----------------------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)
`• Hepatic Toxicity: Monitor liver enzymes at least monthly for the first
`3 months and as needed. Withhold, dose reduce, or discontinue BOSULIF.
`(2.3, 5.3)
`• Cardiac Failure: Monitor and manage as necessary. (5.4)
`• Fluid Retention: Monitor patients and manage using standard of care
`treatment. Withhold, dose reduce, or discontinue BOSULIF. (2.3, 5.5)
`• Renal Toxicity: Monitor patients for renal function at baseline and during
`therapy with BOSULIF. (5.6)
`• Embryo-Fetal Toxicity: BOSULIF can cause fetal harm. Advise patients of
`potential risk to a fetus and to use effective contraception. (5.7)
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------
`Most common adverse reactions in patients with newly-diagnosed CML
`(incidence ≥20%) are diarrhea, nausea, thrombocytopenia, rash, increased
`alanine
`aminotransferase,
`abdominal
`pain,
`increased
`aspartate
`aminotransferase. (6)
`Most common adverse reactions in patients with CML who were resistant or
`intolerant to prior therapy (incidence ≥20%) are diarrhea, nausea, abdominal
`pain, rash, thrombocytopenia, vomiting, anemia, fatigue, pyrexia, cough,
`headache, alanine aminotransferase, and edema. (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-------------------------------
`• Strong and Moderate CYP3A Inhibitors: Avoid concomitant use with
`BOSULIF. (7.1)
`• Strong CYP3A Inducers: Avoid concomitant use with BOSULIF. (7.1)
`• Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an
`alternative to proton pump inhibitors. (7.1)
`
`----------------------------USE IN SPECIFIC POPULATIONS-------------------
`• Lactation: Advise women not to breastfeed. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`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-------------------------
`Warnings and Precautions, Embryo-Fetal Toxicity (5.7)
`8/2019
` 10/2019
`Warnings and Precautions, Cardiac Failure (5.4)
`
`
`----------------------------INDICATIONS AND USAGE--------------------------
`BOSULIF is a kinase inhibitor indicated for the treatment of adult patients
`with
`• Newly-diagnosed chronic phase Ph+ chronic myelogenous leukemia
`(CML). This indication is approved under accelerated approval based on
`molecular and cytogenetic response rates. Continued approval for this
`indication may be contingent upon verification and confirmation of clinical
`benefit in an ongoing long-term follow up trial. (1, 14)
`• Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance
`to prior therapy. (1)
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------
`• Newly-diagnosed chronic phase Ph+ CML: 400 mg orally once daily with
`food. (2.1)
`• Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance
`to prior therapy: 500 mg orally once daily with food. (2.1)
`• Consider dose escalation by increments of 100 mg once daily to a maximum
`of 600 mg daily in patients who do not reach complete hematologic,
`cytogenetic, or molecular response 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, 400 mg, and 500 mg. (3)
`
`-------------------------------CONTRAINDICATIONS----------------------------
`Hypersensitivity to BOSULIF. (4)
`
`
`
`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 Dose Adjustments for Renal Impairment or Hepatic 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 Cardiac Failure
`5.5 Fluid Retention
`5.6 Renal Toxicity
`5.7 Embryo-Fetal Toxicity
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Effect of Other Drugs on BOSULIF
`
`6
`
`7
`
`Revised: 10/2019
`
`_______________________________________________________________________________________________________________________________________
`
`
`8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic 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
`14.1 Newly-Diagnosed CP Ph+ CML
`14.2 Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML
`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: 4504031
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`1
`
`INDICATIONS AND USAGE
`
`BOSULIF is indicated for the treatment of adult patients with:
`• Newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+
`CML). This indication is approved under accelerated approval based on molecular and cytogenetic response rates
`[see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and
`confirmation of clinical benefit in an ongoing long-term follow up trial.
`• Chronic phase, accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior
`therapy.
`
`
`DOSAGE AND ADMINISTRATION
`
`2
`
`
`
`
`2.1 Recommended Dosing
`The recommended dose is taken orally once daily with food. The tablet is to be swallowed whole and should not be
`broken or cut. Continue treatment with BOSULIF until disease progression or intolerance to therapy.
`
`If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the
`following day.
`
`Newly-Diagnosed CP Ph+ CML
`The recommended dose of BOSULIF is 400 mg orally once daily with food.
`
`CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy
`The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food.
`
`2.2 Dose Escalation
`In clinical studies of adult Ph+ CML patients, dose escalation by increments of 100 mg once daily to a maximum of
`600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular
`response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage.
`
`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 National Cancer Institute Common Terminology Criteria for Adverse Events (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 a dose reduced by 100 mg taken once daily. If clinically
`appropriate, consider re-escalating the dose of BOSULIF to the starting dose taken once daily. Doses less than
`300 mg/day have been used in patients; however, efficacy has not been established.
`
`2.4 Dose Adjustments for Myelosuppression
`Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1).
`
`Reference ID: 4504031
`
`2
`
`

`

`ANCa less than 1000×106/L
`
`or
`
`Platelets less than 50,000×106/L
`
`Table 1:
`Dose Adjustments for Neutropenia and Thrombocytopenia
`
`Withhold BOSULIF until ANC greater than or equal to1000×106/L and
`platelets greater than or equal to 50,000×106/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 been used in patients; however, efficacy has
`not been established.
`
`a Absolute Neutrophil Count
`
`2.5 Dose Adjustments for Renal Impairment or Hepatic Impairment
`The recommended starting doses for patients with renal and hepatic impairment are described in Table 2 below.
`
`Table 2:
`Dose Adjustments for Renal and Hepatic Impairment
`
`
`
`
`
`
`Recommended Starting Dosage
`Newly-diagnosed
`Chronic,
`chronic phase Ph+
`accelerated, or blast
`CML2
`phase Ph+ CML
`with resistance or
`intolerance to prior
`therapy
`500 mg daily
`
`400 mg daily
`
`Normal renal and hepatic function
`Renal impairment
`Creatinine clearance 30 to 50 mL/min
`Creatinine clearance less than 30 mL/min
`Hepatic impairment
`Mild (Child-Pugh A), Moderate (Child-Pugh B) or
`200 mg dailya
`Severe (Child-Pugh C)
`[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
`Abbreviations: CML=chronic myelogenous leukemia; Ph+=Philadelphia chromosome-positive.
`a There are no clinical data for efficacy at the dose of 200 mg once daily in patients with CML.
`
`DOSAGE FORMS AND STRENGTHS
`• 100 mg tablets: yellow, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “100” on
`the other.
`• 400 mg tablets: orange, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “400” on
`the other.
`• 500 mg tablets: red, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “500” on the
`other.
`
`300 mg daily
`200 mg daily
`
`400 mg daily
`300 mg daily
`
`200 mg dailya
`
`3
`
` 4
`
`
`
`CONTRAINDICATIONS
`BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included
`anaphylaxis. In the BOSULIF single-agent cancer studies, anaphylactic shock occurred in less than 0.2% of treated
`patients.
`
`
`Reference ID: 4504031
`
`3
`
`

`

`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 randomized clinical trial in patients with newly-diagnosed Ph+ CML, the median time to onset for diarrhea
`(all grades) was 3 days and the median duration per event was 3 days.
`Among 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy,
`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
`Bosutinib may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate
`aminotransferase [AST]).
`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 without
`alternative causes in a breast cancer (a disease for which BOSULIF is not indicated) trial of BOSULIF in combination
`with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of
`1611 patients in BOSULIF clinical trials.
`In the 268 patients from the safety population in the randomized clinical trial in patients with newly-diagnosed
`CML in the BOSULIF treatment group, the incidence of ALT elevation was 31% and AST elevation was 23%. Of
`patients who experienced transaminase elevations of any grade, 79% experienced their first event within the first
`3 months. The median time to onset of increased ALT and AST was 32 and 43 days, respectively, and the median
`duration was 20 and 15 days, respectively.
`Among the 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior
`therapy, 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 in this study 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 35 and 33 days, respectively, and the
`median duration for each was 21 days.
`Perform hepatic enzyme tests monthly for the first 3 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 Cardiac Failure
`Cardiac failure and left ventricular dysfunction have been reported in patients taking BOSULIF. These events
`occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more
`frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure.
`In a randomized study with newly diagnosed CML, cardiac failure occurred in 1.5% of patients treated with
`BOSULIF compared to 0.8% of patients treated with imatinib.
`In a single-arm study in patients with CML who were resistant or intolerant to prior therapy, cardiac failure was
`observed in 5.3% of patients treated with BOSULIF.
`Monitor patients for signs and symptoms consistent with cardiac failure and treat as clinically indicated. Interrupt,
`dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3)].
`
`
`Reference ID: 4504031
`
`4
`
`

`

`5.5 Fluid Retention
`Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema,
`and/or peripheral edema.
`In the randomized clinical trial of 268 patients with newly-diagnosed CML in the bosutinib treatment group,
`1 patient (0.4%) experienced severe fluid retention of Grade 3 pericardial effusion. Among 546 patients in a single-arm
`study in patients with Ph+ CML who were resistant or intolerant to prior therapy, 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)].
`
`5.6 Renal Toxicity
`An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with
`BOSULIF. Table 3 identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the
`pooled leukemia studies regardless of line of therapy. The median duration of therapy with BOSULIF was approximately
`14 months (range, 0.03 to 123) for patients in these studies.
`
`
`Table 3:
`Shift From Baseline to Lowest Observed eGFR Group During Treatment
`Safety Population in Clinical Studies
`(N=1272)*
`
`
`Follow-Up
`Mild to Moderate
`Moderate to Severe
`Mild
`Normal
`n (%)
`n (%)
`n (%)
`n (%)
`N
`Renal Function Status
`102
`46 (9.8)
`16 (3.4)
`298 (63.7)
`468
`Normal
`(21.8)
`250 (39.1)
`83 (13.0)
`11 (1.7) 266 (41.6)
`639
`Mild
`45 (35.2)
`57 (44.5)
`0
`8 (6.3)
`128
`Mild to Moderate
`1 (3.1)
`9 (28.1)
`0
`1 (3.1)
`32
`Moderate to Severe
`0
`0
`0
`0
`1
`Severe
`113
`342 (27.0)
`165 (13.0)
`573 (45.2)
`1268
`Total
`(8.9)
`Abbreviations: eGFR=estimated glomerular filtration rate; N/n=number of patients.
`Notes: Grading is based on Modification in Diet in Renal Disease method (MDRD).
`Kidney Disease: Improving Global Outcomes (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 1272 patients, eGFR was missing in 9 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 (2.5)].
`
`
`Baseline
`
`Severe
`n (%)
`2 (0.4)
`21 (3.3)
`18 (14.1)
`17 (53.1)
`0
`58 (4.6)
`
`Kidney Failure
`n (%)
`2 (0.4)
`3 (0.5)
`0
`3 (9.4)
`1 (100)
`9 (0.7)
`
`5.7 Embryo-Fetal Toxicity
`Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when
`administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In
`animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused
`adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at
`maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day (see Data). Advise
`pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception
`during treatment and for at least 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical
`Pharmacology (12.1)].
`
`
`Reference ID: 4504031
`
`5
`
`

`

`6
`
`
`
`•
`
`ADVERSE REACTIONS
`The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
`
`
`• Gastrointestinal toxicity [see Warnings and Precautions (5.1)].
`• Myelosuppression [see Warnings and Precautions (5.2)].
`• Hepatic toxicity [see Warnings and Precautions (5.3)].
`• Cardiac Failure [see Warnings and Precautions (5.4)]
`• Fluid retention [see Warnings and Precautions (5.5)].
`• Renal toxicity [see Warnings and Precautions (5.6)].
`
`two hundred sixty-eight (268) patients with newly-diagnosed CP CML had a median duration of BOSULIF
`treatment of 14.1 months (range: 0.3 to 24.7 months) and a median dose intensity of 391.8 mg/day.
`
`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 in Patients With Newly-Diagnosed CP CML
`The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive BOSULIF 400 mg
`daily or imatinib 400 mg daily as single agents (Newly-Diagnosed CP CML Study) [see Clinical Studies (14.1)]. The
`safety population (received at least 1 dose of BOSULIF) included:
`
`
`
`
`Adverse reactions reported for greater than or equal to 20% of bosutinib patients with newly-diagnosed CML
`(N=268) were diarrhea (70%), nausea (35%), thrombocytopenia (35%), rash (34%), increased ALT (31%), abdominal
`pain (25%), and increased AST (23%) [see Clinical Studies (14.1)].
`
`
`Table 4 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the
`Phase 3 CP CML safety population.
`
`
`Table 4:
`Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study
`
`Bosutinib 400 mg
`Chronic Phase CML
`N=268
`All Grades
`Grade 3/4
`(%)
`(%)
`70
`8
`35
`0
`35
`14
`34
`1
`31
`19
`
`Adverse Reaction
`
`Diarrhea
`Nausea
`Thrombocytopeniaa
`Rashb
`Alanine aminotransferase
`increased
`Abdominal painc
`Aspartate aminotransferase
`increased
`Anemiad
`Headache
`Fatiguee
`
`Reference ID: 4504031
`
`Imatinib 400 mg
`Chronic Phase CML
`N=265
`All Grades
`Grade 3/4
`(%)
`(%)
`34
`<1
`38
`0
`20
`6
`21
`2
`6
`2
`
`25
`
`23
`19
`19
`19
`
`2
`
`10
`3
`1
`<1
`
`6
`
`15
`
`6
`19
`13
`19
`
`<1
`
`2
`5
`1
`0
`
`

`

`Adverse Reaction
`
`Imatinib 400 mg
`Chronic Phase CML
`N=265
`All Grades
`Grade 3/4
`(%)
`(%)
`16
`0
`8
`5
`8
`0
`12
`<1
`21
`12
`13
`0
`6
`0
`6
`0
`
`Bosutinib 400 mg
`Chronic Phase CML
`N=268
`All Grades
`Grade 3/4
`(%)
`(%)
`Vomiting
`18
`1
`Lipase increasedf
`13
`10
`Pyrexia
`13
`<1
`Respiratory tract infectiong
`12
`<1
`Neutropeniah
`11
`7
`Arthralgia
`11
`<1
`Asthenia
`11
`0
`10
`Appetite decreased
`<1
`Abbreviation: CML=Chronic myelogenous leukemia, N=number of patients.
`a Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia.
`b Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic,
`Dermatitis exfoliative, Drug reaction with eosinophilia and systemic symptoms, Photosensitivity reaction, Rash,
`Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Urticaria.
`c Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain
`lower, Abdominal pain upper, Abdominal tenderness, Gastrointestinal pain.
`d Anemia includes the following preferred terms: Anemia, Hemoglobin decreased
`e Fatigue includes the following preferred terms: Fatigue, Malaise.
`f Lipase increased includes the following preferred terms: Hyperlipasemia, Lipase increased.
`g Respiratory tract infection includes the following preferred terms: Lower respiratory tract infection, Respiratory
`tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract
`infection.
`h Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased.
`
`
`In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with
`
`BOSULIF experienced a Grade 3 QTc prolongation (>500 msec). Patients with uncontrolled or significant cardiovascular
`disease including QT interval prolongation were excluded by protocol.
`
`
`Table 5 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3
`newly-diagnosed CML safety population.
`
`
`Table 5:
`Number (%) of Patients With Clinically Relevant or Grade 3/4 Laboratory Test Abnormalities in Patients With
`Newly-Diagnosed CML in Bosutinib 400 mg Study, Safety Population
`
`Bosutinib
`Chronic Phase CML
`N=268
`n (%)
`
`38 (14.2)
`
`
`
`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
`White Blood Cell Count
`(Low) less than 2×109/L
`
`Reference ID: 4504031
`
`
`
`
`
`Imatinib
`Chronic Phase CML
`N=265
`n (%)
`
`17 (6.4)
`
`24 (9.0)
`
`19 (7.1)
`
`15 (5.6)
`
`7
`
`49 (18.5)
`
`15 (5.7)
`
`20 (7.5)
`
`

`

`
`
`Bosutinib
`Chronic Phase CML
`N=268
`n (%)
`
`
`
`
`
`
`
`
`
`62 (23.1)
`
`32 (11.9)
`
`35 (13.1)
`
`12 (4.5)
`
`3 (1.1)
`
`6 (2.2)
`
`0
`
`Imatinib
`Chronic Phase CML
`N=265
`n (%)
`
`
`
`7 (2.6)
`
`8 (3.0)
`
`16 (6.0)
`
`45 (17.0)
`
`2 (0.8)
`
`4 (1.5)
`
`2 (0.8)
`
`
`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
`Amylase greater than
`2×ULN
`Creatinine greater than
`3.0×baseline; greater than
`3.0×ULN
`Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic
`myelogenous leukemia; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum
`glutamic-oxaloacetic transaminase; N/n=number of patients; ULN=upper limit of normal.
`
`
`Adverse Reactions in Patients With Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML
`
`The single-arm clinical trial enrolled patients with Ph+ CP, AP, or BP 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:
`
`
`
`
`•
`
`two hundred eighty-four (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.
`• one hundred nineteen (119) patients with CP CML previously treated with both imatinib and at least 1 additional
`tyrosine kinase inhibitor (TKI) who had a median duration of BOSULIF treatment of 9 months and a median dose
`intensity of 442 mg/day.
`• one hundred forty-three (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.
`
`
`
`Adverse reactions of any toxicity grade reported for greater than or equal to 20% of patients in the safety
`
`population of the single-arm trial in patients with CP CML (N=546) who were resistant or intolerant to prior therapy were
`diarrhea (85%), nausea (47%), abdominal pain (42%), rash (42%), thrombocytopenia (40%), vomiting (37%), anemia
`(27%), fatigue (26%), pyrexia (23%), cough (22%), headache (21%), ALT (20%), and edema (20%) [see Clinical Studies
`(14.2)].
`
`
`Table 6 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.
`
`
`Reference ID: 4504031
`
`8
`
`

`

`
`
`Advanced Phase CML
`N=143
`All Grades
`Grade 3/4
`(%)
`(%)
`76
`4
`48
`2
`31
`6
`38
`5
`45
`39
`43
`3
`38
`27
`21
`5
`37
`2
`22
`0
`17
`4
`10
`5
`22
`20
`14
`0
`11
`3
`17
`2
`10
`0
`13
`0
`8
`1
`6
`0
`10
`<1
`9
`4
`20
`6
`7
`0
`13
`<1
`15
`12
`6
`<1
`3
`0
`12
`1
`
`Table 6:
`Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in
`Single-Arm Trial*
`
`Chronic Phase CML
`N=403
`All Grades
`Grade 3/4
`(%)
`(%)
`85
`9
`Diarrhea
`47
`1
`Nausea
`Abdominal Paina
`42
`2
`Rashb
`42
`9
`Thrombocytopeniac
`40
`26
`37
`3
`Vomiting
`Anemiad
`27
`11
`Fatiguee
`26
`2
`23
`<1
`Pyrexia
`22
`0
`Cough
`21
`<1
`Headache
`Alanine aminotransferase
`20
`8
`increased
`Neutropeniaf
`18
`12
`Arthralgia
`17
`<1
`Aspartate aminotransferase
`16
`3
`increased
`Edemag
`20
`1
`Respiratory tract infectionh
`15
`<1
`14
`<1
`Decreased appetite
`13
`<1
`Back pain
`13
`0
`Nasopharyngitis
`13
`2
`Asthenia
`12
`4
`Pleural effusion
`12
`2
`Dyspnea
`12
`<1
`Pruritus
`Dizziness
`11
`0
`Leukopeniai
`10
`4
`10
`<1
`Blood creatinine increased
`10
`<1
`Influenza
`Chest painj
`7
`1
`Abbreviations: CML=chronic myelogenous leukemia; N=number of patients.
`*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 Rash includes the following preferred terms: Acne, Dermatitis, Dermatitis acneiform, Dermatitis allergic,
`Drug eruption, Exfoliative rash, Photosensitivity reaction, Rash, Rash erythematous, Rash generalised,
`Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Urticaria
`c Thrombocytopenia includes the following preferred terms: Platelet count decreased, Thrombocytopenia
`d Anemia includes the following preferred terms: Anemia, Hemoglobin decreased.
`e Fatigue includes the following preferred terms: Fatigue, Malaise.
`f Neutropenia includes the following preferred terms: Neutropenia, Neutrophil count decreased
`g Edema includes the following preferred terms containing: Edema, Edema peripheral, Face edema,
`9
`
`Reference ID: 4504031
`
`

`

`
`
`Chronic Phase CML
`N=403
`All Grades
`Grade 3/4
`(%)
`(%)
`
`Advanced Phase CML
`N=143
`All Grades
`Grade 3/4
`(%)
`(%)
`
`Localized edema.
`h Respiratory tract infection includes the following preferred terms: Lower respiratory tract infection,
`Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper
`respiratory tract infection.
`i Leukopenia includes the following preferred terms: Leukopenia, White blood cell count decreased.
`j Chest pain included the following preferred terms: Chest discomfort, Chest pain.
`
`
`
`In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 1 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 7 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population
`of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up.
`
`
`Table 7:
`Number (%) of Patients With Clinically Relevant or Grade 3/4 Laboratory Test Abnormalities in the Safety
`Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior Therapy*
`
`Chronic Phase
`(CP) CML
`N=403
`n (%)
`
`
`
`Advanced
`Phase (AdvP)
`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)
`
`
`105 (26)
`65 (16)
`51 (13)
`
`
`43 (11)
`19 (5)
`42 (10)
`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
`*Based on a Minimum of 48 Months of Follow-up.
`Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia;
`N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate
`aminotransferase; ULN=upper limit of normal.
`
`
`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 adver