GERIATRIC USE SECTION.

8.5 Geriatric Use. In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of bosutinib in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. Of the 268 patients who received bosutinib in the study for newly diagnosed CML, 20% were age 65 and over, 5% 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong and Moderate CYP3A Inhibitors: Avoid concomitant use with bosutinib. (7.1) Strong CYP3A Inducers: Avoid concomitant use with bosutinib. (7.1) Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. (7.1). 7.1 Effect of Other Drugs on Bosutinib Strong or Moderate CYP3A InhibitorsAvoid the concomitant use of strong or moderate CYP3A inhibitors with bosutinib. Bosutinib is CYP3A substrate. Concomitant use with strong or moderate CYP3A inhibitor increases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may increase the risk of toxicities. Strong CYP3A Inducers Avoid the concomitant use of strong CYP3A inducers with bosutinib. Bosutinib is CYP3A substrate. Concomitant use with strong CYP3A inducer decreases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce bosutinib efficacy. Proton Pump Inhibitors (PPI) As an alternative to PPIs, use short-acting antacids or H2 blockers and separate dosing by more than hours from bosutinib dosing. Bosutinib displays pH dependent aqueous solubility, Concomitant use with PPI decreases bosutinib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce bosutinib efficacy.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Gastrointestinal toxicity [see Warnings and Precautions (5.1)]. Myelosuppression [seeWarnings and Precautions (5.2)]. Hepatic toxicity [see Warnings and Precautions (5.3)]. Cardiovascular toxicity [see Warnings and Precautions (5.4)]. Fluid retention [see Warnings and Precautions (5.5)]. Renal toxicity [see Warnings and Precautions (5.6)]. Most common adverse reactions (>=20%), in adult patients with CML are diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, respiratory tract infection. The most common laboratory abnormalities (>=20%) in adult patients are creatinine increased, hemoglobin decreased, lymphocyte count decreased, platelets decreased, ALT increased, calcium decreased, white blood cell count decreased, AST increased, absolute neutrophil count decreased, glucose increased, phosphorus decreased, urate increased, alkaline phosphatase increased, lipase increased, creatine kinase increased, and amylase increased. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddys Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. Most common adverse reactions (>=20%), in adult patients with CML are diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, respiratory tract infection. The most common laboratory abnormalities (>=20%) in adult patients are creatinine increased, hemoglobin decreased, lymphocyte count decreased, platelets decreased, ALT increased, calcium decreased, white blood cell count decreased, AST increased, absolute neutrophil count decreased, glucose increased, phosphorus decreased, urate increased, alkaline phosphatase increased, lipase increased, creatine kinase increased, and amylase increased. (6.1) 6.1 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 adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in >=20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%).Adverse Reactions in Adult Patients With Newly-Diagnosed CP CML The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive bosutinib 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 bosutinib) included:two hundred sixty-eight (268) patients with newly-diagnosed CP CML had median duration of bosutinib 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 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study System Organ Class Preferred Term Bosutinib 400 mg hronic Phase CML (N= 268) Imatinib 400 mg hronic Phase CML (N= 265) All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal disorders Diarrhea 75 40 Abdominal paina 39 27 Nausea 37 42 Vomiting 21 20 Hepatobiliary disorders Constipation 13 6 Skin and subcutaneous tissue disorders Hepatic dysfunctionf 45 27 15 Rashd 40 30 Pruritus 11 <1 0 General disorders and administration-site conditions Fatigueb 33 30 <1 Pyrexia 17 11 Edemag 15 46 Infections and infestations Respiratory tract infectione 27 25 <1 Nervous system disorders Headache 22 15 Musculoskeletal and connective tissue disorders Arthralgia 18 18 <1 Back pain 12 <1 <1 Respiratory, thoracic, and mediastinal disorders Cough 11 10 Dyspnea 11 6 Metabolism and nutrition disorders Decreased appetite 11 <1 0 Vascular disorders Hypertensionc 10 11 Based on Minimum of 57 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on All Grades under Total column. Grade 3, Grade columns indicate maximum toxicity. aAbdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain. bFatigue includes the following preferred terms: Asthenia, Fatigue, Malaise. cHypertension includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive. fHepatic 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. gEdema 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. dRash 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. eRespiratory tract infection includes the following preferred terms: Nasopharyngitis, Respiratory tract congestion, Respiratory tract infection, Respiratory tract infection viral, Upper respiratory tract infection. In the randomized study in patients with newly-diagnosed CP CML, one patient in the group treated with bosutinib 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 8: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with Newly-Diagnosed CML in Bosutinib 400 mg Study Bosutinib N= 268 Imatinib N= 265 All Grade Grade to All GradeGrade to 4Hematology Parameters Platelet Count decreased 68 14 60 Absolute Neutrophil Count decreased 42 65 20 Hemoglobin decreased 89 90 White Blood Cell Count decreased 50 70 Lymphocyte Count decreased 84 12 82 14 Biochemistry ParametersSGPT/ALT increased 68 26 28 SGOT/AST increased 56 13 29 3.4 Lipase increased 53 19 35 Phosphorus decreased 54 69 21 Amylase increased 32 3.4 18 2.3 Alkaline Phosphatase increased 41 43 0.4 Calcium decreased 55 1.5 57 1.1 Glucose increased 57 65 3.4 Creatine Kinase increased 36 65 Creatinine increased 94 1.1 98 0.8 Based on Minimum of 57 Months of Follow-up. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic transaminase; N/n=number of patients; ULN=upper limit of normal. Graded using CTCAE 4.03 Adverse Reactions in Adult Patients With Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML The single-arm clinical trial enrolled patients with Ph+ CP, AP, or BP CML and with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. The safety population (received at least dose of bosutinib) included 546 CML patients:two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had median duration of bosutinib 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 bosutinib 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 bosutinib 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 10 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 9: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm Trial System Organ Class Preferred Term CP CML (N= 403) AdvP CML (N= 143) All Grades Grade 3/4 All Grades Grade 3/4 Gastrointestinal disorders Diarrhea 85 10 76 Abdominal paina 49 36 Nausea 47 48 Vomiting 38 43 Constipation 15 <1 17 Skin and subcutaneous tissue disorders Rashe 48 42 Pruritus 12 7 General disorders and administration- site conditions Fatigue 35 27 Pyrexia 25 37 Edemac 19 <1 17 Chest paing 1 12 Hepatobiliary disorders Hepatic dysfunctionh 29 11 21 10 Infections and infestations Respiratory tract infectionf 27 <1 17 Influenzai 11 3 Pneumoniad 10 18 12 Respiratory, thoracic, and mediastinal disorders Cough 24 22 Pleural effusion 14 9 Dyspnea 12 20 Nervous system disorders Headache 21 18 Dizziness 11 14 Musculoskeletal and connective tissue disorders Arthralgia 19 15 Back pain 14 8 Metabolism and nutrition disorders Decreased appetite 14 14 Vascular disorders Hypertensionb 11 8 ADR DefinitionBased on Minimum of 105 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on All Grades under Total column. Grade 3, Grade columns indicate maximum toxicity aAbdominal 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. gChest pain includes the following preferred terms: Chest discomfort, Chest pain. hHepatic 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. bHypertension includes the following preferred terms: Blood pressure increased, Blood pressure systolic increased, Essential hypertension, Hypertension, Hypertensive crisis, Retinopathy hypertensive. iInfluenza includes the following preferred terms: H1N1 influenza, Influenza. cEdema 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. dPneumonia 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. eRash 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.fRespiratory 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. ADR identified post-marketing In 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 10 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up.Table 10: Number (%) of Patients With Clinically Relevant All Grade or Grade 3/4 Laboratory Test Abnormalities in the Safety Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior Therapy CP CMLN=403%AdvP CML N= 143 All grade Grade 3/4 All grade Grade 3/4 Hematology Parameters Platelet Count decreased 66 26 80 57 Absolute Neutrophil Count decreased 50 16 66 39 Hemoglobin decreased 89 13 97 38 Lymphocyte decreased 79 14 82 21 White Blood Cell Count decreased 51 57 27 Biochemistry Parameters SGPT/ALT increased 58 11 39 SGOT/AST increased 50 37 3.5 Lipase increased 32 12 19 Phosphorus decreased 41 33 Total Bilirubin increased 16 0.7 22 2.8 Creatinine increased 95 87 1.4 Alkaline Phosphatase increased 39 39 1.4 Glucose increased 42 2.7 39 Sodium increased 23 0.5 11 Sodium decreased 18 2.2 27 Calcium decreased 55 4.7 45 3.5 Urate increased 49 43 Magnesium increased 27 18 4.9 Potassium decreased 22 1.7 29 4.9 Potassium increased 25 2.7 19 2.1 Based on Minimum of 105 Months of Follow-up.Abbreviations: AdvP=advanced phase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CML=chronic myelogenous leukemia; CP=chronic phase; N/n=number of patients; SGPT=serum glutamate-pyruvate transaminase; SGOT=serum glutamate-oxaloacetate aminotransferase; ULN=upper limit of normal. Additional Adverse Reactions From Multiple Clinical Trials The following adverse reactions were reported in patients in clinical trials with bosutinib (less than 10% of bosutinib-treated patients). They represent an evaluation of the adverse reaction data from all 1,372 patients with leukemia who received at least dose of single-agent bosutinib. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Blood and Lymphatic System Disorders: 0.1% and less than 1% Febrile neutropenia Cardiac Disorders: 1% and less than 10%-Cardiac ischemia (includes Acute coronary syndrome, Acute myocardial infarction, Angina pectoris, Angina unstable, Arteriosclerosis coronary artery, Coronary artery disease, Coronary artery occlusion, Coronary artery stenosis, Myocardial infarction, Myocardial ischemia, Troponin increased), Pericardial effusion, Cardiac failure (includes Cardiac failure, Cardiac failure acute, Cardiac failure chronic, Cardiac failure congestive, Cardiogenic shock, Cardiorenal syndrome, Ejection fraction decreased, Left ventricular failure); 0.1% and less than 1% Pericarditis Ear and Labyrinth Disorders: 1% and less than 10% Tinnitus Endocrine Disorders: 1% and less than 10% Hypothyroidism; 0.1% and less than 1% Hyperthyroidism Gastrointestinal Disorders: 1% and less than 10% Gastritis, Pancreatitis (includes Edematous pancreatitis, Pancreatic enzymes increased, Pancreatitis, Pancreatitis acute, Pancreatitis chronic), Gastrointestinal hemorrhage (includes Anal hemorrhage, Gastric hemorrhage, Gastrointestinal hemorrhage, Intestinal hemorrhage, Lower gastrointestinal hemorrhage, Rectal hemorrhage, Upper gastrointestinal hemorrhage) General Disorders and Administrative Site Conditions: 1% and less than 10% Pain Immune System Disorders: 1% and less than 10% Drug hypersensitivity; 0.1% and less than 1% Anaphylactic shock Infections and Infestations: 1% and less than 10% Bronchitis Investigations: 1% and less than 10% Electrocardiogram QT prolonged (includes Electrocardiogram QT prolonged, Long QT syndrome) Metabolism and Nutrition Disorders: 1% and less than 10% Dehydration Musculoskeletal and Connective Tissue Disorders: 1% and less than 10% Myalgia Nervous System Disorders: 1% and less than 10% Dysgeusia Renal and Urinary Disorders: 1% and less than 10% Acute kidney injury, Renal impairment, Renal failure Respiratory, Thoracic and Mediastinal Disorders: 1% and less than 10% Pulmonary hypertension (includes Pulmonary hypertension, Pulmonary arterial hypertension, Pulmonary arterial pressure increased); 0.1% and less than 1% Acute pulmonary edema (includes Acute pulmonary edema, Pulmonary edema), Interstitial lung disease, Respiratory failure Skin and Subcutaneous Disorders: 0.1% and less than 1% Erythema multiforme, Cutaneous vasculitisPediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. two hundred sixty-eight (268) patients with newly-diagnosed CP CML had median duration of bosutinib treatment of 55 months (range: 0.3 to 60 months) and median dose intensity of 394 mg/day.. two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had median duration of bosutinib 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 bosutinib 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 bosutinib 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.. 6.2 Postmarketing Experience. The following additional adverse reactions have been identified during post-approval use of bosutinib. 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 microangiopathy Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Bosutinib was not carcinogenic in rats or transgenic mice. The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females. Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose. The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg. 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 1.5 times and equal to the human exposure at the recommended doses of 400 and 500 mg/day, respectively. 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 (1.6 and 1.2 times the human exposure at the recommended doses of 400 and 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Bosutinib is TKI. 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 kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells. 12.2 Pharmacodynamics. greater likelihood of response and greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. Cardiac Electrophysiology At single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. Bosutinib pharmacokinetics were assessed following oral dosing with food in adult patients with CML and were presented as geometric mean (CV%), unless otherwise specified. Bosutinib exhibits dose proportional increases in Cmax and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady state Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2,370 ngoh/mL (34%) following multiple oral doses of bosutinib 400 mg; Bosutinib steady state Cmax was 171 ng/mL (38%), Ctrough was 91 ng/mL (42%) and AUC was 3,150 ngoh/mL (38%) following multiple oral doses of bosutinib 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet dosage forms of bosutinib at the same dose, under fed conditions.AbsorptionThe median bosutinib (minimum, maximum) time--to-Cmax (tmax) was (6, 6) hours following oral administration of single oral dose of bosutinib 500 mg with food. The absolute bioavailability was 34% in healthy subjects.Effect of FoodBosutinib Cmax increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with high fat meal to healthy subjects compared to administration under fasted condition. Bosutinib Cmax increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with high fat meal to healthy subjects compared to administration under fasted condition. The high-fat meal (800 to 1,000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories.No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of bosutinib capsule that was opened and the contents mixed with applesauce or yogurt immediately before use.DistributionThe mean (SD) apparent bosutinib volume of distribution is 6,080 (1,230) after an oral dose of 500 mg of bosutinib.Bosutinib protein binding is 94% in vitro and 96% ex vivo, and is independent of concentration.EliminationThe mean (SD) bosutinib terminal phase elimination half life (t 1/2 was 22.5 (1.7) hours, and the mean (SD) apparent clearance was 189 (48) L/h following single oral dose of bosutinib.MetabolismBosutinib is primarily metabolized by CYP3A4.ExcretionFollowing single oral dose of [14C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose recovered in urine.Specific PopulationsPatients with Renal ImpairmentBosutinib AUC increased 1.4-fold in subjects with moderate renal impairment (CLcr: 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and increased 1.6-fold in subjects with severe renal impairment (CLcr less than 30 mL/min) following single oral dose of bosutinib 200 mg (0.33 times the maximum approved recommended dosage of 600 mg). No clinically significant difference in the pharmacokinetics of bosutinib was observed in subjects with mild renal impairment (CLcr: 51 to 80 mL/min, C-G). Bosutinib has not been studied in patients undergoing hemodialysis.Patients with Hepatic ImpairmentBosutinib Cmax increased 2.4-fold, 2-fold, and 1.5-fold, and AUC increased 2.3-fold, 2-fold, and 1.9-fold in hepatic impairment Child-Pugh A, B, and C, respectively, following single oral dose of bosutinib 200 mg (0.33 times the maximum approved recommended dosage of 600 mg).Drug Interaction StudiesClinical StudiesStrong CYP3A Inhibitors: Bosutinib Cmax increased 5.2-fold and AUC increased 8.6-foldfollowing single dose of bosutinib 100 mg (0.17 times the maximum approved recommended dosage) without food when used concomitantly with 400 mg ketoconazole (a strong CYP3A inhibitor) administered over multiple daily doses.Moderate CYP3A Inhibitors: Bosutinib Cmax increased 1.5-fold and AUC increased 2-fold following single dose of bosutinib 500 mg with food when administered concomitantly with 125 mg aprepitant (a moderate CYP3A inhibitor).Strong CYP3A Inducers: Bosutinib Cmax decreased by 86% and AUC decreased by 94% following single dose of bosutinib 500 mg with food administered concomitantly with multiple daily doses of 600 mg of rifampin (a strong CYP3A inducer).Proton Pump Inhibitors: Lansoprazole decreased bosutinib Cmax by 46% and AUC by 26% following single oral dose of bosutinib 400 mg without food when used concomitantly with lansoprazole 60 mg (proton pump inhibitor) administered over multiple daily doses. Bosutinib displays pH-dependent aqueous solubility, in vitro [see Description (11)]. P-gp Substrates: No clinically significant differences in bosutinib pharmacokinetics were observed when used concomitantly with dabigatran etexilate mesylate (a P-glycoprotein (P-gp) substrate).In Vitro StudiesTransporters Systems: Bosutinib inhibits breast cancer resistance protein (BCRP)but, does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, and OCT2.Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Patients with Newly-Diagnosed CP Ph+ CML. The efficacy of bosutinib in patients with newly-diagnosed chronic phase Ph+ CML was evaluated in the Bosutinib trial in First-line chrOnic myelogenous leukemia tREatment (BFORE) Trial: A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia [NCT02130557]. The BFORE Trial is 2-arm, open-label, randomized, multicenter trial conducted to investigate the efficacy and safety of bosutinib 400 mg once daily alone compared with imatinib 400 mg once daily alone in adult patients with newly-diagnosed CP Ph+ CML. The trial randomized 536 patients (268 in each arm) with Ph+ or Ph- newly-diagnosed CP CML (intent-to-treat [ITT] population) including 487 patients with Ph+ CML harboring b2a2 and/or b3a2 transcripts at baseline and baseline BCR-ABL copies >0 (modified intent-to-treat [mITT] population). Randomization was stratified by Sokal score and geographical region. All patients are being treated and/or followed for up to years (240 weeks). Efficacy was evaluated in the mITT population. The major efficacy outcome measure was major molecular response (MMR) at 12 months (48 weeks) defined as <=0.1% BCR-ABL ratio on international scale (corresponding to >=3 log reduction from standardized baseline) with minimum of 3,000 ABL transcripts as assessed by the central laboratory. Additional efficacy outcomes included CCyR by 12 months, defined as the absence of Ph+ metaphases in chromosome banding analysis of >=20 metaphases derived from bone marrow aspirate or MMR if an adequate cytogenetic assessment was unavailable and MMR by 18 months (72 weeks).In the mITT population in this study, 57% of patients were males, 78% were Caucasian, and 19% were 65 years or older. The median age was 53 years. At baseline, the distribution of Sokal risk scores was similar in bosutinib and imatinib-treated patients (low risk: 35% and 39%; intermediate risk: 44% and 38%; high risk: 22% and 22%, respectively). After minimum of 12 months follow-up, 78% of the 246 bosutinib -treated patients and 72% of the 239 imatinib-treated patients were still receiving treatment and with minimum of 60 months of follow-up, 60% and 60% of patients, respectively, were still receiving treatment. The median treatment duration was 55.1 months for bosutinib and 55 months for imatinib.The efficacy results from the BFORE trial are summarized in Table 13. Table 13: Summary of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR), by Treatment Group in the Modified Intent-to-Treat (mITT) Population Response Bosutinib N=246 (%) Imatinib N=241 (%) 2-sided p-value MMR at Month 12 (Week 48) MMR (%) (95% CI) 116 (47) (41, 53) 89 (37) (31, 43) 0.0200 CCyR by Month 12 (Week 48) CCyR (%) (95% CI) 190 (77) (72, 83) 160 (66) (60, 72) 0.0075 MMR by Month 18 (Week 72) MMR (%) (95% CI) 150 (61) (55, 67) 127 (53) (46, 59) 0.0606 Abbreviations: CCyR=complete cytogenetic response; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; MMR=major molecular response; N/n=number of patients. Derived from CMH test stratified by Geographical region and Sokal score at randomization.The MMR rate at Month 12 for all randomized patients (ITT population) was consistent with the mITT population (47% [95% CI: 41, 53] in the bosutinib treatment group and 36% [95% CI: 30, 42] in the imatinib treatment group; odds ratio of 1.57 [95% CI: 1.10, 2.22]). MMR by Month 60 (Week 240) in the mITT population was 74% (95% CI: 69, 80) in the bosutinib treatment group and 66% (95% CI: 60, 72) in the imatinib treatment group; odds ratio of 1.52 (95% CI: 1.02, 2.25). MMR by Month 60 in the ITT population was also consistent with the mITT population (1.57 [95% CI: 1.08, 2.28]).After 60 months of follow-up, the median time to MMR in responders was months for bosutinib and 11.9 months for imatinib. By 60 months, the MMR rates in each Sokal risk group for the bosutinib and imatinib-treated patients, respectively, were 78% and 72% for low risk, 74% and 67% for intermediate risk and 68% and 52% for high risk. After 60 months of follow-up, (2%) bosutinib patients and (3%) imatinib patients transformed to AP CML or BP CML while on treatment. At 60 months, the estimated overall survival rate was 95% (95% CI: 91, 97) in the bosutinib group and 94% (95% CI: 90, 96) in the imatinib group.. 14.2 Adult Patients with Imatinib-Resistant or -Intolerant Ph+ CP, AP, and BP CML. Study 200 (NCT00261846), single-arm, open-label, multicenter study in patients with CML who were resistant or intolerant to prior therapy was conducted to evaluate the efficacy and safety of bosutinib 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for CP, AP, and BP disease previously treated with prior TKI (imatinib) or more than TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within weeks; (2) failure to achieve 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 prior TKI (imatinib) were the rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with CP CML previously treated with both imatinib and at least additional TKI were the cumulative rate of attaining MCyR by Week 24 and the duration of MCyR. The efficacy endpoints for patients with previously treated AP and BP CML were confirmed CHR and overall hematologic response (OHR). The study enrolled 546 patients with CP, AP or BP CML. Of the total patient population 73% were imatinib resistant and 27% were imatinib intolerant. In this trial, 53% of patients were males, 65% were Caucasian, and 20% were 65 years old or older. Of the 546 treated patients, 506 were considered evaluable for cytogenetic or hematologic efficacy assessment. Patients were evaluable for efficacy if they had received at least dose of bosutinib and had valid baseline efficacy assessment. Among evaluable patients, there were 262 patients with CP CML previously treated with prior TKI (imatinib), 112 patients with CP CML previously treated with both imatinib and at least additional TKI, and 132 patients with advanced phase CML previously treated with at least TKI. Median duration of bosutinib treatment was 26 months in patients with CP CML previously treated with 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 and MCyR at any time results are summarized in Table 14. Table 14: Efficacy Results in Patients with Ph+ CP CML With Resistance to or Intolerance to Imatinib Prior TreatmentWith Imatinib Only (N=262 evaluable) (%) Prior Treatment With Imatinib and Dasatinib or Nilotinib (N=112 evaluable) (%) By Week 24MCyR (95% CI) 105 (40.1)(34.1, 46.3) 29 (25.9)(18.1, 35) MCyR any time 156 (59.5)(53.3, 65.5) 45 (40.2)(31, 49.9) Abbreviations: CI=confidence interval; CML=chronic myelogenous leukemia; CP=chronic phase; MCyR=major cytogenetic response; N/n=number of patients; Ph+=Philadelphia chromosome positive. The long-term follow-up data analysis was based on minimum of 60 months for patients with CP CML treated with prior TKI (imatinib) and minimum of 48 months for patients with CP CML treated with imatinib and at least additional TKI. For the 59.5% of patients with CP CML treated with prior TKI (imatinib) who achieved MCyR at any time, the median duration of MCyR was not reached. Among these patients, 65.4% and 42.9% had MCyR lasting at least 18 and 54 months, respectively. For the 40.2% of patients with CP CML treated with imatinib and at least additional TKI who achieved MCyR at any time, the median duration of MCyR was not reached. Among these patients, 64.4% and 35.6% had MCyR lasting at least and 42 months, respectively. Of the 403 treated patients with CP CML, 20 patients had confirmed disease transformation to AP or BP while on treatment with bosutinib. The 48-week efficacy results in patients with accelerated and blast phases CML previously treated with at least imatinib are summarized in Table 15. Table 15: Efficacy Results in Patients With Accelerated Phase and Blast Phase CML Previously Treated With at Least Imatinib AP CML N= 72 evaluable) (%) BP CML N= 60 evaluable) (%) CHRa by Week 48 (95% CI) 22 (30.6)(20.2, 42.5) 10 (16.7)(8.3, 28.5) OHRa by Week 48 (95% CI) 41 (56.9)(44.7, 68.6) 17 (28.3) (17.5, 41.4) Abbreviations: AP=accelerated phase; BP=blast phase; CHR=complete hematologic response; CI=confidence interval; CML=chronic myelogenous leukemia; CI=confidence interval, OHR=overall hematologic response, CHR=complete hematologic response, N/n=number of patients Overall 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 1x109 /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 1x109 /L). Return to chronic phase (RCP) disappearance of features defining accelerated or blast phases but still in chronic phase. The long-term follow-up data analysis was based on minimum of 48 months for patients with AP CML and BP CML. Of the 79 treated patients with AP CML, patients had confirmed disease transformation to BP while on bosutinib treatment.Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Bosutinib tablets are contraindicated in patients with history of hypersensitivity to bosutinib. Reactions have included anaphylaxis [see Adverse Reactions (6.1)]. Hypersensitivity to bosutinib. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Bosutinib tablets contains bosutinib, kinase inhibitor. The chemical name of bosutinib is 3-Quinolinecarbonitrile, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl) propoxy]-hydrate (1:2). Its chemical formula is C26H29Cl2N5O3.2H2O; its molecular weight is 566.48 Bosutinib has the following chemical structure:Bosutinib is white to yellowish-tan powder. Bosutinib is soluble in dimethyl sulfoxide, sparingly soluble in acetone and practically insoluble in water. Bosutinib tablets are supplied for oral administration in single strength of 400 mg, equivalent to 400 mg of bosutinib on an anhydrous basis. The tablets contain the following inactive ingredients: crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, poloxamer, povidone, titanium dioxide, polyethylene glycol, iron oxide yellow and iron oxide red.. bosutinib-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adult patients with newly-diagnosed chronic phase Ph+ CML: 400 mg orally once daily with food. (2.1)Adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy: 500 mg orally once daily with food. (2.1)Consider dose escalation by increments of 100 mg once daily to maximum of 600 mg daily in adult patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade or greater adverse reactions. (2.2)Adjust dosage for toxicity and organ impairment (2). Adult patients with newly-diagnosed chronic phase Ph+ CML: 400 mg orally once daily with food. (2.1). Adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy: 500 mg orally once daily with food. (2.1). Consider dose escalation by increments of 100 mg once daily to maximum of 600 mg daily in adult patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade or greater adverse reactions. (2.2). Adjust dosage for toxicity and organ impairment (2). 2.1 Recommended Dosage. The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or chew tablets. Continue treatment with bosutinib tablets until disease progression or intolerance to therapy. If dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML The recommended dosage of bosutinib tablet is 400 mg orally once daily with food. Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dosage of bosutinib tablet is 500 mg orally once daily with food. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. 2.2 Dose Escalation. In clinical studies of adult patients with Ph+ CML, dose escalation by increments of 100 mg once daily to maximum of 600 mg once daily was allowed in patients who did not achieve or maintain hematologic, cytogenetic, or molecular response and who did not have Grade or higher adverse reactions at the recommended starting dosage. The maximum dose in adult patients is 600 mg once daily. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Dosage Adjustments for Non-Hematologic Adverse Reactions. Elevated liver transaminases: If elevations in liver transaminases greater than 5xinstitutional upper limit of normal (ULN) occur, withhold bosutinib tablets 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 bosutinib tablets. 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 bosutinib tablets [see Warnings and Precautions (5.3)]. Diarrhea: For National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade to diarrhea (increase of greater than or equal to stools/day over baseline/pretreatment), withhold bosutinib tablets until recovery to Grade less than or equal to 1. Bosutinib tablets 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 bosutinib tablets until the toxicity has resolved, then consider resuming bosutinib tablets at dose reduced by 100 mg taken once daily. If clinically appropriate, consider re-escalating the dose of bosutinib tablets to the starting dose taken once daily. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Dosage Adjustments for Myelosuppression. Dose reductions for severe or persistent neutropenia and thrombocytopenia are described below (Table 3).Table 3: Dose Adjustments for Neutropenia and Thrombocytopenia in Adult PatientsANCa less than 1,000x106/LorPlatelets less than 50,000x106/L Withhold bosutinib tablets until ANC greater than or equal to 1,000x106/L and platelets greater than or equal to 50,000x106/L.Resume treatment with bosutinib tablets 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. Absolute Neutrophil Count Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Dosage Adjustments for Renal Impairment or Hepatic Impairment. The recommended starting doses for patients with renal and hepatic impairment are described in Table below. Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients Recommended Starting Dosage Newly-diagnosed chronic phase Ph+ CML Chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapyNormal renal and hepatic function 400 mg daily 500 mg daily Renal impairment Creatinine clearance 30 to 50 mL/min 300 mg daily 400 mg daily Creatinine clearance less than 30 mL/min 200 mg daily 300 mg daily Hepatic impairment Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) 200 mg daily 200 mg daily [see Use in Specific Populations (8.6, 8.7) andClinical Pharmacology (12.3)]. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 400 mg: orange, oval, biconvex, film-coated tablets debossed with 400 on one side and B on other side.. 400 mg: orange, oval, biconvex, film-coated tablets debossed with 400 on one side and B on other side.. Tablets: 400 mg. (3).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Tablets How Supplied Bosutinib tablets are supplied for oral administration in single strength 400 mg orange, oval, biconvex, film-coated tablets debossed with 400 on one side and B on other side. Bosutinib tablets are available in the following packaging configurations with child-resistant CR) closure (Table 17). Bottles contain desiccant.Table 17: Tablet PresentationsBosutinib Tablets Package Configuration Tablet Strength(mg)NDC Tablet Description 30 tablets per bottle 400 mg 75907-405-30 Orange, oval, biconvex, film-coated tablets, debossed with400 on one side and B on other side. Abbreviation: NDC=National drug code.Storage Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Handling and Disposal Procedures for proper disposal of anticancer drugs should be considered. Touching or handling crushed or broken tablets is to be avoided. 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. Bosutinib tablets are indicated for the treatment of:Adult patients with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see Clinical Studies (14.1, 14.2)]. Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. Adult patients with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see Clinical Studies (14.1, 14.2)]. Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy [see Clinical Studies (14.2)]. Bosutinib tablets are kinase inhibitor indicated for the treatment of adult patients with chronic phase Ph+ chronic myelogenous leukemia (CML), newly-diagnosed or resistant or intolerant to prior therapy. (1) adult patients with accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy. (1) adult patients with chronic phase Ph+ chronic myelogenous leukemia (CML), newly-diagnosed or resistant or intolerant to prior therapy. (1) adult patients with accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Dosage and Administration Instruct patients to take bosutinib exactly as prescribed, not to change their dose or to stop taking bosutinib 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 bosutinib with food. Patients should be advised: Swallow tablets whole. Do not crush, break, or cut tablet. Do not touch or handle crushed or broken tablets. Gastrointestinal Toxicity Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with bosutinib and to seek medical attention promptly for these symptoms [see Warnings and Precautions (5.1)]. Myelosuppression 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 [see Warnings and Precautions (5.2)]. Hepatic Toxicity Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice [see Warnings and Precautions (5.3)]. Cardiovascular Toxicity Advise patients that cardiac failure, left ventricular dysfunction, and cardiac ischemic events have been reported. Advise patients to seek immediate medical attention if any symptoms suggestive of cardiac failure and cardiac ischemia occur, such as shortness of breath, weight gain, or fluid retention [see Warnings and Precautions (5.4)]. 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 [see Warnings and Precautions (5.5)]. Renal Toxicity Advise patients of the possibility of developing renal problems and to immediately report frequent urination, polyuria or oliguria [see Warnings and Precautions (5.6)]. Adverse Reactions Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, headache, dizziness, back pain, arthralgia, pruritus with bosutinib and to seek medical attention if symptoms are significant. There is possibility of anaphylactic shock [see Contraindications (4) and Adverse Reactions (6)]. Embryo-Fetal Toxicity Advise females to inform their healthcare provider if they are pregnant or become pregnant. Advise female patients of the risk to fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential, to use effective contraception during treatment and for weeks after receiving the last dose of bosutinib [see Warnings and Precautions (5.7)and Use in Specific Populations (8.1, 8.3)]. Advise lactating women not to breastfeed during treatment with bosutinib and for weeks after the last dose [see Use in Specific Populations (8.2)]. Drug Interactions Advise patients that bosutinib 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 bosutinib [see Drug Interactions (7)]. Manufactured by: MSN Laboratories Private Limited Telangana 509 228, INDIA Distributor Dr. Reddys Laboratories Inc., Princeton, NJ 08540Made in India Issued: 04/2026.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk Summary No 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 bosutinib and for weeks after the last dose. Animal Data After single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Bosutinib is TKI. 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 kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Bosutinib was not carcinogenic in rats or transgenic mice. The rat 2-year carcinogenicity study was conducted at bosutinib oral doses up to 25 mg/kg in males and 15 mg/kg in females. Exposures at these doses were approximately 1.5 times (males) and 3.1 times (females) the human exposure at the 400 mg dose and 1.2 times (males) and 2.4 times (females) exposure in humans at the 500 mg dose. The 6-month RasH2 transgenic mouse carcinogenicity study was conducted at bosutinib oral doses up to 60 mg/kg. 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 1.5 times and equal to the human exposure at the recommended doses of 400 and 500 mg/day, respectively. 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 (1.6 and 1.2 times the human exposure at the recommended doses of 400 and 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

NURSING MOTHERS SECTION.

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

OVERDOSAGE SECTION.

10 OVERDOSAGE. Experience with bosutinib 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 bosutinib should be observed and given appropriate supportive treatment.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. 400-mg-Container-Label-30s-count bosutinib-400-mg-30s-count.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of bosutinib in pediatric patients younger than year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established.Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. greater likelihood of response and greater likelihood of safety events were observed with higher bosutinib exposure in clinical studies. The time course of bosutinib pharmacodynamic response has not been fully characterized. Cardiac Electrophysiology At single oral dose of 500 mg bosutinib with ketoconazole (a strong CYP3A inhibitor), bosutinib does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Bosutinib pharmacokinetics were assessed following oral dosing with food in adult patients with CML and were presented as geometric mean (CV%), unless otherwise specified. Bosutinib exhibits dose proportional increases in Cmax and AUC over the oral dose range of 200 to 800 mg (0.33 to 1.3 times the maximum approved recommended dosage of 600 mg). Bosutinib steady state Cmax was 127 ng/mL (31%), Ctrough was 68 ng/mL (39%) and AUC was 2,370 ngoh/mL (34%) following multiple oral doses of bosutinib 400 mg; Bosutinib steady state Cmax was 171 ng/mL (38%), Ctrough was 91 ng/mL (42%) and AUC was 3,150 ngoh/mL (38%) following multiple oral doses of bosutinib 500 mg. No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of either the tablet dosage forms of bosutinib at the same dose, under fed conditions.AbsorptionThe median bosutinib (minimum, maximum) time--to-Cmax (tmax) was (6, 6) hours following oral administration of single oral dose of bosutinib 500 mg with food. The absolute bioavailability was 34% in healthy subjects.Effect of FoodBosutinib Cmax increased 1.8-fold and AUC increased 1.7-fold when bosutinib tablets were given with high fat meal to healthy subjects compared to administration under fasted condition. Bosutinib Cmax increased 1.6-fold and AUC increased 1.5-fold when bosutinib capsules were given with high fat meal to healthy subjects compared to administration under fasted condition. The high-fat meal (800 to 1,000 total calories) consisted of approximately 150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories.No clinically significant differences in the pharmacokinetics of bosutinib were observed following administration of bosutinib capsule that was opened and the contents mixed with applesauce or yogurt immediately before use.DistributionThe mean (SD) apparent bosutinib volume of distribution is 6,080 (1,230) after an oral dose of 500 mg of bosutinib.Bosutinib protein binding is 94% in vitro and 96% ex vivo, and is independent of concentration.EliminationThe mean (SD) bosutinib terminal phase elimination half life (t 1/2 was 22.5 (1.7) hours, and the mean (SD) apparent clearance was 189 (48) L/h following single oral dose of bosutinib.MetabolismBosutinib is primarily metabolized by CYP3A4.ExcretionFollowing single oral dose of [14C] radiolabeled bosutinib without food, 91.3% of the dose was recovered in feces and 3.3% of the dose recovered in urine.Specific PopulationsPatients with Renal ImpairmentBosutinib AUC increased 1.4-fold in subjects with moderate renal impairment (CLcr: 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and increased 1.6-fold in subjects with severe renal impairment (CLcr less than 30 mL/min) following single oral dose of bosutinib 200 mg (0.33 times the maximum approved recommended dosage of 600 mg). No clinically significant difference in the pharmacokinetics of bosutinib was observed in subjects with mild renal impairment (CLcr: 51 to 80 mL/min, C-G). Bosutinib has not been studied in patients undergoing hemodialysis.Patients with Hepatic ImpairmentBosutinib Cmax increased 2.4-fold, 2-fold, and 1.5-fold, and AUC increased 2.3-fold, 2-fold, and 1.9-fold in hepatic impairment Child-Pugh A, B, and C, respectively, following single oral dose of bosutinib 200 mg (0.33 times the maximum approved recommended dosage of 600 mg).Drug Interaction StudiesClinical StudiesStrong CYP3A Inhibitors: Bosutinib Cmax increased 5.2-fold and AUC increased 8.6-foldfollowing single dose of bosutinib 100 mg (0.17 times the maximum approved recommended dosage) without food when used concomitantly with 400 mg ketoconazole (a strong CYP3A inhibitor) administered over multiple daily doses.Moderate CYP3A Inhibitors: Bosutinib Cmax increased 1.5-fold and AUC increased 2-fold following single dose of bosutinib 500 mg with food when administered concomitantly with 125 mg aprepitant (a moderate CYP3A inhibitor).Strong CYP3A Inducers: Bosutinib Cmax decreased by 86% and AUC decreased by 94% following single dose of bosutinib 500 mg with food administered concomitantly with multiple daily doses of 600 mg of rifampin (a strong CYP3A inducer).Proton Pump Inhibitors: Lansoprazole decreased bosutinib Cmax by 46% and AUC by 26% following single oral dose of bosutinib 400 mg without food when used concomitantly with lansoprazole 60 mg (proton pump inhibitor) administered over multiple daily doses. Bosutinib displays pH-dependent aqueous solubility, in vitro [see Description (11)]. P-gp Substrates: No clinically significant differences in bosutinib pharmacokinetics were observed when used concomitantly with dabigatran etexilate mesylate (a P-glycoprotein (P-gp) substrate).In Vitro StudiesTransporters Systems: Bosutinib inhibits breast cancer resistance protein (BCRP)but, does not inhibit organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, and OCT2.Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action, bosutinib can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day (see Data). Advise pregnant women of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.DataAnimal Data In rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately to weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).In an embryo-fetal development 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 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 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively.Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in placental-transfer study in pregnant rats. In rat pre- and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. The recommended dosage is taken orally once daily with food. Swallow tablets whole. Do not cut, crush, break or chew tablets. Continue treatment with bosutinib tablets until disease progression or intolerance to therapy. If dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML The recommended dosage of bosutinib tablet is 400 mg orally once daily with food. Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dosage of bosutinib tablet is 500 mg orally once daily with food. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed. (8.2)Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action, bosutinib can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day (see Data). Advise pregnant women of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.DataAnimal Data In rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately to weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).In an embryo-fetal development 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 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 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively.Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in placental-transfer study in pregnant rats. In rat pre- and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).. 8.2 Lactation. Risk Summary No 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 bosutinib and for weeks after the last dose. Animal Data After single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours.. 8.3 Females and Males of Reproductive Potential. Based on findings from animal studies, bosutinib can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Females of reproductive potential should have pregnancy test prior to starting treatment with bosutinib. Contraception Females Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with bosutinib and for weeks after the last dose. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. Based on findings from animal studies, bosutinib may cause reduced fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The safety and effectiveness of bosutinib in pediatric patients younger than year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established.Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. 8.5 Geriatric Use. In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of bosutinib in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. Of the 268 patients who received bosutinib in the study for newly diagnosed CML, 20% were age 65 and over, 5% 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 Renal Impairment. Reduce the bosutinib 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 bosutinib 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)]. Bosutinib has not been studied in patients undergoing hemodialysis.. 8.7 Hepatic Impairment. Reduce the bosutinib 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, dose reduce, or discontinue bosutinib. (2.3, 5.1)Myelosuppression: Monitor blood counts and manage as necessary. Withhold, dose reduce, or discontinue bosutinib. (2.4, 5.2)Hepatic Toxicity: Monitor liver enzymes at least monthly for the first months and as needed. Withhold, dose reduce, or discontinue bosutinib. (2.3, 5.3)Cardiovascular Toxicity: Monitor and manage as necessary. Interrupt, dose reduce, or discontinue bosutinib. (5.4)Fluid Retention: Monitor patients and manage using standard of care treatment. Interrupt, dose reduce, or discontinue bosutinib. (2.3, 5.5)Renal Toxicity: Monitor patients for renal function at baseline and during therapy with bosutinib. (5.6)Embryo-Fetal Toxicity: Bosutinib can cause fetal harm. Advise female patients of reproductive potential of potential risk to fetus and to use effective contraception. (5.7). Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, dose reduce, or discontinue bosutinib. (2.3, 5.1). Myelosuppression: Monitor blood counts and manage as necessary. Withhold, dose reduce, or discontinue bosutinib. (2.4, 5.2). Hepatic Toxicity: Monitor liver enzymes at least monthly for the first months and as needed. Withhold, dose reduce, or discontinue bosutinib. (2.3, 5.3). Cardiovascular Toxicity: Monitor and manage as necessary. Interrupt, dose reduce, or discontinue bosutinib. (5.4). Fluid Retention: Monitor patients and manage using standard of care treatment. Interrupt, dose reduce, or discontinue bosutinib. (2.3, 5.5). Renal Toxicity: Monitor patients for renal function at baseline and during therapy with bosutinib. (5.6). Embryo-Fetal Toxicity: Bosutinib can cause fetal harm. Advise female patients of reproductive potential of potential risk to fetus and to use effective contraception. (5.7). 5.1 Gastrointestinal Toxicity. Diarrhea, nausea, vomiting, and abdominal pain occur with bosutinib treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. In the randomized clinical trial in adult patients with newly-diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) was days and the median duration per event was days. Among 546 adult patients in single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was days and the median duration per event was days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with bosutinib was (range to 268). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue bosutinib as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. 5.2 Myelosuppression. Thrombocytopenia, anemia and neutropenia occur with bosutinib 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 bosutinib as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6)]. 5.3 Hepatic Toxicity. Bosutinib may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). Two cases consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3xULN with total bilirubin greater than 2xULN and alkaline phosphatase less than 2xULN) have occurred without alternative causes. This represented out 1,711 patients in bosutinib clinical trials. In the 268 adult patients from the safety population in the randomized clinical trial in patients with newly-diagnosed CML in the bosutinib treatment group, the incidence of ALT elevation was 68.3% and increased AST was 56%. Of patients who experienced increased transaminases of any grade, 73% experienced their first increase within the first months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively. Among the 546 adult patients in single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of increased ALT was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced increased transaminases of any grade, more than 81% experienced their first increase within the first months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days. Perform hepatic enzyme tests monthly for the first months of bosutinib treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue bosutinib as necessary [seeDosage and Administration (2.3)and Adverse Reactions (6)]. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. 5.4 Cardiovascular Toxicity. Bosutinib can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac ischemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of diabetes, body mass index greater than 30, hypertension, and vascular disorders. In randomized study of adult patients with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with bosutinib compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% of patients treated with bosutinib compared to 0.8% of patients treated with imatinib. In single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 5.1% of patients treated with bosutinib. Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically indicated. Interrupt, dose reduce, or discontinue bosutinib as necessary [see Dosage and Administration (2.3) andAdverse Reactions (6)]. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information. 5.5 Fluid Retention. Fluid retention occurs with bosutinib and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. In the randomized clinical trial of 268 adult patients with newly-diagnosed CML in the bosutinib treatment group, patients (1.1%) experienced severe fluid retention of Grade 3, patient experienced Grade pericardial effusion, and patients experienced Grade pleural effusion. Among 546 adult patients in single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade or fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade or pleural effusions, patients experienced Grade or Grade pericardial effusions, and patients experienced Grade edema. Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue bosutinib as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6)]. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. 5.6 Renal Toxicity. An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with bosutinib. Table identifies the shift from baseline to lowest observed eGFR during bosutinib therapy for patients in the pooled leukemia studies regardless of line of therapy. The median duration of therapy with bosutinib was approximately 24 months (range, 0.03 to 155) for patients in these studies. Table 6: Shift From Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (N= 1,372) Baseline Follow-UpRenal Function Status Normaln (%) Mildn (%) Mild toModeraten (%) Moderate toSeveren (%) Severen (%) Kidney Failuren (%) Normal 527 115(21.8) 330 (62.6) 50 (9.5) 23 (4.4) (0.6) (0.9) Mild 672 10 (1.5) 259 (38.5) 271 (40.3) 96 (14.3) 26 (3.9) (0.9) Mild to Moderate 137 6 (4.4) 40 (29.2) 66 (48.2) 24 (17.5) (0.7) Moderate to Severe 33 1 (3) (3) (24.2) 19 (57.6) (12.1) Severe 0 0 0 1(100) Total 1,370 125(9.1) 596 (43.5) 362 (26.4) 193 (14.1) 72 (5.2) 17 (1.2) Abbreviations: eGFR=estimated glomerular filtration rate; N/n=number of patients.Notes: eGFR was calculated using Modification in Diet in Renal Disease method (MDRD).Notes: Grading is based on Kidney Disease Improving Global Outcomes (KDIGO) Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m2 .Among the 1,372 patients, eGFR was missing in patients at baseline or on-therapy. There were no patients with kidney failure at baseline. Monitor renal function at baseline and during therapy with bosutinib, with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with baseline and treatment emergent renal impairment [see Dosage and Administration (2.5)]. Pediatric use information is approved for PF PRISM CVs BOSULIF(R) (bosutinib) tablets. However, due to PF PRISM CVs marketing exclusivity rights, this drug product is not labeled with that information.. 5.7 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, bosutinib can cause fetal harm when administered to pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].