PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The effect of single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was evaluated in randomized, placebo- and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 60 healthy subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing administration of 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) ngh/mL. When given with high fat meal, the Cmax and AUC of bosutinib increased 1.8- and 1.7-fold, respectively.. DistributionAfter administration of single dose of BOSULIF 500 mg with food in patients with CML, bosutinib had mean apparent volume of distribution +- standard deviation of 6080 +- 1230 L.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 P-gp substrate and inhibitor in vitro. No studies have been conducted with other transporters. MetabolismBosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as minor circulating metabolite. All the metabolites were deemed inactive. EliminationIn patients with CML given single oral doses of BOSULIF 500 mg with food, the mean terminal phase elimination half-life (t1/2) was 22.5 (1.7) hours, and the mean (SD) clearance (Cl/F) was 189 (48) L/h. In six healthy male subjects given single oral dose of [14C] radiolabeled bosutinib, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine. Hepatic ImpairmentIn dedicated hepatic impairment trial, single dose of BOSULIF 200 mg was administered with food to 18 volunteers with hepatic impairment (Child-Pugh classes A, B, and C) and matched healthy volunteers. Cmax of bosutinib increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and bosutinib AUC increased 2.3-fold, 2-fold, and 1.9-fold, respectively [see Dosage and Administration (2.7), and Use in Specific Populations (8.6)]. Renal ImpairmentIn dedicated renal impairment trial, single dose of BOSULIF 200 mg was administered with food to 26 subjects with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50 mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to subjects with normal renal function. Creatinine Clearance for category classification was calculated by the Cockcroft-Gault formula. Subjects with moderate and severe renal impairment had 35% and 60% increase in AUC compared to subjects with normal renal function, respectively. Bosutinib exposure was not changed in subjects with mild renal impairment. The BOSULIF dose should be reduced in patients with severe (CLcr less than 30 mL/min) or moderate (CLcr between 30 to 50 mL/min) renal impairment [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. Drug Interactions. CYP3A InhibitorsIn cross-over trial of 24 healthy volunteers, single dose of 100 mg of BOSULIF was either administered alone or in combination with five daily doses of 400 mg of ketoconazole under fasting conditions. Ketoconazole increased bosutinib Cmax and AUC 5.2-fold and 8.6-fold, respectively [see Dosage and Administration (2.5) and Drug Interactions (7.1)]. CYP3A InducersIn cross-over trial of 24 healthy volunteers, single dose of 500 mg of BOSULIF was either administered alone or in combination with six daily doses of 600 mg of rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by 86% and 94%, respectively [see Dosage and Administration (2.5) and Drug Interactions (7.2)]. P-gp SubstratesAn in vitro study suggests that BOSULIF has the potential to increase the plasma concentrations of drugs that are P-gp substrates. The estimated I/IC50 was 0.19, when considering the Cmax at the 500 mg dose of BOSULIF. pH Altering MedicationsBOSULIF displays pH-dependent aqueous solubility, in vitro. In cross-over trial in 24 healthy volunteers, single oral dose of 400 mg of BOSULIF was either administered alone or in combination with multiple-oral doses of 60 mg of lansoprazole under fasting conditions. Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively.

ADVERSE REACTIONS SECTION.

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)].Renal toxicity [see Warnings and Precautions (5.5)].. 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)].. Renal toxicity [see Warnings and Precautions (5.5)].. 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. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Serious adverse reactions reported include anaphylactic shock [see Contraindications (4)], myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.Adverse reactions 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%) [see Clinical Studies (14)].. Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CMLThe single-arm Phase 1/2 clinical trial (Study 1) enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and with resistance or intolerance to prior therapy [see Clinical Studies (14)]. The safety population (received at least dose of BOSULIF) included 546 CML patients:287 patients with CP CML previously treated with imatinib only who had median duration of BOSULIF treatment of 24 months, and median dose intensity of 484 mg/day. 119 patients with CP CML previously treated with both imatinib and at least additional TKI who had median duration of BOSULIF treatment of months and median dose intensity of 475 mg/day. 140 patients with advanced phase CML including 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 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively. Table identifies adverse reactions greater than or equal to 10% for all grades and grades or for the Phase 1/2 CML safety population. Table 3: Adverse Reactions (10% or Greater) in Patients with CML in Study 1Chronic Phase CMLN=406Advanced Phase CMLN=140All Grades (%)Grade 3/4(%)All Grades (%)Grade 3/4 (%)Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CMLDiarrhea849765Nausea461472Abdominal PainAbdominal pain includes the following terms: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, gastrointestinal pain, abdominal discomfort 401295Thrombocytopenia40264237Vomiting373424RashRash includes the following terms: rash, macular rash, pruritic rash, generalized rash, popular rash, maculo-papular rash 348354FatigueFatigue includes the following terms: fatigue, malaise 261204Anemia2393726Pyrexia22<1363Increased alanine aminotransferase 207105Headache201184Cough200210Increased aspartate aminotransferase 164113Neutropenia16111918EdemaEdema includes the following terms: edema, peripheral edema, localized edema, face edema 14<1141Arthralgia14<1130Decreased appetite131140Respiratory tract infectionRespiratory tract infection includes the following terms: respiratory tract infection, upper respiratory tract infection, lower respiratory tract infection, viral upper respiratory tract infection, viral respiratory tract infection 12<1100Nasopharyngitis12050Back pain12171Asthenia111101Pruritus11180Dizziness100131Dyspnea101196In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population. Table 4: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in Patients with CML in Study 1, Safety PopulationChronic Phase CMLAdvanced Phase CMLAll CP and AdvP CMLN=406N=140N=546n (%)n (%)n (%)Hematology Parameters Platelet Count (Low) less than 50x109/L102 (25)80 (57)182 (33) Absolute Neutrophil Count less than 1x109/L74 (18)52 (37)126 (23) Hemoglobin (Low) less than 80 g/L53 (13)49 (35)102 (19)Biochemistry Parameters SGPT/ALT greater than 5.0xULN39 (10)8 (6)47 (9) SGOT/AST greater than 5.0xULN17 (4)4 (3)21 (4) Lipase greater than 2xULN33 (8)4 (3)37 (7) Phosphorus (Low) less than 0.6 mmol/L30 (7)10 (7)40 (7) Total Bilirubin greater than 3.0xULN3 (1)2 (1)5 (1). 287 patients with CP CML previously treated with imatinib only who had median duration of BOSULIF treatment of 24 months, and median dose intensity of 484 mg/day. 119 patients with CP CML previously treated with both imatinib and at least additional TKI who had median duration of BOSULIF treatment of months and median dose intensity of 475 mg/day. 140 patients with advanced phase CML including 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 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively. Additional Adverse Reactions from Multiple Clinical TrialsThe 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 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 neutropeniaCardiac Disorders: 1% and less than 10% pericardial effusion; 0.1% and less than 1% pericarditisEar and Labyrinth Disorders: 1% and less than 10% tinnitusGastrointestinal Disorders: 1% and less than 10% gastritis; 0.1% and less than 1% acute pancreatitis, gastrointestinal hemorrhage (includes gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage) General Disorders and Administrative Site Conditions: 1% and less than 10% chest pain (includes chest pain and chest discomfort), painHepatobiliary Disorders: 1% and less than 10% hepatotoxicity (includes hepatotoxicity, toxic hepatitis, and cytolytic hepatitis), abnormal hepatic function (includes abnormal hepatic function, liver disorder); 0.1% and less than 1% liver injuryImmune System Disorders: 1% and less than 10% drug hypersensitivity; 0.1% and less than 1% anaphylactic shockInfections and Infestations: 1% and less than 10% pneumonia (includes pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia), influenza, bronchitis Investigations: 1% and less than 10% electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinineMetabolism and Nutrition Disorder: 1% and less than 10% hyperkalemia, dehydrationMusculoskeletal and Connective Tissue Disorder: 1% and less than 10% myalgiaNervous System Disorders: 1% and less than 10% dysgeusiaRenal and Urinary Disorders: 1% and less than 10% acute renal failure, renal failureRespiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% pleural effusion; 0.1% and less than 1% acute pulmonary edema, respiratory failure, pulmonary hypertensionSkin and Subcutaneous Disorders: 1% and less than 10% urticaria, pruritus, acne; 0.1% and less than 1% erythema multiforme, exfoliative rash, drug eruption.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 2-year carcinogenicity study was conducted orally in rats at bosutinib doses up to 25 mg/kg/day in males and 15 mg/kg/day in females. The exposures achieved at the high dose were approximately 1.5- to 3-fold the human exposure (based on AUC) at the bosutinib dose of 500 mg/day. The study was negative for carcinogenic findings. Bosutinib was not mutagenic or clastogenic in battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice.In rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately equal to that in humans at the 500 mg/day dose of bosutinib. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (40% of the human exposure), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (1.4 times the human exposure).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Bosutinib is 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. 12.2 Pharmacodynamics. The effect of single dose of bosutinib 500 mg alone and with ketoconazole on the QTc interval was evaluated in randomized, placebo- and active-controlled (moxifloxacin 400 mg) two or three-period crossover thorough QT study in 60 healthy subjects. No significant changes in placebo adjusted, baseline-corrected QTc were observed. 12.3 Pharmacokinetics. AbsorptionFollowing administration of 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) ngh/mL. When given with high fat meal, the Cmax and AUC of bosutinib increased 1.8- and 1.7-fold, respectively.. DistributionAfter administration of single dose of BOSULIF 500 mg with food in patients with CML, bosutinib had mean apparent volume of distribution +- standard deviation of 6080 +- 1230 L.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 P-gp substrate and inhibitor in vitro. No studies have been conducted with other transporters. MetabolismBosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as minor circulating metabolite. All the metabolites were deemed inactive. EliminationIn patients with CML given single oral doses of BOSULIF 500 mg with food, the mean terminal phase elimination half-life (t1/2) was 22.5 (1.7) hours, and the mean (SD) clearance (Cl/F) was 189 (48) L/h. In six healthy male subjects given single oral dose of [14C] radiolabeled bosutinib, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine. Hepatic ImpairmentIn dedicated hepatic impairment trial, single dose of BOSULIF 200 mg was administered with food to 18 volunteers with hepatic impairment (Child-Pugh classes A, B, and C) and matched healthy volunteers. Cmax of bosutinib increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C, and bosutinib AUC increased 2.3-fold, 2-fold, and 1.9-fold, respectively [see Dosage and Administration (2.7), and Use in Specific Populations (8.6)]. Renal ImpairmentIn dedicated renal impairment trial, single dose of BOSULIF 200 mg was administered with food to 26 subjects with mild (CLcr: 51 to 80 mL/min), moderate (CLcr: 30 to 50 mL/min) or severe renal impairment (CLcr less than 30 mL/min) and to subjects with normal renal function. Creatinine Clearance for category classification was calculated by the Cockcroft-Gault formula. Subjects with moderate and severe renal impairment had 35% and 60% increase in AUC compared to subjects with normal renal function, respectively. Bosutinib exposure was not changed in subjects with mild renal impairment. The BOSULIF dose should be reduced in patients with severe (CLcr less than 30 mL/min) or moderate (CLcr between 30 to 50 mL/min) renal impairment [see Dosage and Administration (2.1) and Use in Specific Populations (8.7)]. Drug Interactions. CYP3A InhibitorsIn cross-over trial of 24 healthy volunteers, single dose of 100 mg of BOSULIF was either administered alone or in combination with five daily doses of 400 mg of ketoconazole under fasting conditions. Ketoconazole increased bosutinib Cmax and AUC 5.2-fold and 8.6-fold, respectively [see Dosage and Administration (2.5) and Drug Interactions (7.1)]. CYP3A InducersIn cross-over trial of 24 healthy volunteers, single dose of 500 mg of BOSULIF was either administered alone or in combination with six daily doses of 600 mg of rifampin under fed conditions. Rifampin decreased bosutinib Cmax and AUC by 86% and 94%, respectively [see Dosage and Administration (2.5) and Drug Interactions (7.2)]. P-gp SubstratesAn in vitro study suggests that BOSULIF has the potential to increase the plasma concentrations of drugs that are P-gp substrates. The estimated I/IC50 was 0.19, when considering the Cmax at the 500 mg dose of BOSULIF. pH Altering MedicationsBOSULIF displays pH-dependent aqueous solubility, in vitro. In cross-over trial in 24 healthy volunteers, single oral dose of 400 mg of BOSULIF was either administered alone or in combination with multiple-oral doses of 60 mg of lansoprazole under fasting conditions. Lansoprazole decreased bosutinib Cmax and AUC by 46% and 26%, respectively.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP) and Blast Phase (BP) CMLA single-arm, Phase 1/2 open-label, multicenter trial (Study 1) 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 chronic, accelerated, and blast phase disease previously treated with one prior TKI (imatinib) or more than one TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within four weeks; (2) failure to achieve complete hematologic response (CHR) by months, cytogenetic response by months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after previous cytogenetic or hematologic response; or (4) presence of 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 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 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 one prior TKI (imatinib) were the rate of attaining MCyR at week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least 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 complete hematologic response (CHR) and overall hematologic response (OHR).The trial 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, 503 were considered evaluable for efficacy. Patients were evaluable for efficacy if they had received at least one dose of BOSULIF and had valid baseline efficacy assessment. Among evaluable patients, there were 266 patients with CP CML previously treated with one prior TKI (imatinib), 108 patients with CP CML previously treated with both imatinib and at least additional TKI, and 129 patients with advanced phase CML previously treated with at least one TKI. Median duration of BOSULIF treatment was 22 months in patients with CP CML previously treated with one TKI (imatinib), months in patients with CP CML previously treated with imatinib and at least additional TKI, 10 months in patients with AP CML previously treated with at least imatinib, and months in patients with BP CML previously treated with at least imatinib. The 24 week efficacy results are present in Table 5.Table 5: Efficacy Results in Patients with Ph+ CP CML with Resistance to or Intolerance to ImatinibPrior Treatment with Imatinib Only(N=266 evaluable)n (%)at 24 WeeksPrior Treatment with Imatinib and Dasatinib or Nilotinib(N=108 evaluable)n (%)by 24 Weeks Abbreviations: CI confidence interval, MCyR major cytogenetic responseWeek 24 MCyR (95% CI) 90 (33.8)(28.2, 39.9)29 (26.9)(18.8, 36.2)The minimum follow-up was 23 months for patients with CP CML treated with one prior TKI (imatinib) and 13 months for patients with CP CML treated with imatinib and at least one additional TKI. For the 53.4% of patients with CP CML treated with one prior TKI (imatinib) who achieved MCyR at any time, the median duration of MCyR was not reached. Among these patients, 52.8% had MCyR lasting at least 18 months. For the 32.4% of patients with CP CML treated with imatinib and at least one additional TKI who achieved MCyR at any time, the median duration of MCyR was not reached. Among these patients, 51.4% had MCyR lasting at least months. Of the 374 evaluable patients with CP CML, 16 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 6. Table 6: Efficacy Results in Patients with Accelerated Phase and Blast Phase CML Previously Treated with at Least ImatinibAP CML(N=69 evaluable)n (%)BP CML(N=60 evaluable)n (%)Abbreviations: CI confidence interval, OHR overall hematologic response, CHR complete hematologic responseCHROverall hematologic response (OHR) major hematologic response (complete hematologic response no evidence of leukemia) or return to chronic phase (RCP). All responses were confirmed after 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/mm3 and less than 450,000/mm3, absolute neutrophil count (ANC) greater than or equal to 1.0x109 /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/mm3 and less than 100,000/mm3) and/or neutropenia (ANC greater than or equal to 0.5x109 /L and less than 1.0x109 /L). Return to chronic phase (RCP) =disappearance of features defining accelerated or blast phases but still in chronic phase. by Week 48 (95% CI) 21 (30.4)19.9, 42.7)9 (15)(7.1, 26.6)OHR by Week 4838 (55.1)17 (28.3) (95% CI)(42.6, 67.1)(17.5, 41.4)The CHR and OHR rates were based on minimum follow-up of 12 months for patients with AP CML and 18 months for patients with BP CML. Of the 69 evaluable patients with AP CML, patients had confirmed disease transformation to BP while on BOSULIF treatment.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Hypersensitivity to BOSULIF. In the BOSULIF clinical trials, anaphylactic shock occurred in less than 0.2% of treated patients.. Hypersensitivity to BOSULIF. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Bosutinib is kinase inhibitor. The chemical name for bosutinib monohydrate is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-, hydrate (1:1). Its chemical formula is C26H29Cl2N5O3H2O (monohydrate); its molecular weight is 548.46 (monohydrate), equivalent to 530.46 (anhydrous). Bosutinib monohydrate has the following chemical structure: Bosutinib monohydrate is white to yellowish-tan powder. Bosutinib monohydrate has pH dependent solubility across the physiological pH range. At or below pH 5, bosutinib monohydrate behaves as highly soluble compound. Above pH 5, the solubility of bosutinib monohydrate reduces rapidly.BOSULIF(R) (bosutinib) tablets are supplied for oral administration in two strengths: 100 mg yellow, oval, biconvex, film-coated tablet debossed with Pfizer on one side and 100 on the other; and 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). Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 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 or complete cytogenetic response by week 12 and do not have Grade or greater adverse reactions. (2.2)Adjust dosage for hematologic and non-hematologic toxicity. (2.3, 2.4)Adjust dosage for hepatic and renal impairment. (2.7). 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 or complete cytogenetic response by week 12 and do not have Grade or greater adverse reactions. (2.2). Adjust dosage for hematologic and non-hematologic toxicity. (2.3, 2.4). Adjust dosage for hepatic and renal impairment. (2.7). 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 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 or complete cytogenetic response (CCyR) by week 12, who did not have Grade 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 5xinstitutional upper limit of normal (ULN) occur, withhold BOSULIF until recovery to less than or equal to 2.5xULN and resume at 400 mg once daily thereafter. If recovery takes longer than weeks, discontinue BOSULIF. If transaminase elevations greater than or equal to 3xULN occur concurrently with bilirubin elevations greater than 2xULN and alkaline phosphatase less than 2xULN (Hys 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 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 ThrombocytopeniaANCAbsolute Neutrophil Count less than 1000x106/LWithhold BOSULIF until ANC greater than or equal to1000x106/L and platelets greater than or equal to 50,000x106/L.orPlatelets less than 50,000x106/LResume treatment with BOSULIF at the same dose if recovery occurs within weeks. If blood counts remain low for greater than 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.. 2.5 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 large reduction in exposure is expected (strong CYP3A inducers include rifampin, phenytoin, carbamazepine, St. Johns Wort, rifabutin and phenobarbital. Moderate CYP3A inducers include bosentan, nafcillin, efavirenz, modafinil and etravirine) [see Drug Interactions (7.2)]. 2.7 Recommended Starting Dosage with Hepatic Impairment or Renal Impairment. Organ Function StatusRecommended Starting DosageNormal hepatic and renal function500 mg once dailyHepatic impairment Mild (Child-Pugh A), Moderate (Child-Pugh B) or severe (Child-Pugh C)200 mg dailyRenal impairment Creatinine clearance 30 to 50 mL/min400 mg daily Creatinine clearance less than 30 mL/min300 mg daily[see Use in Specific Populations (8.6,8.7) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

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. Tablets: 100 mg and 500 mg. (3).

DRUG INTERACTIONS SECTION.

7 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). 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). 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 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 large reduction in exposure is expected [see Dosage and Administration (2.6)]. In 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 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 reduction in bosutinib exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than hours.. 7.3 Drugs That May Have Their Plasma Concentrations Altered By Bosutinib. 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)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. BOSULIF (bosutinib) tablets are supplied for oral administration in two strengths: 100 mg yellow, oval, biconvex, film-coated tablet debossed with Pfizer on one side and 100 on the other; and 500 mg red, oval, biconvex, film-coated tablet debossed with Pfizer on one side and 500 on the other. BOSULIF (bosutinib) tablets are available in the following packaging configurations (Table 7): Table 7: Tablet PresentationsBOSULIF TabletsPackage ConfigurationTablet Strength (mg)NDCTablet Description120 tablets per bottle100 mg0069-0135-01Yellow, oval, biconvex, film-coated tablets, debossed Pfizer on one side and 100 on the other.30 tablets per bottle500 mg0069-0136-01 Red, oval, biconvex, film-coated tablets, debossed Pfizer on one side and 500 on the other.. 16.2 Storage. Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].. 16.3 Handling and Disposal. Procedures for proper disposal of anticancer drugs should be considered. Any unused product or waste material should be disposed of in accordance with local requirements, or drug take back programs.

INDICATIONS & USAGE SECTION.

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.. BOSULIF is 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information).. Dosing and Administration Instruct patients to take BOSULIF exactly as prescribed, not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor. If patients miss dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. double dose should not be taken to make up for any missed dose. Advise patients to take BOSULIF with food. Patients should be advised: Do not crush or cut tablet. Do not touch or handle crushed or broken tablets.. Gastrointestinal Problems Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with BOSULIF and to seek medical attention promptly for these symptoms.. Low Blood Cell Counts Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising.. Liver Problems Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice. o Fluid Retention Advise patients of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention promptly if these symptoms arise.. Renal Problems Advise patients of the possibility of developing renal problems and to immediately report frequent urination, polyuria or oliguria o Other Adverse Reactions Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, or pruritus with BOSULIF and to seek medical attention if symptoms are significant. There is possibility of anaphylactic shock.. Pregnancy and Breast-feeding Advise patients that BOSULIF can cause fetal harm when administered to pregnant woman. Advise women of the potential hazard to the fetus and to avoid becoming pregnant. 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. Because potential risk to the nursing infant cannot be excluded, women that are taking BOSULIF should not breast-feed or provide breast milk to infants.Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after completing treatment with BOSULIF. Instruct patients to contact their physicians immediately if they become pregnant during treatment. Advise patients not to take BOSULIF treatment while pregnant or breastfeeding. If patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician.. Drug Interactions Advise patients that BOSULIF and certain other medicines, including over the counter medications or herbal supplements (such as St. Johns wort) can interact with each other and may alter the effects of BOSULIF [see Dosage and Administration (2.5) and Drug Interactions (7)]. LAB-0443-4.0. Logo.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Bosutinib is 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 2-year carcinogenicity study was conducted orally in rats at bosutinib doses up to 25 mg/kg/day in males and 15 mg/kg/day in females. The exposures achieved at the high dose were approximately 1.5- to 3-fold the human exposure (based on AUC) at the bosutinib dose of 500 mg/day. The study was negative for carcinogenic findings. Bosutinib was not mutagenic or clastogenic in battery of tests, including the bacteria reverse mutation assay (Ames Test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated male mice.In rat fertility study, drug-treated males were mated with untreated females, or untreated males were mated with drug-treated females. Females were administered the drug from pre-mating through early embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in reduced fertility in males as demonstrated by 16% reduction in the number of pregnancies. There were no lesions in the male reproductive organs at this dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats approximately equal to that in humans at the 500 mg/day dose of bosutinib. Fertility (number of pregnancies) was not affected when female rats were treated with bosutinib. However, there were increased embryonic resorptions at greater than or equal to 10 mg/kg/day of bosutinib (40% of the human exposure), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (1.4 times the human exposure).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. 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 single oral dose of radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BOSULIF, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

10 OVERDOSAGE. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg Tablet Bottle Label. PROFESSIONAL SAMPLE NOT FOR SALEPfizerNDC 63539-117-01Bosulif(R) (bosutinib) tablets100 mgDo not crush or cut tabletFor Oncology Use Only120 TabletsRx only. PRINCIPAL DISPLAY PANEL 100 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category [see Warnings and Precautions (5.6)]Based on its mechanism of action and findings in animals, BOSULIF can cause fetal harm when administered to 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 placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. In 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 times those in humans at the 500 mg/day dose of bosutinib.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Recommended Starting Dosage with Hepatic Impairment or Renal Impairment (2.7)11/2014Warnings and Precautions, Renal Toxicity (5.5)11/2014.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. BOSULIF(R) (BAH-su-lif)(bosutinib)tabletsWhat is BOSULIFBOSULIF is prescription medicine used to treat adults who have certain type of leukemia called Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) who no longer benefit from or did not tolerate other treatment.It is not known if BOSULIF is safe and effective in children less than 18 years of age.Who should not take BOSULIFDo not take BOSULIF if you are allergic to bosutinib or any of the ingredients in BOSULIF. See the end of this leaflet for complete list of ingredients of BOSULIF.What should tell my doctor before taking BOSULIFBefore you take BOSULIF, tell your doctor if you:have liver problemshave heart problemshave kidney problemshave any other medical conditionsare pregnant or plan to become pregnant. BOSULIF can harm your unborn baby. You should not become pregnant while taking BOSULIF. Tell your doctor right away if you become pregnant while taking BOSULIF.are woman who may become pregnant. Use effective contraception (birth control) during and for at least 30 days after completing treatment with BOSULIF. Talk to your doctor about forms of birth control.are breastfeeding or plan to breastfeed. It is not known if BOSULIF passes into your breast milk or if it can harm your baby. You and your doctor should decide if you will take BOSULIF or breastfeed. You should not do both.Tell your doctor about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. BOSULIF and certain other medicines can affect each other.Especially tell your doctor if you take:medicines that increase the amount of BOSULIF in your blood stream, such as:amprenavir (Agenerase(R))aprepitant (Emend(R))atazanavir (Reyataz(R))boceprevir (Victrelis(R))ciprofloxacin (Cipro(R), Proquin XR(R))clarithromycin (Biaxin(R), Prevpac(R))conivaptan (Vaprisol(R))crizotinib (Xalkori(R))darunavir (Prezista(R))digoxin (Lanoxin(R))diltiazem (Cardizem(R), Dilacor XR(R), Tiazac(R))erythromycin (Ery-tab(R))fluconazole (Diflucan(R))fosamprenavir (Lexiva(R)) imatinib (Gleevec(R))indinavir (Crixivan(R))itraconazole (Onmel(R), Sporanox(R))ketoconazole (Nizoral(R))nefazodone (Serzone(R))nelfinavir (Viracept(R))posaconazole (Noxafil(R))ritonavir (Kaletra(R), Norvir(R))saquinavir (Invirase(R), Fortovase(R))telaprevir (Incivek(R))telithromycin (Ketek(R)) verapamil (Calan(R), Covera-HS(R), Tarka(R), Verelan PM(R))voriconazole (Vfend(R))medicines that decrease the amount of BOSULIF in your blood stream, such as:bosentan (Tracleer(R))carbamazepine (Carbatrol(R), Equetro(R), Tegretol(R))efavirenz (Sustiva(R))etravirine (Intelence(R))modafinil (Provigil(R))nafcillin (Unipen(R), Nallpen(R))phenobarbital (Solfoton(R))phenytoin (Dilantin(R))rifabutin (Mycobutin(R))rifampin (Rifamate(R), Rifater(R), Rifadin(R))St. Johns wortBOSULIF is best absorbed from your stomach into your blood stream in the presence of stomach acid. You should avoid taking BOSULIF with medicines that reduce stomach acid, such as:esomeprazole (Nexium(R)), esomeprazole strontiumdexlansoprazole (Dexilant(R))lansoprazole (Prevacid(R))omeprazole (Prilosec(R), Vimovo(R), Zegerid(R))pantoprazole sodium (Protonix(R))rabeprazole (AcipHex(R))Medicines that neutralize stomach acid, such as: cimetidine (Tagamet(R)), famotidine (Pepcid(R)), ranitidine (Zantac(R)), aluminum hydroxide/magnesium hydroxide (Maalox(R)), calcium carbonate (Tums(R)), or calcium carbonate and magnesia (Rolaids(R)) may be taken up to hours before or hours after BOSULIF.Know the medicines you take. Keep list of your medicines and show it to your doctor and pharmacist when you get new medicine.How should take BOSULIFTake BOSULIF exactly as prescribed by your doctor.Do not change your dose or stop taking BOSULIF without first talking with your doctor.Take BOSULIF with food.Swallow BOSULIF tablets whole. Do not crush or cut BOSULIF tablets. Do not touch or handle crushed or broken BOSULIF tablets.You should avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract during treatment with BOSULIF. Grapefruit products increase the amount of BOSULIF in your body.Your doctor may change your dose of BOSULIF or tell you to stop taking BOSULIF depending on how you respond to treatment.If you miss dose of BOSULIF, take it as soon as you remember. If you miss dose by more than 12 hours, skip that dose and take your next dose at your regular time. Do not take two doses at the same time.If you take too much BOSULIF, call your doctor or go to the nearest hospital emergency room right away.What are the possible side effects of BOSULIFBOSULIF may cause serious side effects, including:Stomach problems. BOSULIF may cause stomach (abdomen) pain, nausea, diarrhea, or vomiting. Tell your doctor about any stomach problems.Low blood cell counts. BOSULIF may cause low platelet counts (thrombocytopenia), low red blood cell counts (anemia) and low white blood cell counts (neutropenia). Your doctor should do blood tests to check your blood cell counts regularly during your treatment with BOSULIF. Call your doctor right away if you have unexpected bleeding or bruising, blood in your urine or stools, fever, or any signs of an infection.Liver problems. BOSULIF may cause liver problems. Your doctor should do blood tests to check your liver function regularly during your treatment with BOSULIF. Call your doctor right away if your skin or the white part of your eyes turns yellow (jaundice) or you have dark tea color urine.Your body may hold too much fluid (fluid retention). Fluid may build up in the lining of your lungs, the sac around your heart, or your stomach cavity. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF:shortness of breath and coughchest painswelling in your hands, ankles, or feetswelling all over your bodyweight gainKidney problems. BOSULIF may cause kidney problems. Your doctor should do tests to check your kidney function when you start treatment with BOSULIF and during your treatment. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF: you urinate more often than normalyou urinate less often than normalyou make much larger amount of urine than normalyou make much smaller amount of urine than normal Other common side effects of BOSULIF include:rashfevertiredness or weaknessTell your doctor right away if you get respiratory tract infections, loss of appetite, headache, dizziness, back pain, joint pain, or itching while taking BOSULIF. These may be symptoms of severe allergic reaction. Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all of the possible side effects of BOSULIF. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How do store BOSULIFStore BOSULIF between 68F to 77F (20C to 25C).Ask your doctor or pharmacist about the right way to throw away outdated or unused BOSULIF.Keep BOSULIF and all medicines out of the reach of children. General information about BOSULIF.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use BOSULIF for condition for which it is not prescribed. Do not give BOSULIF to other people even if they have the same symptoms you have. It may harm them.This Patient Information leaflet summarizes the most important information about BOSULIF. If you would like more information, talk with your doctor. You may ask your doctor or pharmacist for information about BOSULIF that is written for healthcare professionals.For more information, go to www.Bosulif.com or www.pfizermedicalinformation.com or call 1-800-438-1985. What are the ingredients in BOSULIFActive ingredient: bosutinib.Inactive ingredients: 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).This Patient Information has been approved by the U.S. Food and Drug Administration.LAB-0639-4.0November 2014. have liver problems. have heart problems. have kidney problems. have any other medical conditions. are pregnant or plan to become pregnant. BOSULIF can harm your unborn baby. You should not become pregnant while taking BOSULIF. Tell your doctor right away if you become pregnant while taking BOSULIF.. are woman who may become pregnant. Use effective contraception (birth control) during and for at least 30 days after completing treatment with BOSULIF. Talk to your doctor about forms of birth control.. are breastfeeding or plan to breastfeed. It is not known if BOSULIF passes into your breast milk or if it can harm your baby. You and your doctor should decide if you will take BOSULIF or breastfeed. You should not do both.. medicines that increase the amount of BOSULIF in your blood stream, such as:amprenavir (Agenerase(R))aprepitant (Emend(R))atazanavir (Reyataz(R))boceprevir (Victrelis(R))ciprofloxacin (Cipro(R), Proquin XR(R))clarithromycin (Biaxin(R), Prevpac(R))conivaptan (Vaprisol(R))crizotinib (Xalkori(R))darunavir (Prezista(R))digoxin (Lanoxin(R))diltiazem (Cardizem(R), Dilacor XR(R), Tiazac(R))erythromycin (Ery-tab(R))fluconazole (Diflucan(R))fosamprenavir (Lexiva(R)) imatinib (Gleevec(R))indinavir (Crixivan(R))itraconazole (Onmel(R), Sporanox(R))ketoconazole (Nizoral(R))nefazodone (Serzone(R))nelfinavir (Viracept(R))posaconazole (Noxafil(R))ritonavir (Kaletra(R), Norvir(R))saquinavir (Invirase(R), Fortovase(R))telaprevir (Incivek(R))telithromycin (Ketek(R)) verapamil (Calan(R), Covera-HS(R), Tarka(R), Verelan PM(R))voriconazole (Vfend(R)). amprenavir (Agenerase(R)). aprepitant (Emend(R)). atazanavir (Reyataz(R)). boceprevir (Victrelis(R)). ciprofloxacin (Cipro(R), Proquin XR(R)). clarithromycin (Biaxin(R), Prevpac(R)). conivaptan (Vaprisol(R)). crizotinib (Xalkori(R)). darunavir (Prezista(R)). digoxin (Lanoxin(R)). diltiazem (Cardizem(R), Dilacor XR(R), Tiazac(R)). erythromycin (Ery-tab(R)). fluconazole (Diflucan(R)). fosamprenavir (Lexiva(R)) imatinib (Gleevec(R)). indinavir (Crixivan(R)). itraconazole (Onmel(R), Sporanox(R)). ketoconazole (Nizoral(R)). nefazodone (Serzone(R)). nelfinavir (Viracept(R)). posaconazole (Noxafil(R)). ritonavir (Kaletra(R), Norvir(R)). saquinavir (Invirase(R), Fortovase(R)). telaprevir (Incivek(R)). telithromycin (Ketek(R)) verapamil (Calan(R), Covera-HS(R), Tarka(R), Verelan PM(R)). voriconazole (Vfend(R)). medicines that decrease the amount of BOSULIF in your blood stream, such as:bosentan (Tracleer(R))carbamazepine (Carbatrol(R), Equetro(R), Tegretol(R))efavirenz (Sustiva(R))etravirine (Intelence(R))modafinil (Provigil(R))nafcillin (Unipen(R), Nallpen(R))phenobarbital (Solfoton(R))phenytoin (Dilantin(R))rifabutin (Mycobutin(R))rifampin (Rifamate(R), Rifater(R), Rifadin(R))St. Johns wort. bosentan (Tracleer(R)). carbamazepine (Carbatrol(R), Equetro(R), Tegretol(R)). efavirenz (Sustiva(R)). etravirine (Intelence(R)). modafinil (Provigil(R)). nafcillin (Unipen(R), Nallpen(R)). phenobarbital (Solfoton(R)). phenytoin (Dilantin(R)). rifabutin (Mycobutin(R)). rifampin (Rifamate(R), Rifater(R), Rifadin(R)). St. Johns wort. esomeprazole (Nexium(R)), esomeprazole strontium. dexlansoprazole (Dexilant(R)). lansoprazole (Prevacid(R)). omeprazole (Prilosec(R), Vimovo(R), Zegerid(R)). pantoprazole sodium (Protonix(R)). rabeprazole (AcipHex(R)). Take BOSULIF exactly as prescribed by your doctor.. Do not change your dose or stop taking BOSULIF without first talking with your doctor.. Take BOSULIF with food.. Swallow BOSULIF tablets whole. Do not crush or cut BOSULIF tablets. Do not touch or handle crushed or broken BOSULIF tablets.. You should avoid grapefruit, grapefruit juice, and supplements that contain grapefruit extract during treatment with BOSULIF. Grapefruit products increase the amount of BOSULIF in your body.. Your doctor may change your dose of BOSULIF or tell you to stop taking BOSULIF depending on how you respond to treatment.. If you miss dose of BOSULIF, take it as soon as you remember. If you miss dose by more than 12 hours, skip that dose and take your next dose at your regular time. Do not take two doses at the same time.. If you take too much BOSULIF, call your doctor or go to the nearest hospital emergency room right away.. Stomach problems. BOSULIF may cause stomach (abdomen) pain, nausea, diarrhea, or vomiting. Tell your doctor about any stomach problems.. Low blood cell counts. BOSULIF may cause low platelet counts (thrombocytopenia), low red blood cell counts (anemia) and low white blood cell counts (neutropenia). Your doctor should do blood tests to check your blood cell counts regularly during your treatment with BOSULIF. Call your doctor right away if you have unexpected bleeding or bruising, blood in your urine or stools, fever, or any signs of an infection.. Liver problems. BOSULIF may cause liver problems. Your doctor should do blood tests to check your liver function regularly during your treatment with BOSULIF. Call your doctor right away if your skin or the white part of your eyes turns yellow (jaundice) or you have dark tea color urine.. Your body may hold too much fluid (fluid retention). Fluid may build up in the lining of your lungs, the sac around your heart, or your stomach cavity. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF:shortness of breath and coughchest painswelling in your hands, ankles, or feetswelling all over your bodyweight gain. shortness of breath and cough. chest pain. swelling in your hands, ankles, or feet. swelling all over your body. weight gain. Kidney problems. BOSULIF may cause kidney problems. Your doctor should do tests to check your kidney function when you start treatment with BOSULIF and during your treatment. Call your doctor right away if you get any of the following symptoms during your treatment with BOSULIF: you urinate more often than normalyou urinate less often than normalyou make much larger amount of urine than normalyou make much smaller amount of urine than normal you urinate more often than normal. you urinate less often than normal. you make much larger amount of urine than normal. you make much smaller amount of urine than normal. rash. fever. tiredness or weakness. Store BOSULIF between 68F to 77F (20C to 25C).. Ask your doctor or pharmacist about the right way to throw away outdated or unused BOSULIF.

SPL UNCLASSIFIED SECTION.

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 dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day.

STORAGE AND HANDLING SECTION.

16.2 Storage. Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

TERATOGENIC EFFECTS SECTION.

Pregnancy Category [see Warnings and Precautions (5.6)]Based on its mechanism of action and findings in animals, BOSULIF can cause fetal harm when administered to 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 placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. In 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 times those in humans at the 500 mg/day dose of bosutinib.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category [see Warnings and Precautions (5.6)]Based on its mechanism of action and findings in animals, BOSULIF can cause fetal harm when administered to 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 placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. In 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 times those in humans at the 500 mg/day dose of bosutinib. 8.3 Nursing Mothers. 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 single oral dose of radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BOSULIF, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use. The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established.. 8.5 Geriatric Use. 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.. 8.6 Hepatic Impairment Treat with dose of 200 mg daily in patients with any baseline hepatic impairment. In dedicated hepatic impairment trial, the exposure to bosutinib increased (Cmax increased 1.5- to 2.3-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 Pharmacology (12.3)]. 8.7 Renal Impairment Reduce the BOSULIF starting dose in patients with severe (CLcr less than 30 mL/min) or moderate (CLcr 30 to 50 mL/min) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate 500 mg dose, follow dose adjustment recommendations for toxicity. In dedicated renal impairment trial, compared to subjects with normal renal function, the exposure (AUC) of bosutinib increased by 60% and 35% in subjects with CLcr less than 30 mL/min and CLcr 30 to 50 mL/min, respectively, compared to subjects with normal renal function [see Dosing and Administration (2.7) and Clinical Pharmacology (12.3)]. BOSULIF has not been studied in patients undergoing hemodialysis.

WARNINGS AND PRECAUTIONS SECTION.

5 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)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)Renal Toxicity Monitor patients for renal function at baseline and during therapy with BOSULIF (5.5)Embryofetal Toxicity: May cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated with BOSULIF. (5.6). 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). 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). Renal Toxicity Monitor patients for renal function at baseline and during therapy with BOSULIF (5.5). Embryofetal Toxicity: May cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated with BOSULIF. (5.6). 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 single-arm Phase 1/2 clinical trial, the median time to onset for diarrhea (all grades) was days and the median duration per event was day. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was (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. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6)].. 5.3 Hepatic Toxicity One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3xULN with total bilirubin greater than 2xULN and alkaline phosphatase less than 2xULN) occurred in trial of BOSULIF in combination with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented out of 1209 patients in BOSULIF clinical trials. In the 546 patients from the safety population, the incidence of ALT elevation was 17% and AST elevation was 14%. Twenty percent 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 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 hepatic enzyme tests monthly for the first three months of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.4 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, patients had Grade or pleural effusion, patients experienced both Grade or Grade pleural and pericardial effusions, patient experienced Grade peripheral and pulmonary edema, and patient had Grade 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 Renal Toxicity. An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table identifies the shift from baseline to lowest observed estimated glomerular filtration rate (eGFR) during BOSULIF therapy for patients in the global Ph+ Leukemia studies. The median duration of therapy with BOSULIF was approximately 17 months (range, 0.03 to 95) for patients in these studies.Table 2: Shift from Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (n=818)Among the 818 patients, eGFR was missing in patients at baseline or on-therapy. There were no patients with kidney failure at baseline. BaselineFollow UpRenal Function StatusnNormal (%)Mildn (%)Mild to Moderaten (%)Moderate to Severe (%)Severen (%)Kidney Failuren (%)Notes: Grading is based on Modification in Diet in Renal Disease method (MDRD).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. Normal27453 (19)174 (64)30 (11)14 (5)1 (<1)1 (<1)Mild 43810 (2)170 (39)177 (40)63 (14)14 (3)2 (1)Mild to Moderate 7904 (5)28 (35)37 (47)10 (13)0Moderate to Severe 2401 (4)1 (4)6 (25)15 (63)1 (4)Severe 1000001 (100)Total81663 (8)349 (43)236 (29)120 (15)40 (5)5 (1)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 (2.7)]. 5.6 Embryofetal Toxicity. There are no adequate and well controlled studies of BOSULIF in pregnant women. BOSULIF can cause fetal harm when administered to 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)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The most common adverse reactions, in >=20% of patients with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%).The most common laboratory abnormalities that worsened from baseline in >=20% of patients were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%).. Adverse Reactions in Patients With Newly-Diagnosed CP CMLThe 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 dose of BOSULIF) included:two hundred sixty-eight (268) patients with newly-diagnosed CP CML had median duration of BOSULIF treatment of 55 months (range: 0.3 to 60 months) and 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 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 identifies adverse reactions greater than or equal to 10% for All Grades and Grades or (3/4) for the Phase CP CML safety population.Table 4: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg StudyBased on Minimum of 57 Months of Follow-up. System Organ ClassPreferred TermBosutinib 400 mgChronic Phase CML(N=268)Imatinib 400 mgChronic Phase CML(N=265)All Grades%Grade 3/4%All Grades%Grade 3/4%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 columns indicate maximum toxicity.Gastrointestinal disordersDiarrhea759401Abdominal painAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain. 392271Nausea370420Vomiting211200Constipation13060Hepatobiliary disordersHepatic 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. 4527154Skin and subcutaneous tissue disordersRashRash 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. 402302Pruritus11<140General disorders and administration-site conditionsFatigueFatigue includes the following preferred terms: Asthenia, Fatigue, Malaise. 33130<1Pyrexia171110EdemaEdema 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. 150462Infections and infestationsRespiratory tract infectionRespiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection. 27125<1Nervous system disordersHeadache221151Musculoskeletal and connective tissue disordersArthralgia18118<1Back pain12<19<1Respiratory, thoracic, and mediastinal disordersCough110100Dyspnea11161Metabolism and nutrition disordersDecreased appetite11<160Vascular disordersHypertensionHypertension includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive. 105115In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with BOSULIF experienced Grade QTcF prolongation (>500 msec). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.Table identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase newly-diagnosed CML safety population.Table 5: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with Newly-Diagnosed CML in Bosutinib 400 mg StudyBased on Minimum of 57 Months of Follow-up. BosutinibN=268%ImatinibN=265%All GradeGrade 3-4All GradeGrade 3-4Abbreviations: 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 4.03Hematology ParametersPlatelet Count decreased6814606Absolute Neutrophil Count decreased4296520Hemoglobin decreased899907White Blood Cell Count decreased506708Lymphocyte Count decreased84128214Biochemistry ParametersSGPT/ALT increased6826283SGOT/AST increased5613293.4Lipase increased5319358Phosphorus decreased5496921Amylase increased323.4182.3Alkaline Phosphatase increased410430.4Calcium decreased551.5571.1Glucose increased573653.4Creatine Kinase increased363655Creatinine increased941.1980.8. two hundred sixty-eight (268) patients with newly-diagnosed CP CML had median duration of BOSULIF treatment of 55 months (range: 0.3 to 60 months) and median dose intensity of 394 mg/day.. Adverse Reactions in Patients With Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CMLThe 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 dose of BOSULIF) included 546 CML patients:two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had median duration of BOSULIF treatment of 26 months (range: 0.2 to 155 months), and median dose intensity of 437 mg/day.one hundred nineteen (119) patients with CP CML previously treated with both imatinib and at least additional tyrosine kinase inhibitor (TKI) who had median duration of BOSULIF treatment of months (range: 0.2 to 148 months) and 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 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 for Grade 3/4 laboratory abnormalities.Table identifies adverse reactions greater than or equal to 10% for All Grades and Grades or for the Phase 1/2 CML safety population based on long-term follow-up.Table 6: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm TrialBased on Minimum of 105 Months of Follow-up. System Organ ClassPreferred TermCP CML(N=403)AdvP CML(N=143)All Grades%Grade 3/4%All Grades%Grade 3/4%ADR DefinitionAdverse 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 columns indicate maximum toxicity.Gastrointestinal disordersDiarrhea8510764Abdominal 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. 492367Nausea471482Vomiting383433Constipation15<1171Skin and subcutaneous tissue disordersRashRash 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. 489425Pruritus12170General disorders and administration-site conditionsFatigue353276Pyrexia251373EdemaEdema 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<1171Chest painChest pain includes the following preferred terms: Chest discomfort, Chest pain. 81121Hepatobiliary disordersHepatic 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. 29112110Infections and infestationsRespiratory 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<1170InfluenzaInfluenza includes the following preferred terms: H1N1 influenza, Influenza. 11130PneumoniaPneumonia 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. 1041812Respiratory, thoracic, and mediastinal disordersCough240220Pleural effusion14494Dyspnea122206Nervous system disordersHeadache211184Dizziness110141Musculoskeletal and connective tissue disorders Arthralgia191150Back pain14181Metabolism and nutrition disordersDecreased appetite141140Vascular disordersHypertensionHypertension includes the following preferred terms: Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis, Retinopathy hypertensive. ADR identified post-marketing. 11383In the single-arm study in patients with CML who were resistant or intolerant to prior therapy, 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 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 7: 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 Minimum of 105 Months of Follow-up. CP CMLN=403%AdvP CMLN=143%All gradeGrade 3/4All gradeGrade 3/4Abbreviations: 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 decreased66268057 Absolute Neutrophil Count decreased50166639 Hemoglobin decreased89139738 Lymphocyte decreased79148221 White Blood Cell Count decreased5175727Biochemistry Parameters SGPT/ALT increased5811396 SGOT/AST increased505373.5 Lipase increased3212196 Phosphorus decreased418337 Total Bilirubin increased160.7222.8 Creatinine increased953871.4 Alkaline Phosphatase increased390391.4 Glucose increased422.7396 Sodium increased230.5110 Sodium decreased182.2276 Calcium decreased554.7453.5 Urate increased496436 Magnesium increased277184.9 Potassium decreased221.7294.9 Potassium increased252.7192.1. two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had median duration of BOSULIF treatment of 26 months (range: 0.2 to 155 months), and median dose intensity of 437 mg/day.. one hundred nineteen (119) patients with CP CML previously treated with both imatinib and at least additional tyrosine kinase inhibitor (TKI) who had median duration of BOSULIF treatment of months (range: 0.2 to 148 months) and 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 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.. Additional Adverse Reactions From Multiple Clinical TrialsThe 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 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 neutropeniaCardiac Disorders: 1% and less than 10% Pericardial effusion; 0.1% and less than 1% PericarditisEar and Labyrinth Disorders: 1% and less than 10% TinnitusEndocrine Disorders: 1% and less than 10% Hypothyroidism; 0.1% and less than 1% HyperthyroidismGastrointestinal 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% PainImmune System Disorders: 1% and less than 10% Drug hypersensitivity; 0.1% and less than 1% Anaphylactic shockInfections and Infestations: 1% and less than 10% BronchitisInvestigations: 1% and less than 10% Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome)Metabolism and Nutrition Disorders: 1% and less than 10% DehydrationMusculoskeletal and Connective Tissue Disorders: 1% and less than 10% MyalgiaNervous System Disorders: 1% and less than 10% DysgeusiaRenal and Urinary Disorders: 1% and less than 10% Acute kidney injury, Renal impairment, Renal failureRespiratory, 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), Respiratory failureSkin and Subcutaneous Disorders: 0.1% and less than 1% Erythema multiforme.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. PregnancyBased on findings from animal studies, BOSULIF can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Females of reproductive potential should have pregnancy test prior to starting treatment with BOSULIF.. Contraception. FemalesBased on findings from animal studies, BOSULIF can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BOSULIF and for at least weeks after the last dose.. InfertilityThe risk of infertility in females or males of reproductive potential has not been studied in humans. Based on findings from animal studies, BOSULIF may cause reduced fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. Reduce the BOSULIF dosage in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryNo data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on 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 nursing child, breastfeeding is not recommended during treatment with BOSULIF and for at least weeks after the last dose.. Animal DataAfter single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following additional adverse reactions have been identified during post-approval use of BOSULIF. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System Disorders: Thrombotic microangiopathySkin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. Reduce the BOSULIF starting dose in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and severe (CLcr less than 30 mL/min, C-G) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate the starting dose, follow dose adjustment recommendations for toxicity [see Dosage and Administration (2.3, 2.5) and Clinical Pharmacology (12.3)]. BOSULIF has not been studied in patients undergoing hemodialysis.