.
`
`2
`
`DOSAGE AND ADMINISTRATION
`2.1 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.
`2.2 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.
`2.3 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 (5.3)].
`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 (5.1)].
`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.
`2.4 Dose Adjustments for Myelosuppression
`Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1).
`
`ANCa less than 1000x106/L
`
`or
`
`Platelets less than 50,000x106/L
`
`a Absolute Neutrophil Count
`
`Table 1:
`
`Dose Adjustments for Neutropenia and Thrombocytopenia
`
`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.
`
`2.5 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 (7.1)].
`2.6 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 (7.2)].
`2.7 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
`2
`
`Reference ID: 3381509
`
`

`

`(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 (8.6) and
`Clinical Pharmacology (12.3)].
`2.8 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 (8.7) and Clinical Pharmacology (12.3)].
`
`3
`
`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.
`
`4
`
`CONTRAINDICATIONS
`Hypersensitivity to BOSULIF. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated
`patients.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 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 1/2 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 (2.3) and
`Adverse Reactions (6)].
`5.2 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 (2.4) and
`Adverse Reactions (6)].
`5.3 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 (2.3) and Adverse Reactions (6)].
`5.4 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 1/2 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 (2.3) and Adverse Reactions (6)].
`5.5 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 (8.1)].
`
`Reference ID: 3381509
`
`3
`
`

`

`6
`
`ADVERSE REACTIONS
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`• Gastrointestinal toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
`• Myelosuppression [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)].
`• Hepatic toxicity [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)].
`• Fluid retention [see Warnings and Precautions (5.4)].
`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 (4)], 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 1/2 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%).
`6.1 Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML
`The single-arm Phase 1/2 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 1/2 CML safety
`population.
`
`Table 2:
`
`Adverse Reactions (10% or greater) in patients with CML
`
`All CP and AdvP CML
`CP CML
`AdvP CML
`N=546
`N=406
`N=140
`n (%)
`n (%)
`n (%)
`All Grades
`Grade 3/4 All Grades Grade 3/4
`
`System Organ Class
`Preferred Term
`
`
`Gastrointestinal Disorders
`Diarrhea
`Nausea
`Abdominal Paina
`Vomiting
`Blood and Lymphatic System Disorders
`Thrombocytopenia
`Anemia
`Neutropenia
`General Disorders and Administrative Site Conditions
`Fatigueb
`Pyrexia
`Edemac
`Asthenia
`Infections and Infestations
`Respiratory tract infectiond
`Nasopharyngitis
`Investigations
`Alanine aminotransferase increased
`Aspartate aminotransferase increased
`Metabolism and nutrition disorder
`Decreased appetite
`Musculoskeletal and Connective Tissue Disorder
`Arthralgia
`Back pain
`Nervous System Disorders
`Headache
`Dizziness
`Respiratory, Thoracic and Mediastinal Disorders
`Dyspnea
`
`Reference ID: 3381509
`
`Grade
`3/4
`
`All
`Grades
`
`342 (84)
`186 (46)
`162 (40)
`152 (37)
`
`163 (40)
`94 (23)
`65 (16)
`
`104 (26)
`90 (22)
`56 (14)
`45 (11)
`
`49 (12)
`47 (12)
`
`81 (20)
`64 (16)
`
`53 (13)
`
`58 (14)
`49 (12)
`
`82 (20)
`39 (10)
`
`41 (10)
`
`38 (9)
`5 (1)
`6 (1)
`12 (3)
`
`105 (26)
`35 (9)
`43 (11)
`
`6 (1)
`2 (<1)
`1 (<1)
`5 (1)
`
`2 (<1)
`0
`
`30 (7)
`15 (4)
`
`3 (1)
`
`2 (<1)
`3 (1)
`
`3 (1)
`0
`
`4 (1)
`
`4
`
`107 (76)
`66 (47)
`41 (29)
`59 (42)
`
`59 (42)
`52 (37)
`26 (19)
`
`28 (20)
`51 (36)
`19 (14)
`14 (10)
`
`14 (10)
`7 (5)
`
`14(10)
`15(11)
`
`19 (14)
`
`18 (13)
`10 (7)
`
`25 (18)
`18 (13)
`
`26 (19)
`
`7 (5)
`3 (2)
`7 (5)
`5 (4)
`
`52 (37)
`37 (26)
`25 (18)
`
`6 (4)
`4 (3)
`1 (1)
`1 (1)
`
`0
`0
`
`7(5)
`4 (3)
`
`0
`
`0
`2 (1)
`
`6 (4)
`1 (1)
`
`8 (6)
`
`449 (82)
`252 (46)
`203 (37)
`211 (39)
`
`222 (41)
`146 (27)
`91 (17)
`
`132 (24)
`141 (26)
`75 (14)
`59 (11)
`
`63 (12)
`54 (10)
`
`95(17)
`79(14)
`
`72 (13)
`
`76 (14)
`59 (11)
`
`107 (20)
`57 (10)
`
`67 (12)
`
`45 (8)
`8 (1)
`13 (2)
`17 (3)
`
`157 (29)
`72 (13)
`68 (12)
`
`12 (2)
`6 (1)
`2 (<1)
`6 (1)
`
`2 (<1)
`0
`
`37(7)
`19(3)
`
`3 (1)
`
`2 (<1)
`5 (1)
`
`9 (2)
`1 (<1)
`
`12 (2)
`
`

`

`System Organ Class
`Preferred Term
`
`
`CP CML
`N=406
`n (%)
`All Grades
`
`All CP and AdvP CML
`AdvP CML
`N=546
`N=140
`n (%)
`n (%)
`Grade 3/4 All Grades Grade 3/4
`
`Cough
`Skin and Subcutaneous Disorders
`Rashe
`189 (35)
`6 (4)
`49 (35)
`32 (8)
`140 (34)
`54 (10)
`0
`11 (8)
`3 (1)
`43 (11)
`Pruritus
`CP CML = Chronic Phase CML; AdvP CML = Advanced Phase CML (includes patients with Accelerated Phase and Blast Phase CML)
`a Abdominal pain includes the following preferred terms: Abdominal pain, Abdominal pain upper, Abdominal pain lower, Abdominal tenderness, Gastrointestinal
`pain, Abdominal discomfort
`b Fatigue includes the following preferred terms: Fatigue, Malaise
`c Edema includes the following preferred terms: Edema, Edema peripheral, Localized edema, Face edema
`d Respiratory 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
`e Rash includes the following preferred terms: Rash, Rash macular, Rash pruritic, Rash generalized, Rash papular, Rash maculo-papular
`
`Grade
`3/4
`0
`
`80(20)
`
`All
`Grades
`30(21)
`
`0
`
`110(20)
`
`0
`
`38 (7)
`3 (1)
`
`In the single-arm Phase 1/2 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 1/2 CML safety
`population.
`
`Table 3:
`
`Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities
`
`In the Phase 1/2 Clinical Study, Safety Population
`
`CP CML
`AdvP CML
`N=406
`N=140
`n (%)
`n (%)
`
`All CP and AdvP
`CML
`N=546
`n (%)
`
`Hematology Parameters
`
`Platelet Count (Low) less than 50×109/L
`
`Absolute Neutrophil Count less than 1×109/L
`Hemoglobin (Low) less than 80 g/L
`
`
`Biochemistry Parameters
`SGPT/ALT greater than 5.0×ULN
`
`SGOT/AST greater than 5.0×ULN
`
`Lipase greater than 2×ULN
`
`Phosphorus (Low) less than 0.6 mmol/L
`
`Total Bilirubin greater than 3.0×ULN
`
`
`102 (25)
`74 (18)
`53 (13)
`
`39 (10)
`17 (4)
`33 (8)
`30 (7)
`3 (1)
`
`80 (57)
`52 (37)
`49 (35)
`
`8 (6)
`4 (3)
`4 (3)
`10 (7)
`2 (1)
`
`182 (33)
`126 (23)
`102 (19)
`
`47 (9)
`21 (4)
`37 (7)
`40 (7)
`5 (1)
`
`6.2 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
`
`Reference ID: 3381509
`
`5
`
`

`

`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
`
`a Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper
`gastrointestinal hemorrhage
`b Chest pain includes the following preferred terms: chest pain, chest discomfort
`c Hepatotoxicity includes the following preferred terms: hepatotoxicity, toxic hepatitis, cytolytic hepatitis
`d Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder
`e Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia
`
`7
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`DRUG INTERACTIONS
`7.1 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 (2.5)]. 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 (12.3)].
`7.2 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 (2.6)]. 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 (12.3)].
`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 (12.3)].
`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.
`7.3 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 (12.3)].
`
`8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Pregnancy Category D [see Warnings and Precautions (5.5)]
`
`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.
`6
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`Reference ID: 3381509
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`8.3 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.
`8.4 Pediatric Use
`The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established.
`8.5 Geriatric Use
`In the Phase 1/2 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.
`8.6 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 (2.7), Adverse Reactions (6), and Clinical Pharmacology (12.3)].
`8.7 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 (2.8) and Clinical Pharmacology (12.3)].
`BOSULIF has not been studied in patients undergoing hemodialysis.
`
`10 OVERDOSAGE
`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.
`
`11
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`DESCRIPTION
`Bosutinib is a kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-
`methoxyphenyl)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).
`
`Reference ID: 3381509
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`7
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`12
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`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of
`Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine
`myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of
`CML tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of
`Bcr-Abl.
`12.2 Pharmacodynamics
`The effect of a single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was evaluated in a
`randomized, placebo- and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 60 healthy
`subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed.
`12.3 Pharmacokinetics
`Absorption
`Following administration of a single dose of BOSULIF 500 mg with food in patients with cancer, the median time-to-peak
`concentration (tmax) was 4-6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to
`800 mg. After 15 daily doses of BOSULIF (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL,
`and the mean (SD) AUC was 3650 (425) ng•h/mL. When given with a high fat meal, the