Gemtuzumab ozogamicin

12.1 Mechanism of Action Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). The antibody portion (hP67.6) recognizes human CD33 antigen. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumor cells, followed by internalization of the ADC-CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

1 INDICATIONS AND USAGE MYLOTARG is a CD33-directed antibody and cytotoxic drug conjugate indicated for: • treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults and pediatric patients 1 month and older ( 1.1 ). • treatment of relapsed or refractory CD33-positive AML in adults and pediatric patients 2 years and older ( 1.2 ). 1.1 Newly-Diagnosed CD33-positive Acute Myeloid Leukemia (AML) MYLOTARG is indicated for the treatment of newly-diagnosed CD33-positive acute myeloid leukemia in adults and pediatric patients 1 month and older. 1.2 Relapsed or Refractory CD33-positive AML MYLOTARG is indicated for the treatment of relapsed or refractory CD33-positive acute myeloid leukemia in adults and pediatric patients 2 years and older.

2 DOSAGE AND ADMINISTRATION • Newly-diagnosed, de novo AML (combination regimen) Adults : - Induction: 3 mg/m 2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine ( 2.2 ). - Consolidation: 3 mg/m 2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine ( 2.2 ). Pediatric patients 1 month and older : - 3 mg/m 2 for patients with body surface area (BSA) 0.6 m 2 or greater ( 2.2 ). - 0.1 mg/kg for patients with BSA less than 0.6 m 2 ( 2.2 ). - See Full Prescribing Information for complete dosing information ( 2.2 ). • Newly-diagnosed AML (single-agent regimen): Adults : - Induction: 6 mg/m 2 (not limited to one 4.5 mg vial) on Day 1 and 3 mg/m 2 (not limited to one 4.5 mg vial) on Day 8 ( 2.2 ). - Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of MYLOTARG 2 mg/m 2 (not limited to one 4.5 mg vial) on Day 1 every 4 weeks ( 2.2 ). • Relapsed or refractory AML (single-agent regimen): Adults and pediatric patients 2 years and older: - 3 mg/m 2 (up to one 4.5 mg vial) on Days 1, 4, and 7 ( 2.2 ). • Premedicate with a corticosteroid, antihistamine, and acetaminophen ( 2.1 ). 2.1 Premedication and Special Considerations • Premedicate adults with acetaminophen 650 mg orally and diphenhydramine 50 mg orally or intravenously 1 hour prior to MYLOTARG dosing and 1 mg/kg methylprednisolone or an equivalent dose of an alternative corticosteroid within 30 minutes prior to infusion of MYLOTARG. • Premedicate pediatric patients 1 month and older with acetaminophen 15 mg/kg (maximum of 650 mg) and diphenhydramine 1 mg/kg (maximum of 50 mg) 1 hour prior to MYLOTARG dosing, and 1 mg/kg methylprednisolone orally or intravenously within 30 minutes prior to infusion of MYLOTARG; additional doses of acetaminophen and diphenhydramine may be administered every 4 hours after the initial pretreatment dose. Repeat with the same dose of methylprednisolone or an equivalent corticosteroid for any sign of an infusion reaction, such as fever, chills, hypotension, or dyspnea during the infusion or within 4 hours afterwards [see Warnings and Precautions (5.2) ] . • Use appropriate measures to prevent tumor lysis syndrome. • For patients with hyperleukocytosis (leukocyte count greater than or equal to 30 Gi/L), cytoreduction is recommended prior to administration of MYLOTARG. 2.2 Recommended Dosage Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen) Adults The recommended dose of MYLOTARG in adults is 3 mg/m 2 . A treatment course including MYLOTARG in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles [see Clinical Studies (14.1) ] . For the induction cycle, the recommended dose of MYLOTARG is 3 mg/m 2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine . For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle. For the consolidation cycles, the recommended dose of MYLOTARG is 3 mg/m 2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine. Pediatric Patients 1 Month and Older The recommended dose of MYLOTARG in pediatric patients 1 month and older is: • 3 mg/m 2 for patients with body surface area (BSA) greater than or equal to 0.6 m 2 • 0.1 mg/kg for patients with BSA less than 0.6 m 2 For Induction 1, MYLOTARG is given once in combination with standard chemotherapy. No MYLOTARG is given in the second induction cycle [see Clinical Studies (14.1) ]. No MYLOTARG is given in the first or third intensification cycles. For Intensification 2, MYLOTARG is given once in combination with standard chemotherapy. Consider the risks and potential benefits before giving MYLOTARG during Intensification 2 [see Adverse Reactions (6.1) ] . Newly-Diagnosed CD33-positive AML (Single-agent Regimen) A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy [see Clinical Studies (14.1) ]. For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m 2 (not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m 2 (not limited to one 4.5 mg vial) on Day 8. For continuation, the recommended dose of MYLOTARG is 2 mg/m 2 (not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks. Relapsed or Refractory CD33-positive AML (Single-agent Regimen) The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m 2 (up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG [see Clinical Studies (14.2) ] . 2.3 Dosage Modifications for Toxicities Monitor blood counts frequently through resolution of cytopenias

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hepatotoxicity, including VOD [see Warnings and Precautions (5.1) ] • Infusion-related reactions [see Warnings and Precautions (5.2) ] • Hemorrhage [see Warnings and Precautions (5.3) ] The most common adverse reactions (greater than 15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, mucositis, febrile neutropenia, and decreased appetite ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Combination Therapy in Newly-Diagnosed De Novo CD33-positive AML The safety of MYLOTARG in first-line combination therapy was evaluated in two prospective clinical trials, Study ALFA-0701 in adults and Study AAML0531 in pediatric patients. Study ALFA-0701 The safety evaluation of MYLOTARG (3 mg/m 2 Day 1, 4 and 7 in combination with daunorubicin and cytarabine [DA]) in adults is based on data from ALFA-0701 for 131 patients treated with MYLOTARG plus DA and in 137 patients treated with DA alone [see Clinical Studies (14.1) ]. In this study, 123 patients received all 3 fractionated doses of MYLOTARG and 7 patients missed at least 1 dose, with a mean total dose administered during induction of 14.51 mg (range: 4.6–18.0). MYLOTARG was received by 91 (70%) patients in the MYLOTARG arm during Consolidation 1 and 64 (49%) patients in the MYLOTARG arm during Consolidation 2. Safety data consisting of selected TEAEs considered most important for understanding the safety profile of MYLOTARG as well as all adverse events (AEs) that led to the permanent discontinuation of treatment were retrospectively collected. The selected TEAEs consisted of all grades hemorrhages, all grades VOD, and severe infections. Discontinuation due to any adverse reaction occurred in 31% of patients in the MYLOTARG arm versus 7% in the DA arm. The most frequent (greater than or equal to 1%) adverse reactions for patients treated with MYLOTARG that led to permanent discontinuation were thrombocytopenia (15%), VOD (3%), and septic shock (2%). Fatal adverse reactions occurred in 8 patients (6%) in the MYLOTARG arm versus 3 patients (2%) in the DA arm. In the MYLOTARG arm, 3 patients died of VOD, 4 patients died of hemorrhage-related events (CNS hemorrhage, hemorrhagic shock), and 1 patient died of suspected cardiac cause. In the DA arm, 3 patients died of sepsis. Table 2. Selected Grade 3 and Higher Adverse Reactions in Patients with Newly-Diagnosed De Novo AML in ALFA-0701 MYLOTARG + Daunorubicin + Cytarabine (n, %) Daunorubicin + Cytarabine (n, %) Abbreviations: AML=acute myeloid leukemia; N=number of patients; PT=preferred term. Induction N = 131 N = 137 Infection Infection is a grouped term consisting of multiple preferred terms. 61 (47%) 53 (39%) Hemorrhage Hemorrhage is a grouped term consisting of multiple preferred terms. 24 (18%) 12 (9%) Veno-occlusive liver disease Veno-occlusive liver disease includes the following reported PTs: Veno-occlusive liver disease, veno-occlusive disease. 3 (2%) 0 Consolidation 1 N = 91 N = 103 Infection 50 (55%) 43 (42%) Hemorrhage 5 (5%) 0 Veno-occlusive liver disease 0 0 Consolidation 2 N = 64 N = 107 Infection 32 (50%) 54 (50%) Hemorrhage 4 (6%) 0 Veno-occlusive liver disease 0 0 All patients in ALFA-0701 developed severe neutropenia, thrombocytopenia and anemia. The incidence of Grade 3–4 thrombocytopenia that was prolonged in the absence of active leukemia was higher in patients treated with MYLOTARG (Table 3). Table 3. Prolonged Cytopenias Platelets less than 50 Gi/L or neutrophils less than 0.5 Gi/L lasting past cycle Day 42 in the absence of active leukemia. in ALFA-0701 MYLOTARG + Daunorubicin + Cytarabine (n/N, %) Daunorubicin + Cytarabine (n/N, %) Induction Prolonged thrombocytopenia 19/101 (19%) 7/97 (7%) Prolonged neutropenia 3/106 (3%) 0/101 (0%) Consolidation 1 Prolonged thrombocytopenia 21/87 (24%) 6/91 (7%) Prolonged neutropenia 3/88 (3%) 1/97 (1%) Consolidation 2 Prolonged thrombocytopenia 22/62 (35%) 25/103 (24%) Prolonged neutropenia 1/62 (2%) 2/105 (2%) Table 4 summarizes shifts in selected chemistry abnormalities by treatment arm for patients treated in ALFA-0701. Table 4. Chemistry Laboratory Values: Shifts in Subjects with Baseline Grade 2 or Lower Values in ALFA-0701 MYLOTARG + Daunorubicin + Cytarabine Daunorubicin + Cytarabine Laboratory Abnormality Subjects (n) with baseline Grade less than or equal to 2 Progressed to Grade greater than or equal to 3 (n, %) Subjects (n) with baseline Grade less than or equal to 2 Progressed to Grade greater