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
`
`
`
`
`
`BOSULIF® (bosutinib) capsules, for oral use
`
`Initial U.S. Approval: 2012
`
`----------------------------RECENT MAJOR CHANGES-------------------------
`
`
`Indications and Usage (1)
`9/2023
`
`
`
`
`
`Dosage and Administration, Recommended Dosing (2.1)
`9/2023
`
`
`
`
`Dosage and Administration, Dose Escalation (2.2)
`9/2023
`
`
`Dosage and Administration, Dose Adjustments for Non-Hematologic
`
`
`
`Adverse Reactions (2.3)
`9/2023
`
`
`Dosage and Administration, Dose Adjustments for Myelosuppression (2.4)
`
`
`9/2023
`
`
`
`
`Dosage and Administration, Dosage Adjustments for Renal Impairment or
`
`
`Hepatic Impairment (2.5)
`9/2023
`
`
`
`
`Warnings and Precautions, Gastrointestinal Toxicity (5.1)
`9/2023
`
`
`
`Warnings and Precautions, Hepatic Toxicity (5.3)
`9/2023
`
`
`
`Warnings and Precautions, Cardiovascular Toxicity (5.4)
`9/2023
`
`
`
`
`Warnings and Precautions, Fluid Retention (5.5)
`9/2023
`
`
`
`Warnings and Precautions, Renal Toxicity (5.6)
`9/2023
`
`----------------------------INDICATIONS AND USAGE--------------------------
`BOSULIF is a kinase inhibitor indicated for the treatment of
`
`
`
`
`
`• adult and pediatric patients 1 year of age and older with chronic phase Ph+
`
`
`
`
`
`
`
`
`chronic myelogenous leukemia (CML), newly-diagnosed or resistant or
`
`
`intolerant to prior therapy. (1)
`
`
`
`• adult patients with accelerated, or blast phase Ph+ CML with resistance or
`
`
`intolerance to prior therapy. (1)
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosing
`
`
`2.2 Dose Escalation
`
`
`
`2.3 Dosage Adjustments for Non-Hematologic Adverse Reactions
`
`
`
`
`2.4 Dosage Adjustments for Myelosuppression
`
`
`
`
`2.5 Dosage 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
`
`Reference ID: 5251010
`
`
`
` 1
`
`
`
`
`
`• Capsules 50 mg, 100 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.
`
`
`
`
`Withhold, dose reduce, or discontinue BOSULIF. (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)
`
`• Cardiovascular Toxicity: Monitor and manage as necessary. Interrupt, dose
`
`
`
`
`
`
`reduce, or discontinue BOSULIF. (5.4)
`
`
`• Fluid Retention: Monitor patients and manage using standard of care
`
`
`
`
`
`
`treatment. Interrupt, 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 adult and pediatric patients
`
`
`
`
`
`
`
`with CML are diarrhea, abdominal pain, vomiting, nausea, rash, fatigue,
`hepatic dysfunction, headache, pyrexia, decreased appetite respiratory tract
`
`
`
`infection, and constipation. The most common laboratory abnormalities
`
`
`
`(≥20%) in adult and pediatric patients are creatinine increased, hemoglobin
`
`
`
`
`
`decreased, lymphocyte count decreased, platelets decreased, ALT
`
`increased, calcium decreased, white blood cell count decreased, AST
`
`
`
`increased, absolute neutrophil count decreased, glucose increased,
`
`phosphorus decreased, urate increased, alkaline phosphatase increased,
`
`lipase increased, creatine kinase increased, and amylase increased. (6.1)
`
`
`
`
`
`
`
`
`
`6
`
`
`7
`
`
`8
`
`
`ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
`
`DRUG INTERACTIONS
`
`
`
`7.1 Effect of Other Drugs on BOSULIF
`
`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
`
`
`----------------------DOSAGE AND ADMINISTRATION----------------------
`
`• Adult patients with newly-diagnosed chronic phase Ph+ CML: 400 mg
`
`
`
`
`
`
`orally once daily with food. (2.1)
`
`
`• Adult patients with chronic, accelerated, or blast phase Ph+ CML with
`
`
`
`
`
`resistance or intolerance to prior therapy: 500 mg orally once daily with
`
`
`
`
`
`food. (2.1)
`
`• Pediatric patients with newly-diagnosed chronic phase Ph+ CML:
`
`
`
`
`300 mg/m2 orally once daily with food. (2.1)
`
`
`
`• Pediatric patients with chronic phase Ph+ CML with resistance or
`
`
`
`
`
`
`intolerance to prior therapy: 400 mg/m2 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 adult patients who do not reach complete
`
`
`
`
`hematologic, cytogenetic, or molecular response and do not have Grade 3
`
`or greater adverse reactions. (2.2)
`
`
`
`
`
`
`
`
`• Consider dose escalation by increments of 50 mg for those with a BSA
`<1.1 m2 and 100 mg for those with a BSA ≥1.1 m2 to a maximum of 600
`
`
`
`
`
`
`
`
`
`
`
`
`
`mg daily in pediatric patients who do not reach sufficient response after 3
`
`months. (2.2)
`
`
`
`
`• Adjust dosage for toxicity and organ impairment (2)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`
`• Tablets: 100 mg, 400 mg, and 500 mg. (3)
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`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: 9/2023
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`14.3 Pediatric Patients with Newly-Diagnosed or Resistant or Intolerant
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`to Prior Therapy CP Ph+ CML
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`14 CLINICAL STUDIES
`
`
`
`
`14.1 Adult Patients with Newly-Diagnosed CP Ph+ CML
`
`
`
`
`14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP,
`
`
`
`
`* Sections or subsections omitted from the Full Prescribing Information are
`
`
`and BP CML
`not listed.
` _______________________________________________________________________________________________________________________________________
`
`
`
`Reference ID: 5251010
`
`
`
` 2
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`1
`
`
`
`
`
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
` BOSULIF is indicated for the treatment of:
`
`
`
` • Adult and pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive
`
`
`
`
` chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see
`
`
`
`
`
` Clinical Studies (14.1, 14.2, 14.3)].
`
` • Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior
`
`
` therapy [see Clinical Studies (14.2)].
`
`
`
`
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`2
`
`
`2.1 Recommended Dosage
`
`The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or
`
`
`
`chew tablets. Continue treatment with BOSULIF until disease progression or intolerance to therapy.
`
`
`
`
`
`Capsules may be swallowed whole. For patients who are unable to swallow a whole capsule(s), each capsule can be
`
`
`
`
`opened and the contents mixed with applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot
`
`
`be considered a substitute of a proper meal.
`
`If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the
`
`
`
`
`following day.
`
`
`Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML
`
`
`The recommended dosage of BOSULIF is 400 mg orally once daily with food.
`
`
`
`
`Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy
`
`
`The recommended dosage of BOSULIF is 500 mg orally once daily with food.
`
`
`
`
`Dosage in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or
`
`Intolerance to Prior Therapy
`The recommended dose of BOSULIF for pediatric patients with newly-diagnosed CP Ph+ CML is 300 mg/m2 orally
`
`
`
`once daily with food and the recommended dosage for pediatric patients with CP Ph+ CML that is resistant or intolerant
`
`
`
`
`
`to prior therapy is 400 mg/m2 orally once daily with food and dose recommendations are provided in Table 1. As
`
`
`
`
`
`
`
`appropriate, the desired dose can be attained by combining different strengths of BOSULIF tablets or capsules.
`
`
`BSA1
`
`
`
`
`
`Table 1:
`
`
`Dosing of BOSULIF for Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with
`
`Resistance or Intolerance to Prior Therapy
`
`
` Resistant or Intolerant
` Newly-Diagnosed
`
`
` Recommended Dose
` Recommended Dose
`(Once Daily)
`(Once Daily)
`
`
`
` 200 mg
`
` 150 mg
` < 0.55 m2
`
`
`
` 250 mg
`
` 200 mg
`
`
` 0.55 to < 0.63 m2
`
` 300 mg
`
` 200 mg
`
`
` 0.63 to < 0.75 m2
`
` 350 mg
`
` 250 mg
` 0.75 to < 0.9 m2
`
`
`
` 400 mg
`
` 300 mg
` 0.9 to < 1.1 m2
`
`
`
` 500 mg*
`
` 400 mg*
` ≥ 1.1 m2
`
` * maximum starting dose (corresponding to maximum starting dose in adult indication)
`
`1 BSA=Body Surface Area
`
`
`
`
`
`Reference ID: 5251010
`
`
`3
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt
`
`
`
`
`
`
`For patients who are unable to swallow capsules, the contents of the capsules can be mixed with applesauce or
`
`
`
`
`
`
`
`yogurt. Remove the required number of capsules from the container to prepare the dose as instructed and the amount of
`
`
`either room temperature applesauce or yogurt in a clean container. Carefully open each capsule, add the entire capsule
`
`
`content of each capsule into the applesauce or yogurt, then mix the entire dose into the applesauce or yogurt. Patients
`
`
`
`
`
`should immediately consume the full mixture in its entirety, without chewing. Do not store the mixture for later use. If the
`
`
`
`
`
`
`entire preparation is not swallowed do not take an additional dose. Wait until the next day to resume dosing.
`
`Table 2:
`
`
`BOSULIF Dose Using Capsules and Soft Food Volumes
`
`
`
`Dose
`
`
` 100 mg
` 150 mg
`
`
`
` 200 mg
`
`
` 250 mg
`
`
` 300 mg
`
` 350 mg
`
` 400 mg
`
`
` 450 mg
`
` 500 mg
`
`
` 550 mg
`
`
` 600 mg
`
`
`
` Volume of Applesauce or Yogurt
`
`
` 10 mL (2 teaspoons)
` 15 mL (3 teaspoons)
`
`
`
` 20 mL (4 teaspoons)
`
`
` 25 mL (5 teaspoons)
`
`
` 30 mL (6 teaspoons)
`
` 30 mL (6 teaspoons)
`
`
` 35 mL (7 teaspoons)
`
`
`
` 40 mL (8 teaspoons)
`
`
`
` 45 mL (9 teaspoons)
`
`
` 45 mL (9 teaspoons)
`
` 50 mL (10 teaspoons)
`
`
`
`2.2 Dose Escalation
`
`In clinical studies of adult patients with Ph+ CML, 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.
`
`
`
`
`
`In pediatric patients with BSA <1.1 m2 and an insufficient response after 3 months consider increasing dose by
`
`
`
`50 mg increments up to maximum of 100 mg above starting dose. Dose increases for insufficient response in pediatric
`
`
`
`
`
`patients with BSA ≥1.1 m2 can be conducted similarly to adult recommendations in 100 mg increments.
`
`
`
`
`
`
`The maximum dose in pediatric and adult patients is 600 mg once daily.
`
`
`2.3 Dosage 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.
`
`
`
`In pediatric patients, dose adjustments for non-hematologic toxicities can be conducted similarly to adults, however
`
`
`
`the dose reduction increments may differ. For pediatric patients with BSA <1.1 m2, reduce dose by 50 mg initially
`
`
`
`Reference ID: 5251010
`
`
`
` 4
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
` ANCa less than 1000×106/L
`
`or
`
`
`Platelets less than 50,000×106/L
`
`
`
`
` Table 3:
`
` Dose Adjustments for Neutropenia and Thrombocytopenia in Adult and Pediatric Patients
`
` 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, or by 50 mg in pediatric
`
`
`patients with BSA <1.1 m2 and resume treatment.
`
`
`
`
`
`
`If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and
`
`
`
`
`resume treatment, or by an additional 50 mg in pediatric patients with BSA
` <1.1 m2 and resume treatment.
`
`
`
`
`
`
`
`
`
` followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m2 or
`
`
` greater, reduce dose similarly to adults.
`
` 2.4 Dosage Adjustments for Myelosuppression
`
`
`
` Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` a Absolute Neutrophil Count
`
`
`2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment
`
`
`
`The recommended starting doses for patients with renal and hepatic impairment are described in Table 4 below.
`
`
`
`
` Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients
`
`
`
` Recommended Starting Dosage
`Newly-diagnosed
`Chronic,
` chronic phase Ph+
`
` accelerated, or blast
`CML
` 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 Severe
`200 mg daily
`
`(Child-Pugh C)
`
`
` [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`300 mg daily
`
`200 mg daily
`
`
`400 mg daily
`
`300 mg daily
`
`
`
`
` 200 mg daily
`
`
`Reference ID: 5251010
`
`
`
` 5
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`Table 5:
`
`
`Dosage Adjustments for Renal and Hepatic Impairment in Pediatric Patients
`
`
`
` Newly-Diagnosed CP Ph+ CML Recommended Starting Dose (Once Daily)
`
` By Organ Function
`
`
`
`
`
`
`
` Pediatric Patients by
`
` Separated BSA1 Band
`
`
` Pediatric < 0.55 m2
`
`
`
` Pediatric 0.55 to < 0.63 m2
`
` Pediatric 0.63 to < 0.75 m2
`
` Pediatric 0.75 to < 0.9 m2
`
` Pediatric 0.9 to < 1.1 m2
`
`
` Pediatric ≥ 1.1 m2
`
`
` Pediatric Patients by
`
` Separated BSA1 Band
`
`
`
`Normal renal
`
`and hepatic
`
`function
`
`
`Renal
`Impairment:
`
`Creatinine
`clearance 30 to
`
`50 mL/min
`
`
`Renal Impairment:
`
`Creatinine
`
`
`clearance less than
`
`30 mL/min
`
`
`Normal renal
`
`and hepatic
`
`function
`
`
`Renal Impairment:
`
`Creatinine
`
`
`clearance less than
`
`30 mL/min
`
`
`Hepatic
`Impairment: Mild
`
`(Child-Pugh A),
`Moderate (Child-
`Pugh B) or Severe
`
`(Child-Pugh C)
`
` 150 mg
`
` 100 mg
`
` 100 mg
`
` 100 mg
`
` 200 mg
`
` 100 mg
`
` 100 mg
`
` 150 mg
`
` 200 mg
`
` 100 mg
`
` 100 mg
`
` 150 mg
`
` 250 mg
`
` 100 mg
`
` 150 mg
`
` 200 mg
`
` 300 mg
`
` 150 mg
`
` 200 mg
`
` 200 mg
`400 mg
`
` 200 mg
`
` 200 mg
`
` 300 mg
`
`
` CP Ph+ CML with Resistance or Intolerance to Prior Therapy
`
` Recommended Starting Dose (Once Daily) By Organ Function
`
` Hepatic
`
`
`Renal
`Impairment: Mild
`Impairment:
`
`(Child-Pugh A),
`
`Creatinine
`Moderate (Child-
`clearance 30 to
`Pugh B) or Severe
`
`50 mL/min
`
` (Child-Pugh C)
`
` 150 mg
`
` 100 mg
`
` 200 mg
`
` 100 mg
`
` 200 mg
`
` 150 mg
`
` 250 mg
`
` 150 mg
`
` 300 mg
`
` 200 mg
`
` 400 mg
`
` 200 mg
`
`
`
`
`
`3
`
`
`Tablets:
`
`
`
`• 100 mg: yellow, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “100” on the
`
`other.
`
`
`• 400 mg: orange, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “400” on the
`
`other.
`
`
`
`• 500 mg: red, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “500” on the other.
`
`Capsules:
`
`
`
`
`
`• 50 mg: white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black
`
`ink.
`
`
`
`• 100 mg: white body/brownish-red cap with “BOS 100” printed on the body and “Pfizer” printed on the cap in
`
`black ink.
`
`
`
`Reference ID: 5251010
`
`
`
` 6
`
` Pediatric < 0.55 m2
`
`
`
` Pediatric 0.55 to < 0.63 m2
`
` Pediatric 0.63 to < 0.75 m2
`
` Pediatric 0.75 to < 0.9 m2
`
` Pediatric 0.9 to < 1.1 m2
`
`
` Pediatric ≥ 1.1 m2
` 1 BSA=Body Surface Area
`
`
` [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].
`
`DOSAGE FORMS AND STRENGTHS
`
`
`
` 200 mg
`
` 250 mg
`
` 300 mg
`
` 350 mg
`
` 400 mg
`500 mg
`
`
`
` 100 mg
`
` 150 mg
`
` 200 mg
`
` 200 mg
`
` 250 mg
`
` 300 mg
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`4
`
`
`
` CONTRAINDICATIONS
`
` BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included
`
` anaphylaxis [see Adverse Reactions (6.1)].
`
`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 adult 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 adult 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).
`
`
`
`
`Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or
`
`
`
`intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the duration was 2 days.
`
`
`Among patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with
`
`
`BOSULIF was 2 (range 1 – 198).
`
`
`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 adult 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 increased AST was 56%. Of
`
`
`
`patients who experienced increased transaminases of any grade, 73% experienced their first increase 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 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior
`
`
`
`
`therapy, the incidence of increased ALT 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 increased transaminases of any grade, more than 81% experienced their first
`
`increase 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.
`
`
`
`
`Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or
`
`
`
`
`
`intolerant to prior therapy, the incidence based on laboratory data that worsened from baseline of increased ALT was 59%
`
`
`
`
`and of increased AST 51%. Seventy-six percent of the patients experienced an increase in either ALT or AST. Most cases
`
`
`
`
`
`
`of increased transaminases occurred early in treatment; of patients who experienced increased transaminases of any grade,
`
`
`
`
`84% of patients experienced their first increases within the first 3 months. The median time to onset for adverse reactions
`
`
`
`of increased ALT and AST was 22 and 15 days, respectively. The median duration for adverse reactions of Grade 3 or 4
`increased ALT or AST was 26 and 12 days, respectively.
`
`
`
`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)].
`
`
` 7
`
`Reference ID: 5251010
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`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 of adult patients 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 adult 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.
`
`
`
`
`Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or
`
`
`
`intolerant to prior therapy, 4 (8%) patients had Grade 1-2 cardiac events, including tachycardia (n=2), angina pectoris,
`
`
`right bundle branch block, and sinus tachycardia (n=1 each).
`
`
`
`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)].
`
`
`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 adult 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 adult 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.
`
`
`
`
`Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or
`
`
`
`intolerant to prior therapy, Grade 1-2 pericardial effusion, peripheral edema, and face edema were reported in 1 patient
`
`each.
`
`
`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 5 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.
`
`
`Reference ID: 5251010
`
`
`
` 8
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
` Baseline
`
`
`
`
`
` Kidney Failure
`
`
` n (%)
` 5 (0.9)
`
`
` 6 (0.9)
`
` 1 (0.7)
` 4 (12.1)
`
`
` 1 (100)
`
` 17 (1.2)
`
` Follow-Up
`
`
` Mild to Moderate
` Moderate to Severe
` Normal
`
` Mild
` N
`
` Renal Function Status
`
`
`
`
` n (%)
` n (%)
`
`
` n (%)
`
` n (%)
`
`115
`
` 527
`
` Normal
` 50 (9.5)
`
` 23 (4.4)
`
`
` 330 (62.6)
` (21.8)
`
`
` 672
`
` Mild
` 96 (14.3)
`
` 271 (40.3)
`
`
` 10 (1.5) 259 (38.5)
`
`
` 137
` Mild to Moderate
`
`
` 66 (48.2)
`
` 40 (29.2)
`
`
` 0
` 6 (4.4)
` 33
`
` Moderate to Severe
` 8 (24.2)
`
`
` 1 (3.0)
`
` 0
`
` 1 (3.0)
`
` 1
`
`
`
`
` 0
`
`Severe
` 0
` 0
` 0
`125
` 1370
` 193 (14.1)
` 362 (26.4)
`
`
` 596 (43.5)
`
`
` Total
`
` (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.
`
`
`
`
`Overall, 45% of the pediatric patients with newly diagnosed CP Ph+ CML or resistant or intolerant CP Ph+ CML
`
`
`
`
`
`who had normal eGFR at baseline shifted to a maximum of mild, and 40% pediatric patients who had mild eGFR at
`
`
`baseline shifted to a maximum of moderate during treatment.
`
`
`
`
`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)].
`
`
` Table 6:
`
`
`
` Shift From Baseline to Lowest Observed eGFR Group During Treatment
`
` Safety Population in Clinical Studies
`
`
` (N=1372)*
`
`
`
`
`
`
`
`
`
`
`
`
`Severe
`
`
` n (%)
` 3 (0.6)
`
` 26 (3.9)
`
` 24 (17.5)
`
`
` 19 (57.6)
`
` 0
` 72 (5.2)
`
`
`
`
`
`
`
`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 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
`
`
`
`ADVE