` 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)
`
`
` Cardiovascular Toxicity: 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 female
`
`
`patients of reproductive potential of potential risk to a fetus and to use
`
`
`
`
`effective contraception. (5.7)
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------
`
`
` Most common adverse reactions (≥20%), in patients with CML are diarrhea,
`
`
`
`
`
`rash, nausea, abdominal pain, vomiting, fatigue, hepatic dysfunction,
`
`
`
`respiratory tract infection, pyrexia, and headache. The most common
`
`
`
`laboratory abnormalities (≥20%) are creatinine increased, hemoglobin
`
`
`
`decreased, lymphocyte count decreased, platelets decreased, ALT increased,
`
`
`
`
`
`calcium decreased, white blood cell count decreased, absolute neutrophil
`
`
`
`
`count decreased, AST increased, glucose increased, phosphorus decreased,
`
`
`
`
`urate increased, alkaline phosphatase increased, lipase increased, creatine
`
`
`
`
`kinase increased, and amylase increased. (6.1)
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`Revised: 5/2021
`
`
`
`
`
`
`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-------------------------
`
`Indications and Usage (1)
`5/2021
`
`5/2021
`Warnings and Precautions, Gastrointestinal Toxicity (5.1)
`Warnings and Precautions, Hepatic Toxicity (5.3)
`5/2021
`Warnings and Precautions, Cardiovascular Toxicity (5.4)
`5/2021
`
`Warnings and Precautions, Fluid Retention (5.5)
`5/2021
`Warnings and Precautions, Renal Toxicity (5.6)
`5/2021
`
`
`----------------------------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). (1)
`
`
` 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)
`
`----------------------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
`INDICATIONS AND USAGE
`
`
`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 Cardiovascular Toxicity
`
`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
`
`
`
`8
`USE IN SPECIFIC POPULATIONS
`_______________________________________________________________________________________________________________________________________
`
`
`6
`
`
`7
`
`Reference ID: 4795961
`
`1
`
`
`
`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
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`* Sections or subsections omitted from the Full Prescribing Information are
`not listed.
`
`

`

`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).
`
` Chronic phase, accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior
`therapy.
`
`
`DOSAGE AND ADMINISTRATION
`
`FULL PRESCRIBING INFORMATION
`
`
`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.
`
`
`Reference ID: 4795961
`
`2
`
`
`

`

`
`
`3
`
`
`4
`
`
`
`
`
`Recommended Starting Dosage
`Chronic,
`Newly-diagnosed
`accelerated, or blast
`chronic phase Ph+
`
`CML2
`phase Ph+ CML
`with resistance or
`intolerance to prior
`
`therapy
`500 mg daily
`
` 2.4 Dose Adjustments for Myelosuppression
`
`
`Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1).
`
`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
`
`
`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.
`
`
`
`
`
`
`300 mg daily
`200 mg daily
`
`400 mg daily
`300 mg daily
`
`200 mg dailya
`
`
`
`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.
`
`
`CONTRAINDICATIONS
`BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included
`anaphylaxis [see Adverse Reactions (6.1)].
`
`3
`
`Reference ID: 4795961
`
`

`

`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 4 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]).
`
`Two cases 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) have occurred
`without alternative causes. This represented 2 out 1711 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 68.3% and AST elevation was 56.0%. Of
`patients who experienced transaminase elevations of any grade, 73% experienced their first event within the first
`3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median
`duration was 19 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 53.3% and AST elevation was 46.7%. Sixty 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 81% experienced their first event
`
`within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 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 Cardiovascular Toxicity
`BOSULIF can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac
`ischemic events. Cardiac failure 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. Cardiac ischemic events occurred in both previously treated patients and in patients with newly
`diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of
`diabetes, body mass index greater than 30, hypertension, and vascular disorders.
`In a randomized study with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with
`
`
`BOSULIF compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% 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 and cardiac ischemic events were observed in 4.9% of patients treated with BOSULIF.
`
`Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically
`indicated. Interrupt, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3)].
`4
`
`Reference ID: 4795961
`
`

`

`
`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,
`3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and
`2 patients experienced Grade 3 pleural 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 30 patients (6%). Some patients
`
`experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions,
`9 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
`24 months (range, 0.03 to 155) for patients in these studies.
`
`
`
`
`Table 3:
`
`Shift From Baseline to Lowest Observed eGFR Group During Treatment
`
`Safety Population in Clinical Studies
`
`
`(N=1372)*
`
`
`Follow-Up
`
`
`
`
`Mild to Moderate
`Moderate to Severe
`Normal
`Mild
`Renal Function Status
` N
`
`
`
`
`
`n (%)
`n (%)
`n (%)
`n (%)
`115
`
`
`527
`Normal
`50 (9.5)
`23 (4.4)
`330 (62.6)
`
`(21.8)
`672
`Mild
`271 (40.3)
`96 (14.3)
`10 (1.5) 259 (38.5)
`
`
`
`
`
`
`
`
`
`
`137
`Mild to Moderate
`40 (29.2)
`66 (48.2)
`6 (4.4)
`0
`33
`Moderate to Severe
`1 (3.0)
`8 (24.2)
`0
`1 (3.0)
`
`
`
`
`
`
`1
`Severe
`0
`0
`0
`0
`125
`1370
`Total
`362 (26.4)
`596 (43.5)
`193 (14.1)
`
`
`
`
`(9.1)
`
` Abbreviations: eGFR=estimated glomerular filtration rate; N/n=number of patients.
`
`
` Notes: eGFR was calculated using Modification in Diet in Renal Disease method (MDRD).
`
`
`
`
`
`
` Notes: Grading is based on 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 1372 patients, eGFR was missing in 7 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 (%)
`3 (0.6)
`26 (3.9)
`
`
`
`24 (17.5)
`19 (57.6)
`
`
`
`0
`72 (5.2)
`
`
`
`
`Kidney Failure
`n (%)
`5 (0.9)
`6 (0.9)
`
`1 (0.7)
`4 (12.1)
`
`1 (100)
`17 (1.2)
`
`
`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. 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: 4795961
`
`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)].
`
`
`• Cardiovascular toxicity [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 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 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.
`
`The most common adverse reactions, in ≥20% of patients with newly diagnosed CP Ph+ CML or CP, AP, or BP
`Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%),
`abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%),
`pyrexia (24%), and headache (21%).
`The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine
`increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT
`increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased
`(50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline
`phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%).
`
`
`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:
`
`
`
`
`
`Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib.
`Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary
`artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary
`artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%).
`
`Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-
`
`diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of
`
`
`patients included hepatic dysfunction (9%).
`Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-
`
`diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of
`
`
`patients included hepatic dysfunction (9%).
`Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of
`
`patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of
`
`patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%),
`neutropenia (7%), abdominal pain (6%), rash (5%).
`The most common adverse reactions, in >20% of bosutinib-treated patients with newly-diagnosed CML (N=268)
`were diarrhea (75%), hepatic dysfunction (45%), rash (40%), abdominal pain (39%), nausea (37%), fatigue (33%),
`respiratory tract infection (27%), headache (22%), and vomiting (21%).
`The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine
`increased (94%), hemoglobin decreased (89%), lymphocyte count decreased (84%), ALT increased (68%), platelet count
`decreased (68%), glucose increased (57%), AST increased (56%), calcium decreased (55%), phosphorus decreased (54%),
`lipase increased (53%), white blood cell count decreased (50%), absolute neutrophil count decreased (42%), alkaline
`phosphatase increased (41%), creatine kinase increased (36%), and amylase increased (32%).
`
`
`
`Reference ID: 4795961
`
`6
`
`
`

`

`
`
` 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*
`
`
`
`
`
`
`
`
`
`
`
`
`System Organ Class
`Gastrointestinal disorders
`
`
`
`
`Hepatobiliary disorders
`Skin and subcutaneous tissue disorders
`
`General disorders and administration-site
`conditions
`
`
`Infections and infestations
`Nervous system disorders
`Musculoskeletal and connective tissue
`disorders
`
`Respiratory, thoracic, and mediastinal
`disorders
`Dyspnea
`
`Decreased appetite
`Metabolism and nutrition disorders
`Hypertensionc
`Vascular disorders
`
` *Based on a Minimum of 57 Months of Follow-up.
`
`
`
`
`
` Adverse drug reactions are based on all-causality treatment-emergent adverse events.
`
`The commonality stratification is based on 'All Grades' under Total column.
`
`
`
`
`'Grade 3', 'Grade 4' columns indicate maximum toxicity.
`
`
`
`
`
`
`
`
`aAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain
`
`
`
`upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain.
`
`bFatigue includes the following preferred terms: Asthenia, Fatigue, Malaise.
`
`
`
`
`
`cHypertension* includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart
`
`disease, Retinopathy hypertensive.
`
`
`
`
`
`
`
`fHepatic dysfunction includes the preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate
`
`
`aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased,
`
`Drug-induced liver injury, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic steatosis, Hepatitis, Hepatitis
`
`
`toxic, Hepatocellular injury, Hepatotoxicity, Hyperbilirubinemia, Jaundice, Liver disorder, Liver function test increased, Ocular
`
`icterus, Transaminases increased.
`
`
`
`gEdema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Edema, Edema peripheral, Orbital edema,
`
`
`
`
`Periorbital edema, Periorbital swelling, Peripheral swelling, Swelling, Swelling face, Swelling of eyelid, Swollen tongue.
`
`
`Bosutinib 400 mg
`Chronic Phase
`CML
`
`(N=268)
`
`
`Imatinib 400 mg
`Chronic Phase CML
`(N=265)
`
`
`All
`Grades
`%
`
`75
`
` 39
`37
`
`21
`
`13
`
`
` 45
`
` 40
`11
`
`
` 33
`
`Grade 3/4
`%
`9
`2
`0
`1
`0
`
` 27
`2
`<1
`1
`
`All
`Grades
`%
`
`40
`
` 27
`42
`
`20
`
`6
`
` 15
`
` 30
`4
`
` 30
`
`Grade 3/4
`%
`1
`1
`0
`0
`0
`4
`2
`0
`<1
`
`17
`
`
` 15
`
` 27
`
` 22
`18
`
`
`12
`
`11
`
`
`11
`
`11
`
`
` 10
`
`1
`0
`1
`1
`1
`
`<1
`0
`
`1
`<1
`5
`
`11
`
`
` 46
`
` 25
`
` 15
`18
`
`
`9
`10
`
`
`6
`6
`
` 11
`
`0
`2
`<1
`1
`<1
`
`<1
`0
`
`1
`0
`5
`
`
`
`Preferred Term
`Diarrhea
`Abdominal paina
`
`Nausea
`Vomiting
`Constipation
`Hepatic dysfunctionf
`
`Rashd
`
`Pruritus
`Fatigueb
`
`
`Pyrexia
`Edemag
`
`Respiratory tract infectione
`
` Headache
`Arthralgia
`
`Back pain
`Cough
`
`
`Reference ID: 4795961
`
`7
`
`
`

`

` dRash includes the following preferred terms: Acne, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis
`
`
`
`
` exfoliative generalized, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic,
`
` Erythema, Erythema nodosum, Genital rash, Lichen planus, Perivascular dermatitis, Photosensitivity reaction, Psoriasis, Rash, Rash
`
`
`
`
`
`
` erythematous, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrhoeic keratosis,
`
` Skin discoloration, Skin exfoliation, Skin hypopigmentation, Skin irritation, Skin lesion, Stasis dermatitis.
`
`
`
`eRespiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract
`
`
`
`
`infection, Respiratory tract infection viral, Upper respiratory tract infection.
`
`
`
`In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with BOSULIF
`
`experienced a Grade 3 QTcF 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:
`
`Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with Newly-Diagnosed CML
`
`in Bosutinib 400 mg Study*
`
`
`
`
`
`
`
`Bosutinib
`N=268
`%
`
`
`All Grade
`
`
`Hematology Parameters
`
`Platelet Count
`decreased
`
`Absolute
`Neutrophil Count
`decreased
`
`Hemoglobin
`decreased
`
`White Blood Cell
`Count decreased
`
`Lymphocyte Count
`
`decreased
`Biochemistry Parameters
`
`SGPT/ALT
`increased
`
`SGOT/AST
`increased
`
`Lipase increased
`
`Phosphorus
`decreased
`
`Amylase increased
`
`Alkaline
`Phosphatase
`increased
`
`
` Calcium decreased
`
`Glucose increased
`Creatine Kinase
`
`increased
`Creatinine
`increased
`
` *Based on a Minimum of 57 Months of Follow-up.
`
`
`
`68
`
`
`42
`
`89
`
`50
`
`
`
` 84
`
`68
`
`
`56
`
`
`
`53
`54
`
`
`32
`41
`
` 55
`
`57
`36
`
`
`
` 94
`
`
`
`Grade 3-4
`
`All Grade
`
`Imatinib
`
`N=265
`%
`
`
`Grade 3-4
`
`60
`
`
`
`65
`
`90
`
`
`70
`
`
`82
`
`28
`
`
`29
`
`
`
`35
`69
`
`
`
`18
`
` 43
`
`
` 57
`
` 65
`
` 65
`
`
`
` 98
`
`14
`
`
`9
`
`9
`
`6
`
`12
`
`26
`
`
`13
`
`
`
`19
`9
`
`
`3.4
`0
`
`
` 1.5
`3
`3
`
`
`
` 1.1
`
`8
`
`6
`
`
`
` 20
`
` 7
`
`
` 8
`
`
`14
`
`3
`
`
`3.4
`
`
`
`8
` 21
`
`
`
`2.3
`
` 0.4
`
`
` 1.1
`
` 3.4
`
` 5
`
`
`
` 0.8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4795961
`
`

`

`
`
` 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
`Graded using CTCAE v 4.03
`
`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 (14.2)]. 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 (range: 0.2 to 155 months), and a median dose intensity of
`437 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 (range: 0.2 to
`
`
`
`148 months) and a median dose intensity of 427 mg/day.
`
`
` one hundred forty-three (143) patients with advanced phase (AdvP) 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 (range: 0.1 to 140 months) and 3 months (range: 0.03 to 71 months), respectively. The
`median dose intensity was 406 mg/day, and 456 mg/day, in the AP CML and BP CML cohorts, respectively.
`
`
`
`
`
`Serious adverse reactions occurred in 30% of patients in the safety population of the single-arm trial in patients with
`CML (N=546) who were resistant or intolerant to