`• 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)
`
`
`• Renal Toxicity: Monitor patients for renal function at baseline and during
`
`
`therapy with BOSULIF. (5.5)
`
`
`
`• Embryofetal Toxicity: May cause fetal harm. Females of reproductive
`
`
`
`potential should avoid becoming pregnant while being treated with
`
`BOSULIF. (5.6)
`
`
`
`
`------------------------------ADVERSE REACTIONS-----------------------------­
`
`
`
`
`
`Most common adverse reactions (incidence ≥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)
`
`
`
`
`
`----------------------------USE IN SPECIFIC POPULATIONS------------------­
`
`• Nursing Mothers: Discontinue nursing if drug is important to mother.
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`approved patient labeling.
`
`
`
`
`
`Revised: 11/2016
`
`
`
`
`
`
` IGHLIGHTS 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 (2)
`9/2015
`
`
`Contraindications (4)
`4/2016
`
`
`----------------------------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 toxicity and organ impairment (2)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`Tablets: 100 mg and 500 mg. (3)
`
`
`-------------------------------CONTRAINDICATIONS---------------------------­
`
`
`
`Hypersensitivity to BOSULIF. (4)
`
`
`-------------------------WARNINGS AND PRECAUTIONS--------------------­
`
`
`
`• Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold,
`
`
`dose reduce, or discontinue BOSULIF. (2.3, 5.1)
`
`
`• Myelosuppression: Monitor blood counts and manage as necessary. (2.4,
`
`5.2)
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`2
`
`
`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 Recommended Starting Dosage with Hepatic Impairment or 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 Renal Toxicity
`
`
`5.6 Embryofetal Toxicity
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`DRUG INTERACTIONS
`
`
`7.1 Drugs That May Increase Bosutinib Plasma Concentrations
`
`
`
`7.2 Drugs That May Decrease Bosutinib Plasma Concentrations
`
`
`
`
`6
`
`
`7
`
`
`8
`
`
`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
`
`
`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
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`* Sections or subsections omitted from the Full Prescribing Information
`are not listed.
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`Reference ID: 4015091
`
`
`
` 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.
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
` 2
`
`
`
`
`
`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
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` a Absolute Neutrophil Count
`
`
`
`
`
` 2.5 Concomitant Use With CYP3A Inhibitors
`
`
`
`Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib
`
`
`plasma concentration is expected (strong CYP3A inhibitors include boceprevir, clarithromycin, conivaptan, indinavir,
`
`itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
`
`
` 2
`
`Reference ID: 4015091
`
`

`

`telaprevir, telithromycin, and voriconazole. Moderate CYP3A inhibitors include amprenavir, aprepitant, atazanavir,
`ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit products,
`
`imatinib and verapamil) [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 carbamazepine, phenytoin, rifampin and St. John’s Wort. Moderate CYP3A
`
`
`inducers include bosentan, efavirenz, etravirine, modafinil and nafcillin) [see Drug Interactions (7.2)].
`
`
`
`
`2.7 Recommended Starting Dosage with Hepatic Impairment or Renal Impairment
`
`
`
`
` Organ Function Status
` Recommended Starting Dosage
`
`
`
`
` Normal hepatic and renal function
` 500 mg once daily
`
`
` Hepatic impairment
` Mild (Child-Pugh A), Moderate (Child-Pugh B) or
`
` severe (Child-Pugh C)
`
` Renal impairment
` Creatinine clearance 30 to 50 mL/min
`
`
`
` 400 mg daily
` Creatinine clearance less than 30 mL/min
`
` 300 mg daily
`
`
` [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
`
`
`
`
`
` 200 mg daily
`
`
`
`
`
`
`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.
`
`
`
`3
`
`
`
`4
`
`
`CONTRAINDICATIONS
`
`BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included
`
`
`
`anaphylaxis. 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 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. Perform complete blood counts
`
`
`weekly for the first month of therapy 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%
`
`
`
`
`Reference ID: 4015091
`
`
`
` 3
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` 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 hepatic enzyme tests monthly for the first three months of BOSULIF treatment 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 Renal Toxicity
`
`
` An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with
`
`
`
` BOSULIF. Table 2 identifies the shift from baseline to lowest observed estimated glomerular filtration rate (eGFR) during
`
`
`
`
` BOSULIF therapy for patients in the global Ph+ Leukemia studies. The median duration of therapy with BOSULIF was
` approximately 17 months (range, 0.03 to 95) for patients in these studies.
`
`
`
`
`
` Table 2:
`
`
`
`
`
` Shift from Baseline to Lowest Observed eGFR Group During Treatment
`
` Safety Population in Clinical Studies
`
`
`
`
` (n=818)*
`
`
`
`
`
`
`
` Follow Up
`
`
` Moderate to
`
`Severe
`
` n (%)
`
` 14 (5)
` 63 (14)
`
`
` 37 (47)
` 6 (25)
`
`
` 0
` 120 (15)
`
`
`
` Severe
`
` n (%)
`
` 1 (<1)
`
` 14 (3)
` 10 (13)
`
`
` 15 (63)
`
` 0
` 40 (5)
`
`
`
`
` Kidney Failure
`
` n (%)
`
` 1 (<1)
`
` 2 (1)
`
` 0
` 1 (4)
`
`
` 1 (100)
`
` 5 (1)
`
` Mild to
`
`
` Mild
`Normal
`
` Moderate
`
` n (%)
`
` n (%)
` n
`
`
` Renal Function Status
`
` n (%)
`
` 174 (64)
`
` 53 (19)
`
` 274
` Normal
`
`
` 30 (11)
`
` 170 (39)
` 10 (2)
`
`
` 438
`
` Mild
` 177 (40)
`
`
` 4 (5)
`
` 0
` 79
`
` Mild to Moderate
`
` 28 (35)
`
`
` 1 (4)
`
` 0
`
` 24
` Moderate to Severe
`
`
` 1 (4)
`
` 0
`
` 0
`
` 1
`
`Severe
`
` 0
` 349 (43)
` 63 (8)
` 816
`
`
`
`
`
` 236 (29)
` Total
`
` Notes: Grading is based on Modification in Diet in Renal Disease method (MDRD).
`
`
` KDIGO Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than
`
` 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m2 .
`
`
`
`
`*Among the 818 patients, eGFR was missing in 5 patients at baseline or on-therapy. There were no patients with kidney failure at
`
`
`
`
`
` baseline.
`
`Monitor renal function at baseline and during therapy with BOSULIF, with particular attention to those patients
`
`
`
`who have preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with
`
`
`
`
`baseline and treatment emergent renal impairment [see Dosage and Administration (2.7)].
`
`
`
`
`5.6 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)].
`
`
`
`
`
` Baseline
`
`
`
`
`
`Reference ID: 4015091
`
`
`
` 4
`
`

`

`
`
`
`
` 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)].
`
`
`
`
` • Renal toxicity [see Warnings and Precautions (5.5)].
`
`
`
`
`
`
`
` 6
`
`
`
`
`
` 6.1 Clinical Trials Experience
`
` 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%) [see Clinical Studies (14)].
`
`
`
`
`
`Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated
`Phase (AP), and Blast Phase (BP) CML
`
`
`
`
`The single-arm Phase 1/2 clinical trial (Study 1) enrolled patients with Ph+ chronic, accelerated, or blast phase
`
`
`
`
`chronic myelogenous leukemia (CML) and with resistance or intolerance to prior therapy [see Clinical Studies (14)]. The
`
`
`
`
`safety population (received at least 1 dose of BOSULIF) included 546 CML patients:
`
`
`
`• 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.
`
`
`
`• 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.
`
`
`
`
`
`• 140 patients with advanced phase CML including 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 3 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 3:
`
`
`
`Adverse Reactions (10% or Greater) in Patients with CML in Study 1
`
`
`
`
`
`
` Chronic Phase CML
`
`
` N=406
`
` Grade 3/4
`All Grades
`
` (%)
`
` (%)
`
` 9
`
` 84
`
` 1
`
` 46
`
` 40
`
` 1
`
` 26
`
` 40
`
` 3
`
` 37
`
` 8
`
` 34
`
` 1
`
` 26
`
` 9
`
` 23
` <1
`
` 22
`
`
`
`
`
` Diarrhea
`
` Nausea
` Abdominal Paina
`
` Thrombocytopenia
`
`
` Vomiting
`
` Rashb
`
` Fatiguec
`
` Anemia
`
` Pyrexia
`
`
`
` Advanced Phase CML
`
` N=140
`
` Grade 3/4
`
` All Grades
`
` (%)
`
` (%)
`
` 5
`
` 76
`
` 2
`
` 47
`
` 5
`
` 29
`
` 37
`
` 42
`
` 4
`
` 42
`
` 4
`
` 35
`
` 4
`
` 20
`
` 26
`
` 37
`
`
` 36
` 3
`
`Reference ID: 4015091
`
`
`
` 5
`
`

`

`
`
`
`
` Advanced Phase CML
`
`
` Chronic Phase CML
`
` N=140
`
` N=406
`
` Grade 3/4
`
` All Grades
`
` Grade 3/4
`All Grades
`
` (%)
`
` (%)
`
` (%)
`
` (%)
`
` Increased alanine
`
` 5
`
` 10
`
` 7
`
` 20
` aminotransferase
`
`
` Headache
`
` 4
`
` 18
`
` 1
`
` 20
`
` Cough
`
` 0
`
` 21
`
` 0
`
` 20
`
` Increased aspartate
`
` 3
`
` 11
`
` 4
`
` 16
`
` aminotransferase
`
` Neutropenia
`
` 16
`
` 18
`
` 19
`
` 11
`
` Edemad
`
` 1
`
` 14
`
` <1
`
` 14
` Arthralgia
`
`
` 0
`
` 13
`
` <1
`
` 14
`
` Decreased appetite
`
` 0
`
` 14
`
`
` 13
` 1
` Respiratory tract
`
`
` 0
`
` 10
`
` <1
`
` 12
`
` infectione
`
` Nasopharyngitis
`
` 0
`
` 5
`
` 0
`
` 12
`
`
` 1
`
` 7
`
` 1
`
` 12
` Back pain
`
` 1
`
` 10
`
` 1
`
` 11
`
` Asthenia
`
` 0
`
`
` 1
`
` 11
`
` Pruritus
` 8
`
` Dizziness
`
` 1
`
` 13
`
` 0
`
` 10
`
` 6
`
` 19
`
` 1
`
` 10
`
` Dyspnea
` Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML
`
`
`
`
` a Abdominal pain includes the following terms: abdominal pain, upper abdominal pain, lower
`
`abdominal pain, abdominal tenderness, gastrointestinal pain, abdominal discomfort
` b Rash includes the following terms: rash, macular rash, pruritic rash, generalized rash, popular
`
`
`
` rash, maculo-papular rash
`
`
`c Fatigue includes the following terms: fatigue, malaise
`
`
`
`
`
` d Edema includes the following terms: edema, peripheral edema, localized edema, face edema
`
` e Respiratory tract infection includes the following terms: respiratory tract infection, upper
`
`
`respiratory tract infection, lower respiratory tract infection, viral upper respiratory tract infection,
`
`
`
`
`viral respiratory tract infection
`
`
`
`
`
`
`
`In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than
`
`
`
`
`
`500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were
`
`
`
`
`
`excluded by protocol.
`
`Table 4 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML
`
`
`
`
`
`
`
`safety population.
`
`
`
`Reference ID: 4015091
`
`
`
` 6
`
`

`

`
`
`
`
`
`
`
`
` Table 4:
`
`
` Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in Patients
`
`
`
` with CML in Study 1, Safety Population
`
`
`
` Chronic Phase
`
` CML
`
` N=406
`
` n (%)
`
` 102 (25)
`
` 74 (18)
`
`
` 53 (13)
`
`
`
` 39 (10)
` 17 (4)
`
`
` 33 (8)
`
` 30 (7)
`
` 3 (1)
`
`
` 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
`
`
`
`
`
`Advanced
`
`
` Phase CML
` N=140
`
`
` n (%)
`
`
` 80 (57)
`
` 52 (37)
`
` 49 (35)
`
`
`
` 8 (6)
`
` 4 (3)
`
` 4 (3)
`
` 10 (7)
`
` 2 (1)
`
`All CP and
`
` AdvP CML
`
` N=546
`
` n (%)
`
`
` 182 (33)
`
` 126 (23)
`
` 102 (19)
`
`
`
` 47 (9)
`
` 21 (4)
`
` 37 (7)
`
` 40 (7)
`
` 5 (1)
`
`
`
` Additional Adverse Reactions 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
`
`
`
`Vascular Disorders: 1% and less than 10% - hypertension
`
`
`
`Gastrointestinal Disorders: 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis,
`
`
`
`
`
`
`gastrointestinal hemorrhage (includes gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal
`
`
`hemorrhage)
`
`
`
`General Disorders and Administrative Site Conditions: 1% and less than 10% - chest pain (includes chest pain and
`
`
`
`chest discomfort), pain
`
`
`
`Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity (includes hepatotoxicity, toxic hepatitis, and cytolytic
`
`
`
`
`hepatitis), abnormal hepatic function (includes abnormal hepatic function, liver disorder); 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% - pneumonia (includes pneumonia, bronchopneumonia, lobar
`
`
`
`pneumonia, primary atypical pneumonia), influenza, bronchitis
`
`
`
`
`Reference ID: 4015091
`
`
`
` 7
`
`

`

`
`
` 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
`
`
`DRUG INTERACTIONS
`
`
`
`
`
`
`
`7
`
`
`
`
` 8
`
`
`7.1 Drugs That May Increase Bosutinib Plasma Concentrations
`
`
`
`CYP3A inhibitors: Avoid the concomitant use of strong or moderate CYP3A 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 C max 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.
`
` USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`Pregnancy Category D [see Warnings and Precautions (5.6)]
`
`
`
`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.
`
`
`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
`
` 8
`
`Reference ID: 4015091
`
`

`

`
`
`
`
` 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 (C max 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 starting dose in patients with severe (CLcr less than 30 mL/min) or moderate (CLcr 30 to
`
`
`
`
`
`50 mL/min) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot
`
`
`
`
`
`
`
`tolerate a 500 mg dose, follow dose adjustment recommendations for toxicity. In a dedicated renal impairment trial,
`
`
`
`compared to subjects 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, compared to subjects with normal renal function
`
`
`
`
`
`[see Dosing and Administration (2.7) 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 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 C 26H29Cl2N5O3•H 2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46
`
`
`
`(anhydrous). Bosutinib monohydrate has the following chemical structure:
`
`
`
`
`
`Cl
`
`Cl
`
`MeO
`
`N
`
`O
`
`N
`
`N
`
`Me
`
`HN
`
`OMe
`
`CN
`
`• H2O
`
`
`
`
`
`
` Bosutinib monohydrate is a white to