Bosulif

(Bosutinib)

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Bosulif Prescribing Information

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 Adult Patients with Newly-Diagnosed CP Ph+ CML

The efficacy of BOSULIF in patients with newly-diagnosed chronic phase Ph+ CML was evaluated in the

osutinib trial in

irst-line chr

nic myelogenous leukemia t

atment (BFORE) Trial: "A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia" [NCT02130557].

The BFORE Trial is a 2-arm, open-label, randomized, multicenter trial conducted to investigate the efficacy and safety of BOSULIF 400 mg once daily alone compared with imatinib 400 mg once daily alone in adult patients with newly-diagnosed CP Ph+ CML. The trial randomized 536 patients (268 in each arm) with Ph+ or Ph- newly-diagnosed CP CML (intent-to-treat [ITT] population) including 487 patients with Ph+ CML harboring b2a2 and/or b3a2 transcripts at baseline and baseline BCR-ABL copies >0 (modified intent-to-treat [mITT] population). Randomization was stratified by Sokal score and geographical region. All patients are being treated and/or followed for up to 5 years (240 weeks). Efficacy was evaluated in the mITT population. The major efficacy outcome measure was major molecular response (MMR) at 12 months (48 weeks) defined as ≤0.1% BCR-ABL ratio on international scale (corresponding to ≥3 log reduction from standardized baseline) with a minimum of 3000 ABL transcripts as assessed by the central laboratory. Additional efficacy outcomes included CCyR by 12 months, defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic assessment was unavailable and MMR by 18 months (72 weeks).

In the mITT population in this study, 57% of patients were males, 78% were Caucasian, and 19% were 65 years or older. The median age was 53 years. At baseline, the distribution of Sokal risk scores was similar in bosutinib and imatinib-treated patients (low risk: 35% and 39%; intermediate risk: 44% and 38%; high risk: 22% and 22%, respectively). After a minimum of 12 months follow-up, 78% of the 246 bosutinib-treated patients and 72% of the 239 imatinib-treated patients were still receiving treatment and with a minimum of 60 months of follow-up, 60% and 60% of patients, respectively, were still receiving treatment. The median treatment duration was 55.1 months for BOSULIF and 55.0 months for imatinib.

The efficacy results from the BFORE trial are summarized in Table 13.

Table 13: Summary of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR), by Treatment Group in the Modified Intent-to-Treat (mITT) Population
Response	Bosutinib N=246 n (%)	Imatinib N=241 n (%)	2-sided p-value
Abbreviations: CCyR=complete cytogenetic response; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; MMR=major molecular response; N/n=number of patients.
MMR at Month 12 (Week 48)
MMR (%)	116 (47)	89 (37)	0.0200Derived from CMH test stratified by Geographical region and Sokal score at randomization.
(95% CI)	(41, 53)	(31, 43)
CCyR by Month 12 (Week 48)
CCyR (%)	190 (77)	160 (66)
(95% CI)	(72, 83)	(60, 72)	0.0075
MMR by Month 18 (Week 72)
MMR (%)	150 (61)	127 (53)
(95% CI)	(55, 67)	(46, 59)	0.0606

The MMR rate at Month 12 for all randomized patients (ITT population) was consistent with the mITT population (47% [95% CI: 41, 53] in the bosutinib treatment group and 36% [95% CI: 30, 42] in the imatinib treatment group; odds ratio of 1.57 [95% CI: 1.10, 2.22]). MMR by Month 60 (Week 240) in the mITT population was 74% (95% CI: 69, 80) in the bosutinib treatment group and 66% (95% CI: 60, 72) in the imatinib treatment group; odds ratio of 1.52 (95% CI: 1.02, 2.25). MMR by Month 60 in the ITT population was also consistent with the mITT population (1.57 [95% CI: 1.08, 2.28]).

After 60 months of follow-up, the median time to MMR in responders was 9.0 months for bosutinib and 11.9 months for imatinib.

By 60 months, the MMR rates in each Sokal risk group for the bosutinib and imatinib-treated patients, respectively, were 78% and 72% for low risk, 74% and 67% for intermediate risk and 68% and 52% for high risk.

After 60 months of follow-up, 6 (2%) bosutinib patients and 7 (3%) imatinib patients transformed to AP CML or BP CML while on treatment.

At 60 months, the estimated overall survival rate was 95% (95% CI: 91, 97) in the bosutinib group and 94% (95% CI: 90, 96) in the imatinib group.

14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML

Study 200 (NCT00261846), a single-arm, open-label, multicenter study in patients with CML who were resistant or intolerant to prior therapy was conducted to evaluate the efficacy and safety of BOSULIF 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for CP, AP, and BP disease previously treated with 1 prior TKI (imatinib) or more than 1 TKI (imatinib followed by dasatinib and/or nilotinib)

The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within 4 weeks; (2) failure to achieve a CHR by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-ABL gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a higher dose due to toxicity. The definitions of resistance and intolerance to both dasatinib and nilotinib were similar to those for imatinib. The protocol was amended to exclude patients with a known history of the T315I mutation after 396 patients were enrolled in the trial.

The efficacy endpoints for patients with CP CML previously treated with 1 prior TKI (imatinib) were the rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 1 additional TKI were the cumulative rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed CHR and overall hematologic response (OHR).

The study enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant

In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older

Of the 546 treated patients, 506 were considered evaluable for cytogenetic or hematologic efficacy assessment. Patients were evaluable for efficacy if they had received at least 1 dose of BOSULIF and had a valid baseline efficacy assessment. Among evaluable patients, there were 262 patients with CP CML previously treated with 1 prior TKI (imatinib), 112 patients with CP CML previously treated with both imatinib and at least 1 additional TKI, and 132 patients with advanced phase CML previously treated with at least 1 TKI.

Median duration of BOSULIF treatment was 26 months in patients with CP CML previously treated with 1 TKI (imatinib), 9 months in patients with CP CML previously treated with imatinib and at least 1 additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and 3 months in patients with BP CML previously treated with at least imatinib.

The 24 week efficacy and MCyR at any time results are summarized in Table 14.

Table 14: Efficacy Results in Patients with Ph+ CP CML With Resistance to or Intolerance to Imatinib
	Prior Treatment With Imatinib Only (N=262 evaluable) n (%)	Prior Treatment With Imatinib and Dasatinib or Nilotinib (N=112 evaluable) n (%)
Abbreviations: CI=confidence interval; CML=chronic myelogenous leukemia; CP=chronic phase; MCyR=major cytogenetic response; N/n=number of patients; Ph+=Philadelphia chromosome positive.
By Week 24
MCyR	105 (40.1)	29 (25.9)
(95% CI)	(34.1, 46.3)	(18.1, 35.0)
MCyR any time	156 (59.5)	45 (40.2)
	(53.3, 65.5)	(31.0, 49.9)

The long-term follow-up data analysis was based on a minimum of 60 months for patients with CP CML treated with 1 prior TKI (imatinib) and a minimum of 48 months for patients with CP CML treated with imatinib and at least 1 additional TKI. For the 59.5% of patients with CP CML treated with 1 prior TKI (imatinib) who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 65.4% and 42.9% had a MCyR lasting at least 18 and 54 months, respectively. For the 40.2% of patients with CP CML treated with imatinib and at least 1 additional TKI who achieved a MCyR at any time, the median duration of MCyR was not reached. Among these patients, 64.4% and 35.6% had a MCyR lasting at least 9 and 42 months, respectively. Of the 403 treated patients with CP CML, 20 patients had confirmed disease transformation to AP or BP while on treatment with BOSULIF.

The 48-week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 15.

Table 15: Efficacy Results in Patients With Accelerated Phase and Blast Phase CML Previously Treated With at Least Imatinib
	AP CML (N=72 evaluable) n (%)	BP CML (N=60 evaluable) n (%)
Abbreviations: AP=accelerated phase; BP=blast phase; CHR=complete hematologic response; CI=confidence interval; CML=chronic myelogenous leukemia; CI=confidence interval, OHR=overall hematologic response, CHR=complete hematologic response, N/n=number of patients
CHROverall hematologic response (OHR) = major hematologic response (complete hematologic response + no evidence of leukemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete hematologic response (CHR) for AP and BP CML: WBC less than or equal to institutional ULN, platelets greater than or equal to 100,000/mm³and less than 450,000/mm³, absolute neutrophil count (ANC) greater than or equal to 1.0×10⁹/L, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. No evidence of leukemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm³and less than 100,000/mm³) and/or neutropenia (ANC greater than or equal to 0.5×10⁹/L and less than 1.0×10⁹/L). Return to chronic phase (RCP) = disappearance of features defining accelerated or blast phases but still in chronic phase.by Week 48	22 (30.6)	10 (16.7)
(95% CI)	(20.2, 42.5)	(8.3, 28.5)
OHR by Week 48	41 (56.9)	17 (28.3)
(95% CI)	(44.7, 68.6)	(17.5, 41.4)

The long-term follow-up data analysis was based on a minimum of 48 months for patients with AP CML and BP CML. Of the 79 treated patients with AP CML, 3 patients had confirmed disease transformation to BP while on BOSULIF treatment.

14.3 Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy

The efficacy of BOSULIF in pediatric patients with newly-diagnosed (ND) chronic phase (CP) Ph+ CML and patients with resistant/intolerant (R/I) CP Ph+ CML was evaluated in the BCHILD trial [NCT04258943].

The BCHILD trial is a multicenter, non-randomized, open-label study conducted to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with ND CP Ph+ CML and pediatric patients with R/I CP Ph+ CML who have received at least one prior TKI therapy, to estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population. The study enrolled 28 patients with R/I CP Ph+ CML treated with BOSULIF at 300 mg/m²to 400 mg/m²orally once daily, and 21 patients with ND CP Ph+ CML treated at 300 mg/m²orally once daily. Efficacy outcomes included CCyR (defined as the absence of Ph+ metaphases in chromosome banding analysis of ≥20 metaphases, or <1% BCR-ABL1–positive nuclei of at least 200 peripheral blood interphase nuclei analyzed by Fluorescence

In Situ

Hybridization (FISH), or MMR if an adequate cytogenetic assessment was unavailable), MCyR (defined as CCyR or partial cytogenetic response of 1% to 35% Ph+ metaphases), and MMR (defined as ≤0.1% BCR-ABL ratio on international scale [IS]) at any time on study.

Patients with ND CP Ph+ CML had a median age of 14 years (range 5 to 17 years); 68% were male; 81% were White, 14% were Black/African American, and 5% were race not reported.

The major (MCyR) and complete (CCyR) cytogenetic responses among patients with ND CP Ph+ CML were 76.2% (95% CI: 52.8, 91.8) and 71.4% (95% CI: 47.8, 88.7), respectively. The MMR among patients with ND CP Ph+ CML was 28.6% (95% CI: 11.3, 52.3). The median duration of follow-up was 14.2 months (range: 1.1, 26.3 months) in patients with ND CP CML.

Patients with R/I CP Ph+ CML included n=6 treated at 300 mg/m²(0.75 times the recommended dose), n=11 treated at 350 mg/m²(0.875 times the recommended dose), and n=11 at 400 mg/m². Overall (n=28), patients had a median age of 11.5 years (range: 1 to 17 years); 57% were male; 43% were White, 7% were Black/African American, 14% were Asian, and 36% were race not reported.

The major (MCyR) and complete (CCyR) cytogenetic responses among patients with R/I CP Ph+ CML were 82.1% (95% CI: 63.1, 93.9) and 78.6% (95% CI: 59.0, 91.7), respectively. The MMR among patients with R/I CP Ph+ CML was 50.0% (95% CI: 30.6, 69.4). The MR4.5 (defined as BCR-ABL/ABL IS ≤ 0.0032%) was 17.9% (95% CI: 6.1, 36.9). Among 14 patients who achieved MMR, two patients lost MMR after 13.6 months and 24.7 months on treatment. The median duration of follow-up for overall survival was 23.2 months (range: 1.0, 61.5 months) in patients with R/I CP Ph+ CML.

)]

•Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy

[see

14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML

The study enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant

In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older

The 24 week efficacy and MCyR at any time results are summarized in Table 14.

Table 14: Efficacy Results in Patients with Ph+ CP CML With Resistance to or Intolerance to Imatinib
	Prior Treatment With Imatinib Only (N=262 evaluable) n (%)	Prior Treatment With Imatinib and Dasatinib or Nilotinib (N=112 evaluable) n (%)
Abbreviations: CI=confidence interval; CML=chronic myelogenous leukemia; CP=chronic phase; MCyR=major cytogenetic response; N/n=number of patients; Ph+=Philadelphia chromosome positive.
By Week 24
MCyR	105 (40.1)	29 (25.9)
(95% CI)	(34.1, 46.3)	(18.1, 35.0)
MCyR any time	156 (59.5)	45 (40.2)
	(53.3, 65.5)	(31.0, 49.9)

The 48-week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 15.

Table 15: Efficacy Results in Patients With Accelerated Phase and Blast Phase CML Previously Treated With at Least Imatinib
	AP CML (N=72 evaluable) n (%)	BP CML (N=60 evaluable) n (%)
Abbreviations: AP=accelerated phase; BP=blast phase; CHR=complete hematologic response; CI=confidence interval; CML=chronic myelogenous leukemia; CI=confidence interval, OHR=overall hematologic response, CHR=complete hematologic response, N/n=number of patients
CHROverall hematologic response (OHR) = major hematologic response (complete hematologic response + no evidence of leukemia) or return to chronic phase (RCP). All responses were confirmed after 4 weeks. Complete hematologic response (CHR) for AP and BP CML: WBC less than or equal to institutional ULN, platelets greater than or equal to 100,000/mm³and less than 450,000/mm³, absolute neutrophil count (ANC) greater than or equal to 1.0×10⁹/L, no blasts or promyelocytes in peripheral blood, less than 5% myelocytes + metamyelocytes in bone marrow, less than 20% basophils in peripheral blood, and no extramedullary involvement. No evidence of leukemia (NEL): Meets all other criteria for CHR except may have thrombocytopenia (platelets greater than or equal to 20,000/mm³and less than 100,000/mm³) and/or neutropenia (ANC greater than or equal to 0.5×10⁹/L and less than 1.0×10⁹/L). Return to chronic phase (RCP) = disappearance of features defining accelerated or blast phases but still in chronic phase.by Week 48	22 (30.6)	10 (16.7)
(95% CI)	(20.2, 42.5)	(8.3, 28.5)
OHR by Week 48	41 (56.9)	17 (28.3)
(95% CI)	(44.7, 68.6)	(17.5, 41.4)

]

•Adult patients with newly-diagnosed chronic phase Ph+ CML: 400 mg orally once daily with food. (

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/m²orally 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/m²orally 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.

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
BSA BSA=Body Surface Area	Newly-Diagnosed Recommended Dose (Once Daily)	Resistant or Intolerant Recommended Dose (Once Daily)
< 0.55 m²	150 mg	200 mg
0.55 to < 0.63 m²	200 mg	250 mg
0.63 to < 0.75 m²	200 mg	300 mg
0.75 to < 0.9 m²	250 mg	350 mg
0.9 to < 1.1 m²	300 mg	400 mg
≥ 1.1 m²	400 mgmaximum starting dose (corresponding to maximum starting dose in adult indication)	500 mg

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	Volume of Applesauce or Yogurt
100 mg	10 mL (2 teaspoons)
150 mg	15 mL (3 teaspoons)
200 mg	20 mL (4 teaspoons)
250 mg	25 mL (5 teaspoons)
300 mg	30 mL (6 teaspoons)
350 mg	30 mL (6 teaspoons)
400 mg	35 mL (7 teaspoons)
450 mg	40 mL (8 teaspoons)
500 mg	45 mL (9 teaspoons)
550 mg	45 mL (9 teaspoons)
600 mg	50 mL (10 teaspoons)

)

•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 Recommended Dosage

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

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
BSA BSA=Body Surface Area	Newly-Diagnosed Recommended Dose (Once Daily)	Resistant or Intolerant Recommended Dose (Once Daily)
< 0.55 m²	150 mg	200 mg
0.55 to < 0.63 m²	200 mg	250 mg
0.63 to < 0.75 m²	200 mg	300 mg
0.75 to < 0.9 m²	250 mg	350 mg
0.9 to < 1.1 m²	300 mg	400 mg
≥ 1.1 m²	400 mgmaximum starting dose (corresponding to maximum starting dose in adult indication)	500 mg

Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt

Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes
Dose	Volume of Applesauce or Yogurt
100 mg	10 mL (2 teaspoons)
150 mg	15 mL (3 teaspoons)
200 mg	20 mL (4 teaspoons)
250 mg	25 mL (5 teaspoons)
300 mg	30 mL (6 teaspoons)
350 mg	30 mL (6 teaspoons)
400 mg	35 mL (7 teaspoons)
450 mg	40 mL (8 teaspoons)
500 mg	45 mL (9 teaspoons)
550 mg	45 mL (9 teaspoons)
600 mg	50 mL (10 teaspoons)

)

•Pediatric patients with newly-diagnosed chronic phase Ph+ CML: 300 mg/m²orally once daily with food. (

2.1 Recommended Dosage

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

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
BSA BSA=Body Surface Area	Newly-Diagnosed Recommended Dose (Once Daily)	Resistant or Intolerant Recommended Dose (Once Daily)
< 0.55 m²	150 mg	200 mg
0.55 to < 0.63 m²	200 mg	250 mg
0.63 to < 0.75 m²	200 mg	300 mg
0.75 to < 0.9 m²	250 mg	350 mg
0.9 to < 1.1 m²	300 mg	400 mg
≥ 1.1 m²	400 mgmaximum starting dose (corresponding to maximum starting dose in adult indication)	500 mg

Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt

Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes
Dose	Volume of Applesauce or Yogurt
100 mg	10 mL (2 teaspoons)
150 mg	15 mL (3 teaspoons)
200 mg	20 mL (4 teaspoons)
250 mg	25 mL (5 teaspoons)
300 mg	30 mL (6 teaspoons)
350 mg	30 mL (6 teaspoons)
400 mg	35 mL (7 teaspoons)
450 mg	40 mL (8 teaspoons)
500 mg	45 mL (9 teaspoons)
550 mg	45 mL (9 teaspoons)
600 mg	50 mL (10 teaspoons)

)

•Pediatric patients with chronic phase Ph+ CML with resistance or intolerance to prior therapy: 400 mg/m²orally once daily with food. (

2.1 Recommended Dosage

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

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
BSA BSA=Body Surface Area	Newly-Diagnosed Recommended Dose (Once Daily)	Resistant or Intolerant Recommended Dose (Once Daily)
< 0.55 m²	150 mg	200 mg
0.55 to < 0.63 m²	200 mg	250 mg
0.63 to < 0.75 m²	200 mg	300 mg
0.75 to < 0.9 m²	250 mg	350 mg
0.9 to < 1.1 m²	300 mg	400 mg
≥ 1.1 m²	400 mgmaximum starting dose (corresponding to maximum starting dose in adult indication)	500 mg

Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt

Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes
Dose	Volume of Applesauce or Yogurt
100 mg	10 mL (2 teaspoons)
150 mg	15 mL (3 teaspoons)
200 mg	20 mL (4 teaspoons)
250 mg	25 mL (5 teaspoons)
300 mg	30 mL (6 teaspoons)
350 mg	30 mL (6 teaspoons)
400 mg	35 mL (7 teaspoons)
450 mg	40 mL (8 teaspoons)
500 mg	45 mL (9 teaspoons)
550 mg	45 mL (9 teaspoons)
600 mg	50 mL (10 teaspoons)

)

•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 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 m²and 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 m²can be conducted similarly to adult recommendations in 100 mg increments.
The maximum dose in pediatric and adult patients is 600 mg once daily.
)
•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 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 m²and 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 m²can be conducted similarly to adult recommendations in 100 mg increments.
The maximum dose in pediatric and adult patients is 600 mg once daily.
)

•Adjust dosage for toxicity and organ impairment (

2 DOSAGE AND ADMINISTRATION

•Adult patients with newly-diagnosed chronic phase Ph+ CML: 400 mg orally once daily with food.
•Adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy: 500 mg orally once daily with food.
•Pediatric patients with newly-diagnosed chronic phase Ph+ CML: 300 mg/m²orally once daily with food.
•Pediatric patients with chronic phase Ph+ CML with resistance or intolerance to prior therapy: 400 mg/m²orally once daily with food.
•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.
•Consider dose escalation by increments of 50 mg for those with a BSA <1.1 m²and 100 mg for those with a BSA ≥1.1 m²to a maximum of 600 mg daily in pediatric patients who do not reach sufficient response after 3 months.
•Adjust dosage for toxicity and organ impairment

2.1 Recommended Dosage

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

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
BSA BSA=Body Surface Area	Newly-Diagnosed Recommended Dose (Once Daily)	Resistant or Intolerant Recommended Dose (Once Daily)
< 0.55 m²	150 mg	200 mg
0.55 to < 0.63 m²	200 mg	250 mg
0.63 to < 0.75 m²	200 mg	300 mg
0.75 to < 0.9 m²	250 mg	350 mg
0.9 to < 1.1 m²	300 mg	400 mg
≥ 1.1 m²	400 mgmaximum starting dose (corresponding to maximum starting dose in adult indication)	500 mg

Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt

Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes
Dose	Volume of Applesauce or Yogurt
100 mg	10 mL (2 teaspoons)
150 mg	15 mL (3 teaspoons)
200 mg	20 mL (4 teaspoons)
250 mg	25 mL (5 teaspoons)
300 mg	30 mL (6 teaspoons)
350 mg	30 mL (6 teaspoons)
400 mg	35 mL (7 teaspoons)
450 mg	40 mL (8 teaspoons)
500 mg	45 mL (9 teaspoons)
550 mg	45 mL (9 teaspoons)
600 mg	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 m²and 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 m²can 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 followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m²or 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).

Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult and Pediatric Patients
ANCAbsolute Neutrophil Countless than 1000×10⁶/L or Platelets less than 50,000×10⁶/L	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 m²and 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 m²and resume treatment.

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
[see Use in Specific Populations (8.6, 8.7)and Clinical Pharmacology (12.3)] .
		Newly-diagnosed chronic phase Ph+ CML	Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy
Normal renal and hepatic function		400 mg daily	500 mg daily
Renal impairment
	Creatinine clearance 30 to 50 mL/min	300 mg daily	400 mg daily
	Creatinine clearance less than 30 mL/min	200 mg daily	300 mg daily
Hepatic impairment
	Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C)	200 mg daily	200 mg daily

Table 5: Dosage Adjustments for Renal and Hepatic Impairment in Pediatric Patients
[see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)] .
	Newly-Diagnosed CP Ph+ CML Recommended Starting Dose (Once Daily) By Organ Function
Pediatric Patients by Separated BSA BSA=Body Surface Area Band	Normal renal and hepatic function	Renal Impairment: Creatinine clearance 30 to 50 mL/min	Renal Impairment: Creatinine clearance less than 30 mL/min	Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C)
Pediatric < 0.55 m²	150 mg	100 mg	100 mg	100 mg
Pediatric 0.55 to < 0.63 m²	200 mg	150 mg	100 mg	100 mg
Pediatric 0.63 to < 0.75 m²	200 mg	150 mg	100 mg	100 mg
Pediatric 0.75 to < 0.9 m²	250 mg	200 mg	150 mg	100 mg
Pediatric 0.9 to < 1.1 m²	300 mg	200 mg	200 mg	150 mg
Pediatric ≥ 1.1 m²	400 mg	300 mg	200 mg	200 mg
	CP Ph+ CML with Resistance or Intolerance to Prior Therapy Recommended Starting Dose (Once Daily) By Organ Function
Pediatric Patients by Separated BSA Band	Normal renal and hepatic function	Renal Impairment: Creatinine clearance 30 to 50 mL/min	Renal Impairment: Creatinine clearance less than 30 mL/min	Hepatic Impairment: Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C)
Pediatric < 0.55 m²	200 mg	150 mg	100 mg	100 mg
Pediatric 0.55 to < 0.63 m²	250 mg	200 mg	150 mg	100 mg
Pediatric 0.63 to < 0.75 m²	300 mg	200 mg	200 mg	150 mg
Pediatric 0.75 to < 0.9 m²	350 mg	250 mg	200 mg	150 mg
Pediatric 0.9 to < 1.1 m²	400 mg	300 mg	250 mg	200 mg
Pediatric ≥ 1.1 m²	500 mg	400 mg	300 mg	200 mg

)

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.

Lactation: Advise women not to breastfeed. (

8.2 Lactation

Risk Summary

No data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, bosutinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment with BOSULIF and for 2 weeks after the last dose.

Animal Data

After a single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours.

)

BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis

[see

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 adults 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 adults 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%).

The most common adverse reactions, in ≥20% of pediatric patients (N=49) were diarrhea (82%), abdominal pain (73%), vomiting (55%), nausea (49%), rash (49%), fatigue (37%), hepatic dysfunction (37%), headache (35%), pyrexia (31%), decreased appetite (27%), and constipation (20%).

The most common laboratory abnormalities that worsened from baseline in ≥20% of pediatric patients were creatinine increased (92%), alanine aminotransferase increased (59%), white blood cell count decreased (53%), aspartate aminotransferase increased (51%), platelet count decreased (49%), glucose increased (41%), calcium decreased (31%), hemoglobin decreased (31%), neutrophil count decreased (31%), lymphocyte count decreased (29%), serum amylase increased (27%), and CPK increased (25%).

Adverse Reactions in Adult 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 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 mg/day.

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%).

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%).

Table 7 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 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg StudyBased 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.
		Bosutinib 400 mg Chronic Phase CML (N=268)		Imatinib 400 mg Chronic Phase CML (N=265)
System Organ Class	Preferred Term	All Grades %	Grade 3/4 %	All Grades %	Grade 3/4 %
Gastrointestinal disorders	Diarrhea	75	9	40	1
	Abdominal painAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain.	39	2	27	1
	Nausea	37	0	42	0
	Vomiting	21	1	20	0
	Constipation	13	0	6	0
Hepatobiliary disorders	Hepatic dysfunctionHepatic 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.	45	27	15	4
Skin and subcutaneous tissue disorders	RashRash 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.	40	2	30	2
	Pruritus	11	<1	4	0
General disorders and administration-site conditions	FatigueFatigue includes the following preferred terms: Asthenia, Fatigue, Malaise.	33	1	30	<1
	Pyrexia	17	1	11	0
	EdemaEdema 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.	15	0	46	2
Infections and infestations	Respiratory tract infectionRespiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection.	27	1	25	<1
Nervous system disorders	Headache	22	1	15	1
Musculoskeletal and connective tissue disorders	Arthralgia	18	1	18	<1
	Back pain	12	<1	9	<1
Respiratory, thoracic, and mediastinal disorders	Cough	11	0	10	0
	Dyspnea	11	1	6	1
Metabolism and nutrition disorders	Decreased appetite	11	<1	6	0
Vascular disorders	HypertensionHypertension* includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive.	10	5	11	5

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 8 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3 newly-diagnosed CML safety population.

Table 8: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with Newly-Diagnosed CML in Bosutinib 400 mg StudyBased on a Minimum of 57 Months of Follow-up.
	Bosutinib N=268 %		Imatinib N=265 %
	All Grade	Grade 3–4	All Grade	Grade 3–4
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
Hematology Parameters
Platelet Count decreased	68	14	60	6
Absolute Neutrophil Count decreased	42	9	65	20
Hemoglobin decreased	89	9	90	7
White Blood Cell Count decreased	50	6	70	8
Lymphocyte Count decreased	84	12	82	14
Biochemistry Parameters
SGPT/ALT increased	68	26	28	3
SGOT/AST increased	56	13	29	3.4
Lipase increased	53	19	35	8
Phosphorus decreased	54	9	69	21
Amylase increased	32	3.4	18	2.3
Alkaline Phosphatase increased	41	0	43	0.4
Calcium decreased	55	1.5	57	1.1
Glucose increased	57	3	65	3.4
Creatine Kinase increased	36	3	65	5
Creatinine increased	94	1.1	98	0.8

Adverse Reactions in Adult 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 prior therapy. Serious adverse reactions reported in >2% of patients included pneumonia (7%), pleural effusion (6%), pyrexia (3.7%), coronary artery disease (3.5%), dyspnea (2.6%), rash (2.2%), thrombocytopenia (2%), abdominal pain (2%), and diarrhea (2%).

Fatal adverse reactions occurred in 12 patients (2.2%) due to coronary artery disease (0.9%), pneumonia (0.4%), respiratory failure (0.4%), gastrointestinal hemorrhage (0.2%), acute kidney injury (0.2%), and acute pulmonary edema (0.2%).

Permanent discontinuation of bosutinib due to an adverse reaction occurred in 22% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which resulted in permanent discontinuation in >2% of patients included thrombocytopenia (6%), hepatic dysfunction (3.3%), and neutropenia (2%).

Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 66% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia (24%), diarrhea (14%), rash (13%), hepatic dysfunction (10%), neutropenia (9%), pleural effusion (8%), vomiting (7%), anemia (6%), and abdominal pain (6%).

The most common adverse reactions, in ≥20% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy were diarrhea (83%), nausea (47%), rash (46%), abdominal pain (45%), vomiting (39%), fatigue (33%), pyrexia (28%), hepatic dysfunction (27%), respiratory tract infection (24%), cough (23%), and headache (21%)

The most common laboratory abnormalities that worsened from baseline in ≥20% were creatinine increased (93%), hemoglobin decreased (91%), lymphocyte decreased (80%), platelets decreased (69%), absolute neutrophil count (54%), ALT increased (53%), calcium decreased (53%), white blood cell count decreased (52%), urate increased (48%), AST increased (47%), phosphorus decreased (39%), alkaline phosphatase increased (39%), lipase increased (28%), magnesium increased (25%), potassium decreased (24%), potassium increased (23%). See Table 10for Grade 3/4 laboratory abnormalities.

Table 9 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up.

Table 9: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm TrialBased on a Minimum of 105 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
		CP CML (N=403)		AdvP CML (N=143)
System Organ Class	Preferred Term	All Grades %	Grade 3/4 %	All Grades %	Grade 3/4 %
ADR Definition
Gastrointestinal disorders	Diarrhea	85	10	76	4
	Abdominal painAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain.	49	2	36	7
	Nausea	47	1	48	2
	Vomiting	38	3	43	3
	Constipation	15	<1	17	1
Skin and subcutaneous tissue disorders	RashRash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis psoriasiform, Drug eruption, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Exfoliative rash, Lichenoid keratosis, Palmar erythema, Photosensitivity reaction, Pigmentation disorder, Psoriasis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalised, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Seborrhoeic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin toxicity, Stasis dermatitis.	48	9	42	5
	Pruritus	12	1	7	0
General disorders and administration-site conditions	Fatigue	35	3	27	6
	Pyrexia	25	1	37	3
	EdemaEdema includes the following preferred terms: Eye edema, Eyelid edema, Face edema, Generalized edema, Localized edema, Edema, Edema peripheral, Penile edema, Periorbital edema, Periorbital swelling, Peripheral swelling, Scrotal edema, Scrotal swelling, Swelling, Swelling face, Swelling of eyelid, Testicular edema, Tongue edema.	19	<1	17	1
	Chest painChest pain includes the following preferred terms: Chest discomfort, Chest pain.	8	1	12	1
Hepatobiliary disorders	Hepatic dysfunctionHepatic dysfunction includes the following preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic function abnormal, Hepatic steatosis, Hepatitis toxic, Hepatomegaly, Hepatotoxicity, Hyperbilirubinemia, Liver disorder, Liver function test abnormal, Liver function test increased, Transaminases increased.	29	11	21	10
Infections and infestations	Respiratory tract infectionRespiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection, Viral upper respiratory tract infection.	27	<1	17	0
	InfluenzaInfluenza includes the following preferred terms: H1N1 influenza, Influenza.	11	1	3	0
	PneumoniaPneumonia includes the following preferred terms: Atypical pneumonia, Lower respiratory tract congestion, Lower respiratory tract infection, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia fungal, Pneumonia necrotising, Pneumonia streptococcal.	10	4	18	12
Respiratory, thoracic, and mediastinal disorders	Cough	24	0	22	0
	Pleural effusion	14	4	9	4
	Dyspnea	12	2	20	6
Nervous system disorders	Headache	21	1	18	4
	Dizziness	11	0	14	1
Musculoskeletal and connective tissue disorders	Arthralgia	19	1	15	0
	Back pain	14	1	8	1
Metabolism and nutrition disorders	Decreased appetite	14	1	14	0
Vascular disorders	HypertensionHypertension* includes the following preferred terms: Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis, Retinopathy hypertensive. * ADR identified post-marketing	11	3	8	3

In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 2 patients (0.4%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.

Table 10 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up.

Table 10: Number (%) of Patients With Clinically Relevant All Grade or Grade 3/4 Laboratory Test Abnormalities in the Safety Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior TherapyBased on a Minimum of 105 Months of Follow-up.
	CP CML N=403 %		AdvP CML N=143 %
	All grade	Grade 3/4	All grade	Grade 3/4
Abbreviations: AdvP=advanced phase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; CP=chronic phase; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal.
Hematology Parameters
Platelet Count decreased	66	26	80	57
Absolute Neutrophil Count decreased	50	16	66	39
Hemoglobin decreased	89	13	97	38
Lymphocyte decreased	79	14	82	21
White Blood Cell Count decreased	51	7	57	27
Biochemistry Parameters
SGPT/ALT increased	58	11	39	6
SGOT/AST increased	50	5	37	3.5
Lipase increased	32	12	19	6
Phosphorus decreased	41	8	33	7
Total Bilirubin increased	16	0.7	22	2.8
Creatinine increased	95	3	87	1.4
Alkaline Phosphatase increased	39	0	39	1.4
Glucose increased	42	2.7	39	6
Sodium increased	23	0.5	11	0
Sodium decreased	18	2.2	27	6
Calcium decreased	55	4.7	45	3.5
Urate increased	49	6	43	6
Magnesium increased	27	7	18	4.9
Potassium decreased	22	1.7	29	4.9
Potassium increased	25	2.7	19	2.1

Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML that is Resistant or Intolerant to Prior Therapy

The safety of BOSULIF was evaluated in BCHILD, a single-arm trial for the treatment of pediatric patients aged 1 year and older with newly-diagnosed CP Ph+ CML or in patients with CP Ph+ CML who are resistant or intolerant to prior therapy

[see Clinical Studies (14.3)]

. Patients received BOSULIF (n = 49) 300 mg/m²to 400 mg/m²orally once daily until disease progression or unacceptable toxicity. The median time on treatment with BOSULIF was 12.2 months (range, 0.2 to 60.9 months). Among patients who received BOSULIF, 77.6% were exposed for 6 months or longer and 51% were exposed for one year or longer.

Permanent discontinuation of BOSULIF due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation in 2 or more patients included ALT increased (6%), AST increased (4%), diarrhea (4%), fatigue (4%) and rash maculo-papular (4%).

The most common adverse reactions, in ≥20% of BOSULIF-treated pediatric patients were diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, and constipation.

Table 11 summarizes the adverse reactions in BCHILD.

Table 11: Adverse Reactions (10% or Greater) in Pediatric Patients with Newly Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF in BCHILD
Adverse drug reactions are based on all-causality treatment-emergent adverse reactions.
The commonality stratification is based on 'All Grades' under Bosutinib 400 mg column.
'Grade 3/4 columns indicate maximum toxicity.
System Organ Class	Preferred Term	BOSULIF Total (N=49) %
System Organ Class	Preferred Term	All Grades	Grade 3/4
Gastrointestinal disorders	Diarrhea	82	12
	Abdominal painAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain, Hepatic pain.	73	4
	Vomiting	55	6
	Nausea	49	2
	Constipation	20	0
Skin and subcutaneous tissue disorders	RashRash includes the following preferred terms: Acarodermatitis, Acne, Angular cheilitis, Blister, Dermatitis, Dermatitis acneiform, Dermatitis bullous, Dermatitis exfoliative generalized, Dermatitis psoriasiform, Drug eruption, Drug reaction with eosinophilia and systemic symptoms, Dyshidrotic eczema, Eczema, Eczema asteatotic, Erythema, Erythema annulare, Erythema nodosum, Exfoliative rash, Genital rash, Lichen planus, Lichenoid keratosis, Palmar erythema, Palmar-plantar erythrodysesthesia syndrome, Perivascular dermatitis, Photosensitivity reaction, Pigmentation disorder, Pruritus allergic, Psoriasis, Punctate keratitis, Pyoderma gangrenosum, Pyogenic granuloma, Rash, Rash erythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic, Rash pustular, Rash vesicular, Seborrheic dermatitis, Seborrhoeic keratosis, Skin depigmentation, Skin discoloration, Skin disorder, Skin exfoliation, Skin hyperpigmentation, Skin hypopigmentation, Skin irritation, Skin lesion, Skin plaque, Skin reaction, Skin toxicity, Stasis dermatitis.	49	8
Hepatobiliary disorders	Hepatic dysfunctionHepatic dysfunction includes the following preferred terms: Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Blood bilirubin unconjugated increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatomegaly, Hepatosplenomegaly, Hyperbilirubinaemia, Jaundice, Liver function test abnormal, Liver function test increased, Ocular icterus, Transaminases increased, Hepatic function abnormal, Drug-induced liver injury, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatobiliary disease, Hepatocellular injury, Hepatotoxicity, Liver disorder, Liver injury.	37	14
General disorders and administration-site conditions	FatigueFatigue includes the following preferred terms: Asthenia, Fatigue, Malaise.	37	4
	Pyrexia	31	4
Nervous system disorders	Headache	35	2
Metabolism and nutrition disorders	Decreased appetite	27	2
Infections and infestations	Respiratory tract infectionRespiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract congestion, Upper respiratory tract infection, Upper respiratory tract inflammation, Viral upper respiratory tract infection.	12	2

The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased, alanine aminotransferase increased, white blood cell count decreased, aspartate aminotransferase increased, platelet count decreased, glucose increased, calcium decreased, hemoglobin decreased, neutrophil count decreased, lymphocyte count decreased, serum amylase increased and CPK increased.

Table 12 summarizes laboratory test abnormalities in BCHILD.

Table 12: Laboratory Abnormalities (≥ 20%) That Worsened From Baseline in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or CP Ph+ CML Resistant or Intolerant to Prior Therapy Who Received BOSULIF in BCHILD
Grades are defined using CTCAE V4.03. Based on CTCAE grading without regard to fasting status for 'Hyperglycemia' lab parameter.
Includes data up to 28 days after last dose of study treatment.
	BOSULIF (N= 49)
	All Grade	Grade 3/4
	%	%
Creatinine increased	92	0
Alanine aminotransferase increased	59	14
White blood cell count decreased	53	4
Aspartate aminotransferase increased	51	6
Platelet count decreased	49	18
Glucose increased	41	0
Calcium decreased	31	0
Hemoglobin decreased	31	8
Neutrophil count decreased	31	12
Lymphocyte count decreased	29	2
Serum amylase increased	27	4
CPK increased	25	0

Additional Adverse Reactions From Multiple Clinical Trials

The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from all 1372 patients with leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.

Blood and Lymphatic System Disorders

0.1% and less than 1%

- Febrile neutropenia

Cardiac Disorders

1% and less than 10%

- Cardiac ischemia (includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischemia, Troponin increased), Pericardial effusion, Cardiac failure (includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure);

0.1% and less than 1%

- Pericarditis

Ear and Labyrinth Disorders

1% and less than 10%

- Tinnitus

Endocrine Disorders

1% and less than 10%

- Hypothyroidism;

0.1% and less than 1%

- Hyperthyroidism

Gastrointestinal Disorders

1% and less than 10%

- Gastritis, Pancreatitis (includes Edematous pancreatitis, Pancreatic enzymes increased, Pancreatitis, Pancreatitis acute, Pancreatitis chronic), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage, Upper gastrointestinal hemorrhage)

General Disorders and Administrative Site Conditions

1% and less than 10%

- Pain

Immune System Disorders

1% and less than 10%

- Drug hypersensitivity;

0.1% and less than 1%

- Anaphylactic shock

Infections and Infestations

1% and less than 10%

- Bronchitis

Investigations

1% and less than 10%

- Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome)

Metabolism and Nutrition Disorders

1% and less than 10%

- Dehydration

Musculoskeletal and Connective Tissue Disorders

1% and less than 10%

- Myalgia

Nervous System Disorders

1% and less than 10%

- Dysgeusia

Renal and Urinary Disorders

1% and less than 10%

- Acute kidney injury, Renal impairment, Renal failure

Respiratory, Thoracic and Mediastinal Disorders

1% and less than 10%

- Pulmonary hypertension (includes Pulmonary hypertension, Pulmonary arterial hypertension, Pulmonary arterial pressure increased);

0.1% and less than 1%

- Acute pulmonary edema (includes Acute pulmonary edema, Pulmonary edema), Interstitial lung disease, Respiratory failure

Skin and Subcutaneous Disorders

0.1% and less than 1%

- Erythema multiforme

]

•Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. (
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 followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m²or greater, reduce dose similarly to adults.
,
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)]
.
)

•Myelosuppression: Monitor blood counts and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. (

2.4 Dosage Adjustments for Myelosuppression

Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3).

Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult and Pediatric Patients
ANCAbsolute Neutrophil Countless than 1000×10⁶/L or Platelets less than 50,000×10⁶/L	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 m²and 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 m²and resume treatment.

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)]

)

•Hepatic Toxicity: Monitor liver enzymes at least monthly for the first 3 months and as needed. Withhold, dose reduce, or discontinue BOSULIF. (
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 followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m²or greater, reduce dose similarly to adults.
,
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)]
.
)
•Cardiovascular Toxicity: Monitor and manage as necessary. Interrupt, dose reduce, or discontinue BOSULIF. (
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 5.1% 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)and Adverse Reactions (6)]
.
)
•Fluid Retention: Monitor patients and manage using standard of care treatment. Interrupt, dose reduce, or discontinue BOSULIF. (
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 followed by additional 50 mg increment if the adverse reaction (AR) persists. For pediatric patients with BSA ≥1.1 m²or greater, reduce dose similarly to adults.
,
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)]
.
)

•Renal Toxicity: Monitor patients for renal function at baseline and during therapy with BOSULIF. (

5.6 Renal Toxicity

An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table 6 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 6: Shift From Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (N=1372)Among the 1372 patients, eGFR was missing in 7 patients at baseline or on-therapy. There were no patients with kidney failure at baseline.
Baseline		Follow-Up
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.
Renal Function Status	N	Normal n (%)	Mild n (%)	Mild to Moderate n (%)	Moderate to Severe n (%)	Severe n (%)	Kidney Failure n (%)
Normal	527	115 (21.8)	330 (62.6)	50 (9.5)	23 (4.4)	3 (0.6)	5 (0.9)
Mild	672	10 (1.5)	259 (38.5)	271 (40.3)	96 (14.3)	26 (3.9)	6 (0.9)
Mild to Moderate	137	0	6 (4.4)	40 (29.2)	66 (48.2)	24 (17.5)	1 (0.7)
Moderate to Severe	33	0	1 (3.0)	1 (3.0)	8 (24.2)	19 (57.6)	4 (12.1)
Severe	1	0	0	0	0	0	1 (100)
Total	1370	125 (9.1)	596 (43.5)	362 (26.4)	193 (14.1)	72 (5.2)	17 (1.2)

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)]

)

•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 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)]
.
)

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