`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203341Orig1s000
`LABELING
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`BOSULIF safely and effectively. See full prescribing information for
`BOSULIF.
`
`BOSULIF® (bosutinib) tablets, for oral use
`Initial U.S. Approval: 2012
`----------------------------INDICATIONS AND USAGE---------------------------
` BOSULIF is a kinase inhibitor indicated for the treatment of adult patients
`with chronic, accelerated, or blast phase Ph+ chronic myelogenous
`leukemia (CML) with resistance or intolerance to prior therapy. (1)
`
`
`
` Hepatic toxicity: Monitor liver enzymes at least monthly for the first
`three months and as needed. Withhold, dose reduce, or discontinue
`BOSULIF. (2.3,5.3)
` Fluid retention: Monitor patients and manage using standard of care
`treatment. Withhold, dose reduce, or discontinue BOSULIF. (2.3,5.4)
` Embryofetal toxicity: May cause fetal harm. Females of reproductive
`potential should avoid becoming pregnant while being treated with
`BOSULIF. (5.5)
`----------------------------ADVERSE REACTIONS-------------
`Most common adverse reactions (incidence greater than 20%) are diarrhea,
`nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia,
`and fatigue. (6)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
` CYP3A Inhibitors and Inducers: Avoid concurrent use of BOSULIF with
`strong or moderate CYP3A inhibitors and inducers. (2.5, 2.6, 7.1,7.2)
` Proton Pump Inhibitors: May decrease bosutinib drug levels. Consider
`short-acting antacids in place of proton pump inhibitors. (7.2)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`Revised: 9/2012
`
`
`
`
`
`
`
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
` Recommended Dose: 500 mg orally once daily with food. (2.1)
` Consider dose escalation to 600 mg daily in patients who do not reach
`complete hematologic response by week 8 or complete cytogenetic
`response by week 12 and do not have Grade 3 or greater adverse
`reactions. (2.2)
` Adjust dosage for hematologic and non-hematologic toxicity. (2.3, 2.4)
` Hepatic impairment (at baseline): reduce BOSULIF dose to 200 mg daily.
`(2.7)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Tablets: 100 mg and 500 mg. (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Hypersensitivity to BOSULIF. (4)
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
` Gastrointestinal toxicity: Monitor and manage as necessary. Withhold, dose
`reduce, or discontinue BOSULIF. (2.3,5.1)
` Myelosuppression: Monitor blood counts and manage as necessary. (2.4,
`5.2)
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`12.4 QT/QTc Prolongation
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`16.3 Handling and Disposal
`17 PATIENT COUNSELING INFORMATION
`Dosing and Administration
`
`Gastrointestinal Problems
`
`Low Blood Cell Counts
`
`Liver Problems
`
`Fluid Retention
`
`Other Adverse Reactions
`
`Pregnancy and Breast-feeding
`
`Drug Interactions
`
` *
`
` Sections or subsections omitted from the full prescribing information
`are not listed.
`
` 1
`
`
`2
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Dose Escalation
`2.3 Dose Adjustments for Non-Hematologic Adverse Reactions
`2.4 Dose Adjustments for Myelosuppression
`2.5 Concomitant Use With CYP3A Inhibitors
`2.6 Concomitant Use With CYP3A Inducers
`2.7 Hepatic Impairment
`3
`DOSAGE FORMS AND STRENGTHS
`4
`CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Gastrointestinal Toxicity
`5.2 Myelosuppression
`5.3 Hepatic Toxicity
`5.4 Fluid Retention
`5.5 Embryofetal Toxicity
`ADVERSE REACTIONS
`6.1
`Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP),
`Accelerated Phase (AP), and Blast Phase (BP) CML
`6.2 Additional Data from Multiple Clinical Trials
`DRUG INTERACTIONS
`7.1 Drugs That May Increase Bosutinib Plasma Concentrations
`7.2 Drugs That May Decrease Bosutinib Plasma Concentrations
`7.3 Drugs That May Have Their Plasma Concentration Altered By
`Bosutinib
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`
`6
`
`7
`
`8
`
`
`
`Reference ID: 3184097
`
`1
`
`

`

`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`BOSULIF is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive
`(Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`
`The recommended dose and schedule of BOSULIF is 500 mg orally once daily with food. Continue treatment with BOSULIF until
`disease progression or patient intolerance.
`
`If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day.
`
`
`2.2 Dose Escalation
`
`Consider dose escalation to 600 mg once daily with food in patients who do not reach complete hematological response (CHR) by
`week 8 or a complete cytogenetic response (CCyR) by week 12, who did not have Grade 3 or higher adverse reactions, and who are
`currently taking 500 mg daily.
`
`2.3 Dose Adjustments for Non-Hematologic Adverse Reactions
`
`Elevated liver transaminases: If elevations in liver transaminases greater than 5 x institutional upper limit of normal (ULN) occur,
`withhold BOSULIF until recovery to less than or equal to 2.5 x 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 x ULN occur concurrently with
`bilirubin elevations greater than 2 x ULN and alkaline phosphatase less than 2 x ULN (Hy’s law case definition), discontinue
`BOSULIF [see Warnings and Precautions (5.3)].
`
`Diarrhea: For 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 400 mg once daily. If clinically appropriate, consider re-escalating the dose of BOSULIF to 500
`mg once daily.
`
`2.4 Dose Adjustments for Myelosuppression
`
`Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 1).
`
`
`Table 1:
`Dose Adjustments for Neutropenia and Thrombocytopenia
`
`
`ANCa less than 1000x106/L
`
`or
`
`Platelets less than 50,000x106/L
`
`a Absolute Neutrophil Count
`
`
`
`Reference ID: 3184097
`
`Withhold BOSULIF until ANC greater than or equal to1000x106/L and platelets
`greater than or equal to 50,000x106/L.
`
`Resume treatment with BOSULIF at the same dose if recovery occurs within 2 weeks.
`If blood counts remain low for greater than 2 weeks, upon recovery, reduce dose by
`100 mg and resume treatment.
`
`If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume
`treatment.
`
`Doses less than 300 mg/day have not been evaluated.
`
`2
`
`

`

`
`
`
`2.5 Concomitant Use With CYP3A Inhibitors
`
`Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with BOSULIF as an increase in bosutinib plasma
`concentration is expected (strong CYP3A inhibitors include ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir,
`telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan. Moderate CYP3A
`inhibitors include fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib,
`imatinib, verapamil, grapefruit products and ciprofloxacin) [see Drug Interactions (7.1)].
`
`2.6 Concomitant Use With CYP3A Inducers
`
`Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected (strong
`CYP3A inducers include rifampin, phenytoin, carbamazepine, St. John’s Wort, rifabutin and phenobarbital. Moderate CYP3A
`inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine) [see Drug Interactions (7.2)].
`
`2.7 Hepatic Impairment
`
`In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of BOSULIF is 200 mg daily. A
`daily dose of 200 mg in patients with hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar
`to the AUC seen in patients with normal hepatic function receiving 500 mg daily. However, there are no clinical data for efficacy at
`the dose of 200 mg once daily in patients with hepatic impairment and CML [see Use in Special Populations (8.6)].
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`
`
`100 mg tablets: yellow, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “100” on the other.
`
`500 mg tablets: red, oval, biconvex, film-coated tablets debossed with “Pfizer” on one side and “500” on the other.
`
` 4
`
` CONTRAINDICATIONS
`
`
`Hypersensitivity to BOSULIF. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients.
`
`
` WARNINGS AND PRECAUTIONS
`
` 5
`
`
`
`
`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/or fluid replacement. In the single-arm Phase 1/2 clinical trial, the median time to onset
`for diarrhea (all grades) was 2 days and the median duration per event was 1 day. Among the patients who experienced diarrhea, the
`median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-221). 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. Patients with CML who are receiving BOSULIF should
`have a complete blood count performed weekly for the first month 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
`
`One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3 x
`ULN with total bilirubin greater than 2 x ULN and alkaline phosphatase less than 2 x ULN) occurred in a trial of BOSULIF in
`combination with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of 1209
`patients in BOSULIF clinical trials.
`
`
`
`Reference ID: 3184097
`
`3
`
`

`

`In the 546 patients from the safety population, the incidence of ALT elevation was 17% and AST elevation was 14 %. Twenty per
`cent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations occurred early in
`treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the
`first 3 months. The median time to onset of increased ALT and AST was 30 and 33 days, respectively, and the median duration for
`each was 21 days.
`
`Perform monthly hepatic enzyme tests for the first three months of treatment with BOSULIF and as clinically indicated. In patients
`with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary
`[see Dosage and Administration (2.3) and Adverse Reactions (6)].
`
`5.4 Fluid Retention
`
`Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral
`edema.
`
` In the single-arm Phase 1/2 clinical trial in 546 patients with CML treated with prior therapy, severe fluid retention was reported in 14
`patients (3%). Specifically, 9 patients had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4 pleural and
`pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary edema, and 1 patient had a Grade 3 edema.
`
`Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary [see Dosage and
`Administration (2.3) and Adverse Reactions (6)].
`
`5.5 Embryofetal Toxicity
`
`There are no adequate and well controlled studies of BOSULIF in pregnant women. BOSULIF can cause fetal harm when
`administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the
`clinical exposure at the recommended bosutinib dose of 500 mg/day. Females of reproductive potential should be advised to avoid
`pregnancy while being treated with BOSULIF. If this drug is used during pregnancy, or if the patient becomes pregnant while taking
`this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
`
` 6
`
` ADVERSE REACTIONS
`
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`• Gastrointestinal toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
`• Myelosuppression [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)].
`• Hepatic toxicity [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)].
`• Fluid retention [see Warnings and Precautions (5.4)].
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug
`cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`Serious adverse reactions reported include anaphylactic shock [see Contraindications (4)], myelosuppression, gastrointestinal toxicity
`(diarrhea), fluid retention, hepatoxicity and rash.
`
`Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase 1/2 safety population (n=546) were
`diarrhea (82%), nausea (46%), thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia
`(26%), and fatigue (24%).
`
`6.1 Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML
`
`The single-arm Phase 1/2 clinical trial enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia
`(CML) and Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. The safety population (received
`at least 1 dose of BOSULIF) included 546 CML patients. Within the safety population there were 287 patients with CP CML
`previously treated with imatinib only who had a median duration of BOSULIF treatment of 24 months, and a median dose intensity of
`484 mg/day. There were 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a
`median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg/day. There were 76 patients with AP
`CML, and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10
`months and 3 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML
`cohorts, respectively.
`
`
`
`Reference ID: 3184097
`
`4
`
`

`

`Table 2 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.
`
`Table 2:
`Adverse Reactions (10% or greater) in patients with CML
`
`
`Gastrointestinal Disorders
` Diarrhea
` Nausea
` Abdominal Paina
` Vomiting
`Blood and Lymphatic System Disorders
` Thrombocytopenia
` Anemia
` Neutropenia
`General Disorders and Administrative Site
`Conditions
` Fatigueb
` Pyrexia
` Edemac
`Asthenia
`Infections and Infestations
` Respiratory tract infectiond
` Nasopharyngitis
`Investigations
` Alanine aminotransferase increased
` Aspartate aminotransferase increased
`Metabolism and nutrition disorder
`Decreased appetite
`Musculoskeletal and Connective Tissue
`Disorder
`Arthalgia
`Back pain
`Nervous System Disorders
` Headache
`Dizziness
`Respiratory, Thoracic and Mediastinal
`Disorders
`Dyspnea
` Cough
`Skin and Subcutaneous Disorders
` Rashe
` Pruritus
`
`CP CML = Chronic Phase CML; AdvP CML = Advanced Phase CML (includes patients with Accelerated Phase and Blast Phase CML)
`
`a. Abdominal pain includes the following preferred terms: Abdominal pain, Abdominal pain upper, Abdominal pain lower, Abdominal tenderness, Gastrointestinal
`pain, Abdominal discomfort
`Fatigue includes the following preferred terms: Fatigue, Malaise
`b.
`Edema includes the following preferred terms: Edema, Edema peripheral, Localized edema, Face edema
`c.
`d. Respiratory tract infection includes the following preferred terms: Respiratory tract infection, Upper respiratory tract infection, Lower respiratory tract infection,
`Viral upper respiratory tract infection, Respiratory tract infection viral
`e. Rash includes the following preferred terms: Rash, Rash macular, Rash pruritic, Rash generalized, Rash papular, Rash maculo-papular
`
`
`AdvP CML
`All CP and AdvP CML
`N=140
`N=546
`n (%)
`n (%)
`Grade 3/4 All Grades Grade 3/4
`
`
`449 (82)
`252 (46)
`203 (37)
` 211 (39)
`
`222 (41)
`146 (27)
`91 (17)
`
`
`132 (24)
`141 (26)
`75 (14)
`59 (11)
`
`63 (12)
`54 (10)
`
`95(17)
`79(14)
`
`72 (13)
`
`
`76 (14)
`59 (11)
`
`107 (20)
`57 (10)
`
`
`67 (12)
`110(20)
`
`189 (35)
`54 (10)
`
`
`45 (8)
`8 (1)
`13 (2)
`17 (3)
`
`157 (29)
`72 (13)
`68 (12)
`
`
`12 (2)
`6 (1)
`2 (<1)
`6 (1)
`
`2 (<1)
`0
`
`37(7)
`19(3)
`
`3 (1)
`
`
`2 (<1)
`5 (1)
`
`9 (2)
`1 (<1)
`
`
`12 (2)
`0
`
`38 (7)
`3 (1)
`
`
`7 (5)
`3 (2)
`7 (5)
`5 (4)
`
`52 (37)
`37 (26)
`25 (18)
`
`
`6 (4)
`4 (3)
`1 (1)
`1 (1)
`
` 0
`
`
`0
`
`7(5)
`4 (3)
`
` 0
`
`
`
`
` 0
`
`
`2 (1)
`
`6 (4)
`1 (1)
`
`
`8 (6)
`0
`
`6 (4)
`0
`
`All
`Grades
`
`107 (76)
`66 (47)
`41 (29)
`59 (42)
`
`59 (42)
`52 (37)
`26 (19)
`
`
`28 (20)
`51 (36)
`19 (14)
`14 (10)
`
`14 (10)
`7 (5)
`
`14(10)
`15(11)
`
`19 (14)
`
`
`18 (13)
`10 (7)
`
`25 (18)
`18 (13)
`
`
`26 (19)
`30(21)
`
`49 (35)
`11 (8)
`
`
`System Organ Class
` Preferred Term
`
`
`CP CML
`N=406
`n (%)
`All Grades
`
`Grade
`3/4
`
`38 (9)
`5 (1)
`6 (1)
`12 (3)
`
`105 (26)
`35 (9)
`43 (11)
`
`
`6 (1)
` 2 (<1)
` 1 (<1)
`5 (1)
`
` 2 (<1)
`0
`
`30 (7)
`15 (4)
`
`3 (1)
`
`
`2 (<1)
`3 (1)
`
`3 (1)
`0
`
`
`4 (1)
`0
`
`32 (8)
`3 (1)
`
`
`342 (84)
`186 (46)
`162 (40)
`152 (37)
`
`163 (40)
`94 (23)
`65 (16)
`
`
`104 (26)
`90 (22)
`56 (14)
`45 (11)
`
`
` 49 (12)
` 47 (12)
`
`81 (20)
`64 (16)
`
`53 (13)
`
`
`
` 58 (14)
`49 (12)
`
`82 (20)
`39 (10)
`
`
`41 (10)
`80(20)
`
`140 (34)
`43 (11)
`
`
`In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with
`uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.
`Table 3 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population.
`
`
`
`Reference ID: 3184097
`
`5
`
`

`

`
`Table 3:
`Number (%) of Patients with Clinically Relevant or Severe
`Grade 3/4 Laboratory Test Abnormalities
`In the Phase 1/2 Clinical Study, Safety Population
`
`
`
`
`CP CML
`N=406
`n (%)
`
`AdvP CML
`N=140
`n (%)
`
`Hematology Parameters
` Platelet Count (Low) less than 50 x 109/L
` Absolute Neutrophil Count less than 1 x 109/L
` Hemoglobin (Low) less than 80 g/L
`
`Biochemistry Parameters
` SGPT/ALT greater than 5.0 x ULN
` SGOT/AST greater than 5.0 x ULN
` Lipase greater than 2 x ULN
` Phosphorus (Low) less than 0.6 mmol/L
` Total Bilirubin greater than 3.0 x ULN
`
`
`102 (25)
`74 (18)
`53 (13)
`
`
`39 (10)
`17 (4)
`33 (8)
`30 (7)
`3 (1)
`
`
`80 (57)
`52 (37)
`49 (35)
`
`
`8 (6)
`4 (3)
`4 (3)
`10 (7)
`2 (1)
`
`All CP and AdvP
`CML
`N=546
`n (%)
`
`182 (33)
`126 (23)
`102 (19)
`
`47 (9)
`21 (4)
`37 (7)
`40 (7)
`5 (1)
`
`
`
`
`6.2 Additional Data 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 870 patients with Ph+ 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: 1% and less than 10% - febrile neutropenia
`
`Cardiac Disorders: 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis
`
`Ear and Labyrinth Disorders: 1% and less than 10% - tinnitus
`
`Gastrointestinal Disorders: 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis, gastrointestinal hemorrhagea
`
`General Disorders and Administrative Site Conditions: 1% and less than 10% - chest painb, pain
`
`Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicityc, abnormal hepatic functiond; 0.1% and less than 1% - liver injury
`
`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% - pneumoniae, influenza, bronchitis
`
`Investigations: 1% and less than 10% - electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood
`creatinine
`
`Metabolism and Nutrition Disorder: 1% and less than 10% - hyperkalemia, dehydration
`
`Musculoskeletal and Connective Tissue Disorder: 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 renal failure, renal failure
`
`
`6
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`Reference ID: 3184097
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`Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% - pleural effusion; 0.1% and less than 1% - acute pulmonary
`edema, respiratory failure, pulmonary hypertension
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`Skin and Subcutaneous Disorders: 1% and less than 10% - urticaria, pruritus, acne; 0.1% and less than 1% - erythema multiforme,
`exfoliative rash, drug eruption
`
`a. Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper
`gastrointestinal hemorrhage
`b. Chest pain includes the following preferred terms: chest pain, chest discomfort
`c. Hepatotoxicity includes the following preferred terms: hepatoxicity, toxic hepatitis, cytolytic hepatitis
`d. Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder
`e. Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical
`pneumonia
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` 7
`
` DRUG INTERACTIONS
`
`
`7.1 Drugs That May Increase Bosutinib Plasma Concentrations
`
`CYP3A or P-glycoprotein (P-gp) inhibitors: Avoid the concomitant use of strong or moderate CYP3A and/or P-gp inhibitors with
`BOSULIF as an increase in bosutinib plasma concentration is expected [see Dosage and Administration (2.5)]. In a dedicated cross-
`over drug-interaction trial in healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib Cmax
`5.2-fold and AUC 8.6-fold compared to BOSULIF alone [see Clinical Pharmacology (12.3)].
`
`7.2 Drugs That May Decrease Bosutinib Plasma Concentrations
`
`CYP3A Inducers: Avoid the concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure
`is expected [see Dosage and Administration (2.6)]. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24),
`concomitant rifampin (strong CYP3A inducer) decreased bosutinib Cmax by 86% and AUC by 94% compared to BOSULIF alone [see
`Clinical Pharmacology (12.3)].
`
`Proton Pump Inhibitors: In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant lansoprazole (PPI)
`decreased bosutinib Cmax by 46% and AUC by 26% compared to BOSULIF alone [see Clinical Pharmacology (12.3)].
`
`Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in bosutinib exposure. Separate antacid or H2
`blocker dosing and BOSULIF dosing by more than 2 hours.
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`7.3 Drugs That May Have Their Plasma Concentrations Altered By Bosutinib
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`Substrates of P-glycoprotein: An in vitro study suggests that BOSULIF may have the potential to increase the plasma concentrations
`of drugs that are P-gp substrates, such as digoxin [see Clinical Pharmacology (12.3)].
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` 8
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` USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
`
`Pregnancy Category D [see Warnings and Precautions (5.5)]
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`Based on its mechanism of action and findings in animals, BOSULIF can cause fetal harm when administered to a pregnant woman.
`Studies in animals showed reproductive toxicities. If BOSULIF is used during pregnancy, or if the patient becomes pregnant while
`taking BOSULIF, the patient should be apprised of the potential hazard to the fetus.
`
`Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats.
`Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, 3 and 10 mg/kg/day. This study
`did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes.
`
`In a study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of
`3, 10 and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and
`two fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day
`resulted in exposures (AUC) approximately 4 times those in humans at the 500 mg/day dose of bosutinib.
`7
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`Reference ID: 3184097
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`8.3 Nursing Mothers
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`It is not known whether bosutinib is excreted in human milk. Bosutinib and/or its metabolites were excreted in the milk of lactating
`rats. Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of
`radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in
`musing infants from BOSULIF. a decision should be made whether to discontinue nursing or to discontinue the drug. taking into
`account the importance of the drug to the mother.
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`8.4 Pediatric Use
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`The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established.
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`8.5 Geriatric Use
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`In the Phase 1/2 clinical trial of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. No overall
`differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical
`experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older
`individuals cannot be ruled out.
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`8.6 Hepatic Impairment
`
`Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment. In a dedicated hepatic impairment trial. the
`exposure to bosutinib increased (Cm-x increased 1.5- to 23—fold and the AUC increased 1.9- to 2.4—fold) in patients with hepatic
`impairment (Child-Pugh classes A, B, and C; N=18) compared to matched healthy volunteers (N=9) [see Dosage and Administration
`(2. 7), Adverse Reactions (6), and Clinical Pharmacologv (12.3)].
`
`8.7 Renal Impairment
`
`Based on population PK analysis. creatinine clearance had no meaningful influence on the exposure to BOSULIF. The population PK
`analysis included CrCL range of 25 to 120 mL/min [see Clinical Pharmacologv (12.3)].
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`10 OVERDOSAGE
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`Experience with BOSULIF overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse
`events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate
`supportive treatment.
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`11 DESCRIPTION
`
`Bosutinib is a kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-
`methoxyphenyl)amino]-6-methoxy—7-[3-(4—methyl-l-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is
`C25H29C12N503'H20 (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib
`monohydrate has the following chemical structure:
`
`Cl
`
`Cl
`
`HN
`
`OMe
`
`CN
`
`‘/\N/\/\O
`
`N/
`
`° HzO
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`Reference ID: 31 84097
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`Bosutinib monohydrate is a white to yellowish-tan powder. Bosutinib monohydrate has a pH dependent solubility across the
`physiological pH range. At or below pH 5, bosutinib monohydrate behaves as a highly soluble compound. Above pH 5, the solubility
`of bosutinib monohydrate reduces rapidly.
`
`BOSULIF® (bosutinib) tablets are supplied for oral administration in two strengths: a 100 mg yellow, oval, biconvex, film-coated
`tablet debossed with “Pfizer” on one side and “100” on the other; and a 500 mg red, oval, biconvex, film-coated tablet debossed with
`“Pfizer” on one side and “500” on the other.
`
`Each 100 mg BOSULIF tablet contains 103.40 mg of bosutinib monohydrate, equivalent to 100 mg of bosutinib; each 500 mg
`BOSULIF tablet contains 516.98 mg of bosutinib monohydrate, equivalent to 500 mg of bosutinib. The following inactive ingredients
`are included in the tablets: microcrystalline cellulose, croscarmellose sodium, poloxamer, povidone, magnesium stearate, polyvinyl
`alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide yellow (for 100 mg tablet) and iron oxide red (for 500 mg tablet).
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Bosutinib is a tyrosine kinase inhibitor. Bosutinib inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family
`kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid
`cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. In mice, treatment with bosutinib reduced the size of CML
`tumors relative to controls and inhibited growth of murine myeloid tumors expressing several imatinib-resistant forms of Bcr-Abl.
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`12.3 Pharmacokinetics
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`Absorption
`Following administration of a single dose of BOSULIF (500 mg) with food in patients with cancer, the median time-to-peak
`concentration (tmax) was 4-6 hours. Bosutinib exhibits dose proportional increases in AUC and Cmax, over the dose range of 200 to 800
`mg. After 15 daily doses of BOSULIF (500 mg) with food in patients with CML, the mean (SD) Cmax value was 200 (12) ng/mL, and
`the mean (SD) AUC was 3650 (425) ng•h/mL. When given with a high fat meal, the Cmax and AUC of bosutinib increased 1.8- and
`1.7-fold, respectively.
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`Distribution
`After administration of a single dose of BOSULIF (500mg) with food in patients with CML, bosutinib had a mean apparent volume of
`distribution ± standard deviation of 6080 ± 1230 L.
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`Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not
`concentration-dependent. Bosutinib is a P-gp substrate and inhibitor in vitro. No studies have been conducted with other transporters.
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`Metabolism
`Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2)
`bosutinib (19% of parent exposure) and N-desmethylated