`
`
`
` 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------------------------­
`
`
`
`8/2019
`Warnings and Precautions, Embryo-Fetal Toxicity (5.7)
`
`
`
`
`
`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)
`
`• 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
`
`
`aminotransferase,
`abdominal
`aspartate
`alanine
`pain,
`increased
`
`
`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.
`
`
`
`
`
`
`
`
`
`Revised: 6/2020
`
`
`
`
`
`----------------------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)
`_______________________________________________________________________________________________________________________________________
`
`
`
`8
`
`
`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 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
`
`
`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: 4626211
`
`
`
` 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: 4626211
`
`
`
` 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
`
`
`
`
` 300 mg daily
`
` 200 mg daily
`
`
` 400 mg daily
`
` 300 mg daily
`
`
`
`
`
` 200 mg dailya
`
`
`
`
` 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.
`
`
`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: 4626211
`
`
`
` 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: 4626211
`
`
`
` 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)*
`
`
`
` Mild to Moderate
`
` Normal
`
` Mild
`
` n (%)
` N
`
`
` Renal Function Status
`
` n (%)
`
` n (%)
`102
` 46 (9.8)
`
`
` 468
` Normal
`
`
` 298 (63.7)
` (21.8)
`
`
` 250 (39.1)
`
` 639
`
` Mild
`
`
` 11 (1.7) 266 (41.6)
`
` 45 (35.2)
`
` 128
` Mild to Moderate
`
`
`
` 0
` 8 (6.3)
`
` 1 (3.1)
` 32
`
` Moderate to Severe
`
`
` 0
`
` 1 (3.1)
`
` 0
`
` 1
`
`
` 0
`
`Severe
` 0
`113
` 342 (27.0)
` 1268
`
`
` 573 (45.2)
`
`
` 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
`
`
`
` Follow-Up
`
`
`
` Moderate to Severe
`
` n (%)
`
` 16 (3.4)
` 83 (13.0)
`
`
` 57 (44.5)
` 9 (28.1)
`
`
` 0
` 165 (13.0)
`
`
`
`
`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)].
`
`
`ADVERSE REACTIONS
`
`
`6
`
`
`Reference ID: 4626211
`
`
`
` 5
`
`

`

` 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:
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`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
`
` Grade 3/4
`
` (%)
`
` 8
`
` 0
`
` 14
`
` 1
` 19
`
`
`Adverse Reaction
`
`
`
`
`
`Diarrhea
`
`Nausea
` Thrombocytopeniaa
`
` Rashb
`Alanine aminotransferase
`
` increased
`
`Abdominal painc
` Aspartate aminotransferase
`
` increased
`
`
` Anemiad
`
`Headache
`
`Fatiguee
`
`Vomiting
`
`Reference ID: 4626211
`
`
`
`
`
`
`
` Imatinib 400 mg
` Chronic Phase CML
`
`
` N=265
`
` Grade 3/4
`All Grades
`
` (%)
`
` (%)
`
` <1
`
` 34
`
` 0
`
` 38
`
` 6
`
` 20
`
` 2
`
` 21
`
` 2
`
` 6
`
`All Grades
`
` (%)
`
` 70
`
` 35
`
` 35
`
` 34
`
` 31
`
`
`
` 25
`
`
` 23
`
` 19
`
` 19
`
` 19
`
` 18
`
`
`
` 2
`
`
` 10
`
` 3
`
` 1
`
` <1
`
` 1
`
`
`
` 6
`
`
`
` 15
`
`
` 6
`
` 19
`
` 13
`
` 19
`
` 16
`
`
`
` <1
`
`
` 2
`
` 5
`
` 1
`
` 0
`
` 0
`
`

`

`
`
` Adverse Reaction
`
`
`
`
`
`
`
` Imatinib 400 mg
` Chronic Phase CML
`
`
` N=265
`
` Grade 3/4
`All Grades
`
` (%)
`
` (%)
`
` 5
`
` 8
`
` 0
`
` 8
`
` <1
`
` 12
`
` 12
`
` 21
`
` 0
`
` 13
`
` 0
`
` 6
`
` 0
`
` 6
`
`
`
`
`
`
` Bosutinib 400 mg
` Chronic Phase CML
`
`
` N=268
`
` Grade 3/4
`All Grades
` (%)
`
`
` (%)
`
`Lipase increasedf
`
` 10
`
` 13
`
`Pyrexia
`
` <1
`
` 13
`
`Respiratory tract infectiong
`
` <1
`
` 12
`
`Neutropeniah
`
` 7
`
` 11
`
`Arthralgia
`
` <1
`
` 11
`
`Asthenia
`
` 11
`
` 0
` Appetite decreased
`
`
` 10
` <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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)
`
`
`
`Reference ID: 4626211
`
`

`

`
`
`
`
`
` 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: 4626211
`
`
`
` 8
`
`

`

`
`
`
`
`
`
`
` Advanced Phase CML
`
` N=143
` Grade 3/4
`
`
` All Grades
`
` (%)
`
` (%)
`
`
`4
`76
`
`
`2
`48
`
`
`6
`31
`
` 5
`
` 38
`
`
`39
`45
`
`
`3
`43
`
` 27
`
` 38
`
`
`5
`21
`
`
`2
`37
`
` 0
`
` 22
`
`
`4
`17
`
`
`5
`10
`
`
`20
`22
`
` 0
`
` 14
`
` 3
`
` 11
`
`
`2
`17
`
`
`0
`10
`
`
`0
`13
`
` 1
`
` 8
`
` 0
`
` 6
`
` <1
`
` 10
`
` 4
`
` 9
`
` 6
`
` 20
`
` 0
`
` 7
`
` <1
`
` 13
`
` 12
`
` 15
`
` <1
`
` 6
`
` 0
`
` 3
`
` 1
` 12
`
`
`
`
` 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
`
` Grade 3/4
`
` All Grades
`
` (%)
`
` (%)
`
`
`
`Diarrhea
`9
`85
`
`
`
`Nausea
`1
`47
`
`
`Abdominal Paina
`42
`
`2
`
` Rashb
`
` 42
`
` 9
`Thrombocytopeniac
`
`
`
`26
`40
`
`
`
`Vomiting
`3
`37
`Anemiad
`
` 11
`
` 27
`
`
`
`
`Fatiguee
`2
`26
`
`
`
`Pyrexia
`<1
`23
`
` Cough
`
`
` 22
` 0
`
`
`
`Headache
`<1
`21
`Alanine aminotransferase
`
`
`8
`20
`
`increased
`
`Neutropeniaf
`18
`
`
`12
`
` Arthralgia
`
` <1
`
` 17
`Aspartate aminotransferase
`
` 3
`
` 16
`
` increased
`
`
`
`Edemag
`1
`20
`
`
`
` Respiratory tract infectionh
`
`
`<1
`15
`
`
`
`Decreased appetite
`<1
`14
`
` Back pain
`
` <1
`
` 13
` Nasopharyngitis
`
` 0
`
` 13
`
` Asthenia
`
` 2
`
` 13
` Pleural effusion
`
` 4
`
` 12
`
` Dyspnea
`
` 2
`
` 12
`
` Pruritus
`
` <1
`
` 12
` Dizziness
`
`
` 0
`
` 11
`Leukopeniai
`
` 4
`
` 10
`
`
` <1
`
` 10
` Blood creatinine increased
`
` <1
`
` 10
`
` 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, Phot