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-------------------------
`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)
`_______________________________________________________________________________________________________________________________________
`
`
`
`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
`
`
`8
`
` *
`
` Sections or subsections omitted from the Full Prescribing Information
`are not listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`2
`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
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Drugs That May Increase Bosutinib Plasma Concentrations
`7.2 Drugs That May Decrease Bosutinib Plasma Concentrations
`
`6
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`Reference ID: 4083804
`
`1
`
`• 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,
`rash, vomiting, abdominal pain,
`respiratory
`tract
`infections, anemia, pyrexia, liver test abnormalities, fatigue, cough, and
`headache. (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: 04/2017
`
`

`

`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,
`2
`
`Reference ID: 4083804
`
`

`

`itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
`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
`400 mg daily
`Creatinine clearance 30 to 50 mL/min
`300 mg daily
`Creatinine clearance less than 30 mL/min
`[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
`
`
`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.
`
`200 mg daily
`
`3
`
` 4
`
`
`
` WARNINGS AND PRECAUTIONS
`
`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
`
`
`
`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. Among 546 patients in a 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 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during
`treatment with BOSULIF was 3 (range 1-268). 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.
`Among the 546 patients in a single-arm Phase 1/2 clinical trial the incidence of ALT elevation was 18% and AST
`elevation was 15%. 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,
`3
`
`Reference ID: 4083804
`
`

`

`more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and
`AST was 35 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.
`Among 546 patients in a single-arm Phase 1/2 clinical trial, Grade 3 or 4 fluid retention was reported in 26 patients
`(5%). Some patients experienced more than one fluid retention event. Specifically, 21 patients experienced Grade 3 or 4
`pleural effusions, 7 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced 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)*
`
`Baseline
`
`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
`Moderate
`Mild
`Normal
`n (%)
`n (%)
`n (%)
`n
`Renal Function Status
`30 (11)
`174 (64)
`53 (19)
`274
`Normal
`177 (40)
`170 (39)
`10 (2)
`438
`Mild
`28 (35)
`4 (5)
`0
`79
`Mild to Moderate
`1 (4)
`1 (4)
`0
`24
`Moderate to Severe
`0
`0
`0
`1
`Severe
`236 (29)
`349 (43)
`63 (8)
`816
`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
`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. There are no adequate and well controlled studies of BOSULIF in pregnant women. Advise females of
`reproductive potential to use effective contraceptive measures to prevent pregnancy while being treated with BOSULIF
`and for at least 30 days after the final dose. 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: 4083804
`
`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 Phase 1/2 trial (n=546) were
`diarrhea (82%), nausea (47%), thrombocytopenia (42%), rash (41%), vomiting (39%), abdominal pain (39%), respiratory
`tract infection (39%), anemia (30%), pyrexia (27%), liver test abnormalities (24%), fatigue (25%), cough (22%), and
`headache (20%) [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:
`
`• 284 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF
`treatment of 26 months, and a median dose intensity of 442 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 442 mg/day.
`• 143 patients with advanced phase CML including 79 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 425 mg/day, and 456 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 based on long-term follow-up.
`
`
`Table 3:
`Adverse Reactions (10% or Greater) in Patients with CML in Study 1*
`
`Chronic Phase CML
`Advanced Phase CML
`N=403
`N=143
`All Grades
`Grade 3/4
`All Grades
`Grade 3/4
`(%)
`(%)
`(%)
`(%)
`85
`9
`76
`4
`47
`1
`48
`2
`42
`31
`6
`2
`45
`39
`40
`26
`38
`12
`39
`5
`37
`3
`43
`3
`42
`8
`38
`4
`26
`9
`20
`10
`
`Diarrhea
`Nausea
`Abdominal Paina
`Thrombocytopeniab
`Respiratory tract
`infectionc
`Vomiting
`Rashd
`Liver test
`
`Reference ID: 4083804
`
`5
`
`

`

`2
`11
`<1
`<1
`0
`12
`1
`<1
`<1
`2
`<1
`2
`<1
`0
`2
`4
`4
`1
`
`21
`38
`37
`17
`22
`22
`17
`14
`13
`13
`8
`10
`7
`13
`20
`9
`15
`12
`
`5
`27
`2
`4
`0
`20
`2
`0
`0
`5
`1
`<1
`0
`<1
`6
`4
`12
`1
`
`
`
`Chronic Phase CML
`N=403
`All Grades
`Grade 3/4
`(%)
`(%)
`
`Advanced Phase CML
`N=143
`All Grades
`Grade 3/4
`(%)
`(%)
`
`abnormalitiese
`Fatiguef
`26
`Anemiag
`27
`23
`Pyrexia
`21
`Headache
`22
`Cough
`Neutropeniah
`18
`Edemai
`20
`17
`Arthralgia
`14
`Decreased appetite
`Renal impairmentj
`13
`13
`Back pain
`13
`Asthenia
`12
`Pruritus
`Dizziness
`11
`12
`Dyspnea
`12
`Pleural effusion
`Leukopeniak
`10
`Chest painl
`7
`*Based on a Minimum of 48 Months of Follow-up
`Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML
`a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain,
`Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain
`b Thrombocytopenia includes the following preferred terms: Platelet count decreased,
`Thrombocytopenia
`c Respiratory tract infection includes the following preferred terms: Acute sinusitis, Acute
`tonsillitis, Atypical pneumonia, Bronchitis, Bronchitis bacterial, Bronchitis pneumococcal,
`Bronchopneumonia, Chronic tonsillitis, H1N1 influenza, Influenza, Laryngitis, Lobar pneumonia,
`Lower respiratory tract infection, Lung infection, Nasopharyngitis, Pertussis, Pharyngitis,
`Pharyngotonsillitis, Pneumonia, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising,
`Pneumonia pneumococcal, Pneumonia streptococcal, Pulmonary mycosis, Respiratory tract
`infection, Respiratory tract infection viral, Rhinitis, Sinusitis, Tonsillitis, Tonsillitis bacterial,
`Tracheitis, Upper respiratory tract infection, Viral upper respiratory tract infection
`d Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis
`allergic, Eczema, Eczema asteatotic, Erythema, Generalised erythema, Intertrigo, Palmar
`erythema, Prurigo, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-
`papular, Skin irritation, Stasis dermatitis
`e Liver Test Abnormalities includes the following preferred terms:
`Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated
`increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin
`unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased,
`Hepatic function abnormal, Hyperbilirubinaemia, Liver function test abnormal, Transaminases
`increased
`f Fatigue includes the following preferred terms: Fatigue, Malaise
`g Anaemia includes the following preferred terms: Anaemia, Haemoglobin decreased
`h Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased
`i Edema includes the following preferred terms containing:
`Acute pulmonary edema, Allergic edema, Angioedema, Bone marrow edema, Circumoral edema,
`Eyelid edema, Eye edema, Face edema, Gastrointestinal edema, Localised edema, Edema, Edema
`peripheral, Periorbital edema, Pharyngeal edema, Pulmonary edema, Scrotal edema, Testicular
`edema, Tongue edema, Weight increased
`
`Reference ID: 4083804
`
`6
`
`

`

`
`
`Advanced Phase CML
`Chronic Phase CML
`N=143
`N=403
`All Grades
`Grade 3/4
`All Grades
`Grade 3/4
`(%)
`(%)
`(%)
`(%)
`j Renal impairment includes the following preferred terms: Acute kidney injury, Acute prerenal
`failure, Anuria, Blood creatinine abnormal, Blood creatinine increased, Chronic kidney disease,
`Oliguria, Prerenal failure, Renal failure, Renal impairment
`k Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased
`l Chest pain included the following preferred terms: Chest pain, chest discomfort.
`
`
`
`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 based on long-term follow-up.
`
`
`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=403
`n (%)
`
`105 (26)
`65 (16)
`51 (13)
`
`
`43 (11)
`19 (5)
`42 (10)
`30 (7)
`3 (1)
`
`Advanced
`Phase CML
`N=143
`n (%)
`
`82 (57)
`55 (39)
`54 (38)
`
`
`8 (6)
`5 (4)
`9 (6)
`10 (7)
`4 (3)
`
`All CP and
`AdvP CML
`N=546
`n (%)
`
`187 (34)
`120 (22)
`105 (19)
`
`
`51 (9)
`24 (4)
`51 (9)
`40 (7)
`7 (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
`*Based on a Minimum of 48 Months of Follow-up
`
`
`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 881 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; less than 1% - granulocytopenia
`
`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
`
`
`Reference ID: 4083804
`
`7
`
`

`

`Gastrointestinal Disorders: 1% and less than 10% - gastritis, gastrointestinal hemorrhage (Anal hemorrhage, Gastric
`hemorrhage, Gastrointestinal hemorrhage, Hematemesis, Hematochezia, Intestinal hemorrhage, Lower
`gastrointestinal hemorrhage, Melena, Rectal hemorrhage, Upper gastrointestinal hemorrhage); 0.1% and less than
`1% - acute pancreatitis
`
`General Disorders and Administrative Site Conditions: 1% and less than 10% - pain
`
`Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity (includes Allergic hepatitis, Ascites, Cholestasis,
`Drug-induced liver injury, Hepatic steatosis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Liver disorder,
`Liver injury)
`Immune System Disorders: 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic
`shock
`
`Investigations: 1% and less than 10% - electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged,
`Long QT syndrome), blood creatine phosphokinase increased, amylase increased.
`Metabolism and Nutrition Disorder: 1% and less than 10% - hyperkalemia, dehydration, hypophosphatemia
`
`Musculoskeletal and Connective Tissue Disorder: 1% and less than 10% - myalgia
`
`Nervous System Disorders: 1% and less than 10% - dysgeusia
`
`Respiratory, Thoracic and Mediastinal Disorders: 0.1% and less than 1% - respiratory failure, pulmonary
`hypertension
`
`Skin and Subcutaneous Disorders: 1% and less than 10% - urticaria, pruritus; 0.1% and less than 1% - erythema
`multiforme, exfoliative rash, drug eruption
`
`
`6.2 Post-Marketing Experience
`
`
`
`The following additional adverse reactions have been identified during post-approval use of BOSULIF. Because
`these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
`their frequency or establish a causal relationship to drug exposure.
`
`Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome
`
`
`DRUG INTERACTIONS
`
`7
`
`
`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 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.
`
`
`Reference ID: 4083804
`
`8
`
`

`

`8
`
`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. Advise females of reproductive potential to use
`effective contraceptive measures to prevent pregnancy while being treated with BOSULIF and for at least 30 days after
`the final dose. 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.
`
`8.3Nursing 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 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 Dosage 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 obs