Bosutinib

12.1 Mechanism of Action Bosutinib is a 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.

1 INDICATIONS AND USAGE BOSULIF is indicated for the treatment of: • Adult and pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see Clinical Studies ( 14.1 , 14.2 , 14.3 )] . • Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy [see Clinical Studies (14.2) ] . BOSULIF is a kinase inhibitor indicated for the treatment of • adult and pediatric patients 1 year of age and older 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 )

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 ) • Pediatric patients with newly-diagnosed chronic phase Ph+ CML: 300 mg/m 2 orally once daily with food. ( 2.1 ) • Pediatric patients with chronic phase Ph+ CML with resistance or intolerance to prior therapy: 400 mg/m 2 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 ) • Consider dose escalation by increments of 50 mg for those with a BSA <1.1 m 2 and 100 mg for those with a BSA ≥1.1 m 2 to a maximum of 600 mg daily in pediatric patients who do not reach sufficient response after 3 months. ( 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 BOSULIF until disease progression or intolerance to therapy. Capsules may be swallowed whole. For patients who are unable to swallow a whole capsule(s), each capsule can be opened and the contents mixed with applesauce or yogurt. Mixing the capsule contents with applesauce or yogurt cannot be considered a substitute of a proper meal. If a dose is missed beyond 12 hours, the patient should skip the dose and take the usual prescribed dose on the following day. Dosage in Adult Patients with Newly-Diagnosed CP Ph+ CML The recommended dosage of BOSULIF is 400 mg orally once daily with food. Dosage in Adult Patients with CP, AP, or BP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dosage of BOSULIF is 500 mg orally once daily with food. Dosage in Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy The recommended dose of BOSULIF for pediatric patients with newly-diagnosed CP Ph+ CML is 300 mg/m 2 orally once daily with food and the recommended dosage for pediatric patients with CP Ph+ CML that is resistant or intolerant to prior therapy is 400 mg/m 2 orally once daily with food and dose recommendations are provided in Table 1. As appropriate, the desired dose can be attained by combining different strengths of BOSULIF tablets or capsules. Table 1: Dosing of BOSULIF for Pediatric Patients with Newly-Diagnosed CP Ph+ CML or with CP Ph+ CML with Resistance or Intolerance to Prior Therapy BSA BSA=Body Surface Area Newly-Diagnosed Recommended Dose (Once Daily) Resistant or Intolerant Recommended Dose (Once Daily) < 0.55 m 2 150 mg 200 mg 0.55 to < 0.63 m 2 200 mg 250 mg 0.63 to < 0.75 m 2 200 mg 300 mg 0.75 to < 0.9 m 2 250 mg 350 mg 0.9 to < 1.1 m 2 300 mg 400 mg ≥ 1.1 m 2 400 mg maximum starting dose (corresponding to maximum starting dose in adult indication) 500 mg Preparation Instructions for BOSULIF Capsules Mixed with Applesauce or Yogurt For patients who are unable to swallow capsules, the contents of the capsules can be mixed with applesauce or yogurt. Remove the required number of capsules from the container to prepare the dose as instructed and the amount of either room temperature applesauce or yogurt in a clean container. Carefully open each capsule, add the entire capsule content of each capsule into the applesauce or yogurt, then mix the entire dose into the applesauce or yogurt. Patients should immediately consume the full mixture in its entirety, without chewing. Do not store the mixture for later use. If the entire preparation is not swallowed do not take an additional dose. Wait until the next day to resume dosing. Table 2: BOSULIF Dose Using Capsules and Soft Food Volumes Dose Volume of Applesauce or Yogurt 100 mg 10 mL (2 teaspoons) 150 mg 15 mL (3 teaspoons) 200 mg 20 mL (4 teaspoons) 250 mg 25 mL (5 teaspoons) 300 mg 30 mL (6 teaspoons) 350 mg 30 mL (6 teaspoons) 400 mg 35 mL (7 teaspoons) 450 mg 40 mL (8 teaspoons) 500 mg 45 mL (9 teaspoons) 550 mg 45 mL (9 teaspoons) 600 mg 50 mL (10 teaspoons) 2.2 Dose Escalation In clinical studies of adult patients with Ph+ CML, dose escalation by increments of 100 mg once daily to a maximum of 600 mg once daily was allowed in patients who did not achieve or maintain a hematologic, cytogenetic, or molecular response and who did not have Grade 3 or higher adverse reactions at the recommended starting dosage. In pediatric patients with BSA <1.1 m 2 and an insufficient response after 3 months consider increasing dose by 50 mg increments up to maximum of 100 mg above starting dose. Dose increases for insufficient response in pediatric patients with BSA ≥1.1 m 2 can be conducted similarly to adult recommendations in 100 mg increments. The

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 and pediatric patients with CML are diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite respiratory tract infection, and constipation. The most common laboratory abnormalities (≥20%) in adult and pediatric 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 Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions, in ≥20% of adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%). The most common adverse reactions, in ≥20% of pediatric patients (N=49) were diarrhea (82%), abdominal pain (73%), vomiting (55%), nausea (49%), rash (49%), fatigue (37%), hepatic dysfunction (37%), headache (35%), pyrexia (31%), decreased appetite (27%), and constipation (20%). The most common laboratory abnormalities that worsened from baseline in ≥20% of pediatric patients were creatinine increased (92%), alanine aminotransferase increased (59%), white blood cell count decreased (53%), aspartate aminotransferase increased (51%), platelet count decreased (49%), glucose increased (41%), calcium decreased (31%), hemoglobin decreased (31%), neutrophil count decreased (31%), lymphocyte count decreased (29%), serum amylase increased (27%), and CPK increased (25%). Adverse Reactions in Adult Patients With Newly-Diagnosed CP CML The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents (Newly-Diagnosed CP CML Study) [see Clinical Studies (14.1) ] . The safety population (received at least 1 dose of BOSULIF) included: • two hundred sixty-eight (268) patients with newly-diagnosed CP CML had a median duration of BOSULIF treatment of 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 mg/day. Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib. Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of patients included hepatic dysfunction (9%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%), neutropenia (7%), abdominal pain (6%), rash (5%). The most common adverse reactions, in >

7 DRUG INTERACTIONS • Strong and Moderate CYP3A Inhibitors: Avoid concomitant use with BOSULIF. ( 7.1 ) • Strong CYP3A Inducers: Avoid concomitant use with BOSULIF. ( 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 BOSULIF Strong or Moderate CYP3A Inhibitors Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF. 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 BOSULIF. 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 BOSULIF 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 BOSULIF 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 BOSULIF efficacy.