Bosutinib

Brand names: BOSULIF, Bosutinib

Warnings

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 3 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 a 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 4 days and the median duration per event was 3 days. Among 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with bosutinib was 3 (range 1 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 CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) have occurred without alternative causes. This represented 2 out 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 3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively. Among the 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of increased ALT was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced increased transaminases of any grade, more than 81% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days. Perform hepatic enzyme tests monthly for the first 3 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 [see Dosage and Administration (2.3) and Adverse Reactions (6)]. Pediatric use information is approved for PF PRISM CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 a 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 a single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 5.1% of patients treated with 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 ) and Adverse Reactions (6 )]. Pediatric use information is approved for PF PRISM CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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, 3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and 2 patients experienced Grade 3 pleural effusion. Among 546 adult patients in a single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3 or 4 fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions, 9 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema. 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 CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 6 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-Up Renal Function Status N Normal n (%) Mild n (%) Mild to Moderate n (%) Moderate to Severe n (%) Severe n (%) Kidney Failure n (%) Normal 527 115 (21.8) 330 (62.6) 50 (9.5) 23 (4.4) 3 (0.6) 5 (0.9) Mild 672 10 (1.5) 259 (38.5) 271 (40.3) 96 (14.3) 26 (3.9) 6 (0.9) Mild to Moderate 137 0 6 (4.4) 40 (29.2) 66 (48.2) 24 (17.5) 1 (0.7) Moderate to Severe 33 0 1 (3) 1 (3) 8 (24.2) 19 (57.6) 4 (12.1) Severe 1 0 0 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 m 2 . *Among the 1,372 patients, eGFR was missing in 7 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 CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1) ].

Contraindications

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

Overdose

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.

Drug interactions

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 Inhibitors Avoid the concomitant use of strong or moderate CYP3A inhibitors with bosutinib. Bosutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases bosutinib C max 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 a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases bosutinib C max 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 2 hours from bosutinib dosing. Bosutinib displays pH dependent aqueous solubility, Concomitant use with a PPI decreases bosutinib C max and AUC [see Clinical Pharmacology (12.3 )] which may reduce bosutinib efficacy.

Uses

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 CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information. Bosutinib tablets are a 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 )

Dosage forms & strengths

TABLET, FILM COATED POWDER CAPSULE
BOSUTINIB MONOHYDRATE 400 mg/1 BOSUTINIB MONOHYDRATE 1 kg/kg BOSUTINIB MONOHYDRATE 100 mg/1 BOSUTINIB 100 mg/1 BOSUTINIB 1 kg/kg BOSUTINIB MONOHYDRATE 50 mg/1 BOSUTINIB 25 kg/25kg BOSUTINIB 500 mg/1 BOSUTINIB MONOHYDRATE 500 mg/1 BOSUTINIB 400 mg/1

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 a maximum of 600 mg daily in adult patients who do not reach complete hematologic, cytogenetic, or molecular response and do not have Grade 3 or greater adverse reactions. ( 2.2 ) 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 a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML The recommended dosage of 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 CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage. The maximum dose in adult patients is 600 mg once daily. Pediatric use information is approved for PF PRISM CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 5×institutional upper limit of normal (ULN) occur, withhold bosutinib tablets until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue bosutinib tablets. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy’s law case definition), discontinue bosutinib tablets [see Warnings and Precautions (5.3 )]. Diarrhea: For National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3 to 4 diarrhea (increase of greater than or equal to 7 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 a 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 CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 Patients ANC a less than 1,000×10 6 /L or Platelets less than 50,000×10 6 /L Withhold bosutinib tablets until ANC greater than or equal to 1,000×10 6 /L and platelets greater than or equal to 50,000×10 6 /L. Resume treatment with bosutinib tablets at the same dose if recovery occurs within 2 weeks. If blood counts remain low for greater than 2 weeks, upon recovery, reduce dose by 100 mg and resume treatment. If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment. a Absolute Neutrophil Count Pediatric use information is approved for PF PRISM CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s 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 4 below. Table 4: Dose Adjustments for Renal and Hepatic Impairment in Adult Patients R ecommended Starting Dosage N ewly-diagnosed chronic phase Ph+ CML C hronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy Normal renal and hepatic function 400 mg daily 500 mg daily Renal impairment Creatinine clearance 30 to 50 mL/min 300 mg daily 400 mg daily Creatinine clearance less than 30 mL/min 200 mg daily 300 mg daily Hepatic impairment Mild (Child-Pugh A), Moderate (Child-Pugh B) or Severe (Child-Pugh C) 200 mg daily 200 mg daily [see Use in Specific Populations (8.6 , 8.7 ) and Clinical Pharmacology (12.3 )] . Pediatric use information is approved for PF PRISM CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information.

All identified pills

Side effects

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 [see Warnings 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. Reddy's Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions, in ≥20% of adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%). 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 1 dose of bosutinib) included: two hundred sixty-eight (268) patients with newly-diagnosed CP CML had a median duration of bosutinib treatment of 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 mg/day. Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib. Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of patients included hepatic dysfunction (9%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%), neutropenia (7%), abdominal pain (6%), rash (5%). The most common adverse reactions, in >20% of bosutinib-treated patients with newly-diagnosed CML (N=268) were diarrhea (75%), hepatic dysfunction (45%), rash (40%), abdominal pain (39%), nausea (37%), fatigue (33%), respiratory tract infection (27%), headache (22%), and vomiting (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased (94%), hemoglobin decreased (89%), lymphocyte count decreased (84%), ALT increased (68%), platelet count decreased (68%), glucose increased (57%), AST increased (56%), calcium decreased (55%), phosphorus decreased (54%), lipase increased (53%), white blood cell count decreased (50%), absolute neutrophil count decreased (42%), alkaline phosphatase increased (41%), creatine kinase increased (36%), and amylase increased (32%). Table 7 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the Phase 3 CP CML safety population. Table 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study* System Organ Class Preferred Term B osutinib 400 mg C hronic Phase CML (N= 268) Imatinib 400 mg C hronic Phase CML (N= 265) A l l Grades % G rade 3/4 % A l l Grades % G rade 3/4 % Gastrointestinal disorders Diarrhea 75 9 40 1 Abdominal pain a 39 2 27 1 Nausea 37 0 42 0 Vomiting 21 1 20 0 Hepatobiliary disorders Constipation 13 0 6 0 Skin and subcutaneous tissue disorders Hepatic dysfunction f 45 27 15 4 Rash d 40 2 30 2 Pruritus 11 <1 4 0 General disorders and administration-site conditions Fatigue b 33 1 30 <1 Pyrexia 17 1 11 0 Edema g 15 0 46 2 Infections and infestations Respiratory tract infection e 27 1 25 <1 Nervous system disorders Headache 22 1 15 1 Musculoskeletal and connective tissue disorders Arthralgia 18 1 18 <1 Back pain 12 <1 9 <1 Respiratory, thoracic, and mediastinal disorders Cough 11 0 10 0 Dyspnea 11 1 6 1 Metabolism and nutrition disorders Decreased appetite 11 <1 6 0 Vascular disorders Hypertension c 10 5 11 5 *Based on a Minimum of 57 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on 'All Grades' under Total column. 'Grade 3', 'Grade 4' columns indicate maximum toxicity. a Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain. b Fatigue includes the following preferred terms: Asthenia, Fatigue, Malaise. c Hypertension* includes the preferred terms: Blood pressure systolic increased, Hypertension, Hypertensive crisis, Hypertensive heart disease, Retinopathy hypertensive. f Hepatic 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. g Edema 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. d Rash 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. e Respiratory 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 a Grade 3 QTcF prolongation (>500 msec). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 8 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 3 newly-diagnosed CML safety population. Table 8: Select Laboratory Abnormalities (>20%) That Worsened From Baseline in Patients with Newly-Diagnosed CML in Bosutinib 400 mg Study* B osutinib N= 268 % Imatinib N= 265 % All Grade Grade 3 to 4 All Grade Grade 3 to 4 Hematology Parameters Platelet Count decreased 68 14 60 6 Absolute Neutrophil Count decreased 42 9 65 20 Hemoglobin decreased 89 9 90 7 White Blood Cell Count decreased 50 6 70 8 Lymphocyte Count decreased 84 12 82 14 B i ochemistry Parameters SGPT/ALT increased 68 26 28 3 SGOT/AST increased 56 13 29 3.4 Lipase increased 53 19 35 8 Phosphorus decreased 54 9 69 21 Amylase increased 32 3.4 18 2.3 Alkaline Phosphatase increased 41 0 43 0.4 Calcium decreased 55 1.5 57 1.1 Glucose increased 57 3 65 3.4 Creatine Kinase increased 36 3 65 5 Creatinine increased 94 1.1 98 0.8 *Based on a 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 v 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 1 dose of bosutinib) included 546 CML patients: two hundred eighty-four (284) patients with CP CML previously treated with imatinib only who had a median duration of bosutinib treatment of 26 months (range: 0.2 to 155 months), and a median dose intensity of 437 mg/day. one hundred nineteen (119) patients with CP CML previously treated with both imatinib and at least 1 additional tyrosine kinase inhibitor (TKI) who had a median duration of bosutinib treatment of 9 months (range: 0.2 to 148 months) and a median dose intensity of 427 mg/day. one hundred forty-three (143) patients with advanced phase (AdvP) CML including 79 patients with AP CML and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of bosutinib treatment was 10 months (range: 0.1 to 140 months) and 3 months (range: 0.03 to 71 months), respectively. The median dose intensity was 406 mg/day, and 456 mg/day, in the AP CML and BP CML cohorts, respectively. Serious adverse reactions occurred in 30% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy. Serious adverse reactions reported in >2% of patients included pneumonia (7%), pleural effusion (6%), pyrexia (3.7%), coronary artery disease (3.5%), dyspnea (2.6%), rash (2.2%), thrombocytopenia (2%), abdominal pain (2%), and diarrhea (2%). Fatal adverse reactions occurred in 12 patients (2.2%) due to coronary artery disease (0.9%), pneumonia (0.4%), respiratory failure (0.4%), gastrointestinal hemorrhage (0.2%), acute kidney injury (0.2%), and acute pulmonary edema (0.2%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 22% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which resulted in permanent discontinuation in >2% of patients included thrombocytopenia (6%), hepatic dysfunction (3.3%), and neutropenia (2%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 66% of patients with CML who were resistant or intolerant to prior therapy. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia (24%), diarrhea (14%), rash (13%), hepatic dysfunction (10%), neutropenia (9%), pleural effusion (8%), vomiting (7%), anemia (6%), and abdominal pain (6%). The most common adverse reactions, in ≥20% of patients in the safety population of the single-arm trial in patients with CML (N=546) who were resistant or intolerant to prior therapy were diarrhea (83%), nausea (47%), rash (46%), abdominal pain (45%), vomiting (39%), fatigue (33%), pyrexia (28%), hepatic dysfunction (27%), respiratory tract infection (24%), cough (23%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% were creatinine increased (93%), hemoglobin decreased (91%), lymphocyte decreased (80%), platelets decreased (69%), absolute neutrophil count (54%), ALT increased (53%), calcium decreased (53%), white blood cell count decreased (52%), urate increased (48%), AST increased (47%), phosphorus decreased (39%), alkaline phosphatase increased (39%), lipase increased (28%), magnesium increased (25%), potassium decreased (24%), potassium increased (23%). See Table 10 for Grade 3/4 laboratory abnormalities. Table 9 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 for the Phase 1/2 CML safety population based on long-term follow-up. Table 9: Adverse Reactions (10% or Greater) in Patients With CML Who Were Resistant or Intolerant to Prior Therapy in Single-Arm Trial* System Organ Class Preferred Term C P CML (N= 403) A dvP CML (N= 143) A l l Grades % G rade 3/4 % A l l Grades % G rade 3/4 % Gastrointestinal disorders Diarrhea 85 10 76 4 Abdominal pain a 49 2 36 7 Nausea 47 1 48 2 Vomiting 38 3 43 3 Constipation 15 <1 17 1 Skin and subcutaneous tissue disorders Rash e 48 9 42 5 Pruritus 12 1 7 0 General disorders and administration- site conditions Fatigue 35 3 27 6 Pyrexia 25 1 37 3 Edema c 19 <1 17 1 Chest pain g 8 1 12 1 Hepatobiliary disorders Hepatic dysfunction h 29 11 21 10 Infections and infestations Respiratory tract infection f 27 <1 17 0 Influenza i 11 1 3 0 Pneumonia d 10 4 18 12 Respiratory, thoracic, and mediastinal disorders Cough 24 0 22 0 Pleural effusion 14 4 9 4 Dyspnea 12 2 20 6 Nervous system disorders Headache 21 1 18 4 Dizziness 11 0 14 1 Musculoskeletal and connective tissue disorders Arthralgia 19 1 15 0 Back pain 14 1 8 1 Metabolism and nutrition disorders Decreased appetite 14 1 14 0 Vascular disorders Hypertension b 11 3 8 3 ADR Definition * Based on a Minimum of 105 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on 'All Grades' under Total column. 'Grade 3', 'Grade 4' columns indicate maximum toxicity a Abdominal 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. g Chest pain includes the following preferred terms: Chest discomfort, Chest pain. h Hepatic 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. b Hypertension* 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. c Edema 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. d Pneumonia 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. e Rash 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. f Respiratory 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, 2 patients (0.4%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol. Table 10 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the safety population of the study in patients with CML who were resistant or intolerant to prior therapy based on long-term follow-up. Table 10: Number (%) of Patients With Clinically Relevant All Grade or Grade 3/4 Laboratory Test Abnormalities in the Safety Population of the Study of Patients With CML Who Were Resistant or Intolerant to Prior Therapy* C P CML N= 403% A dvP CML N= 143 % All grade Grade 3/4 All grade Grade 3/4 H e m atology Parameters Platelet Count decreased 66 26 80 57 Absolute Neutrophil Count decreased 50 16 66 39 Hemoglobin decreased 89 13 97 38 Lymphocyte decreased 79 14 82 21 White Blood Cell Count decreased 51 7 57 27 Biochemistry Parameters SGPT/ALT increased 58 11 39 6 SGOT/AST increased 50 5 37 3.5 Lipase increased 32 12 19 6 Phosphorus decreased 41 8 33 7 Total Bilirubin increased 16 0.7 22 2.8 Creatinine increased 95 3 87 1.4 Alkaline Phosphatase increased 39 0 39 1.4 Glucose increased 42 2.7 39 6 Sodium increased 23 0.5 11 0 Sodium decreased 18 2.2 27 6 Calcium decreased 55 4.7 45 3.5 Urate increased 49 6 43 6 Magnesium increased 27 7 18 4.9 Potassium decreased 22 1.7 29 4.9 Potassium increased 25 2.7 19 2.1 *Based on a 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 1 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 vasculitis Pediatric use information is approved for PF PRISM CV’s BOSULIF ® (bosutinib) tablets. However, due to PF PRISM CV’s marketing exclusivity rights, this drug product is not labeled with that information. 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Thrombotic microangiopathy Skin and Subcutaneous Tissue Disorders : Stevens-Johnson syndrome

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