Mylotarg

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 singl…

5 WARNINGS AND PRECAUTIONS • Infusion-related reactions (including anaphylaxis): Premedicate with a corticosteroid, acetaminophen, and diphenhydramine. Monitor patients during and for at least 1 hour after the end of the infusion. Interrupt the infusion, administer steroids or antihistamines, or permanently discontinue treatment as necessary ( 2.1 , 5.2 , 6 ). • Hemorrhage: Severe, including fatal, hemorrhage may occur when MYLOTARG is used at recommended doses. Monitor platelet counts frequently ( 5.3 , 6.1 ). • Embryo-fetal toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.6 , 8.1 , 8.3 ). 5.1 Hepatotoxicity, Including Veno-occlusive Liver Disease (VOD) Hepatotoxicity, including life-threatening and sometimes fatal hepatic VOD events, have been reported in patients receiving MYLOTARG as a single agent or as part of a combination chemotherapy regimen [see Adverse Reactions (6) ]. In ALFA-0701, VOD events were reported in 6/131 (5%) adult patients during or following treatment with MYLOTARG, or following later hematopoietic stem cell transplantation (HSCT). The median time from the MYLOTARG dose to onset of VOD was 9 days (range: 2–298 days), with 5 events occurring within 28 days of any dose of MYLOTARG and 1 event occurring greater than 28 days after the last dose of MYLOTARG. Three of the 6 VOD events were fatal. VOD was also reported in 2 patients in the control arm of ALFA-0701 after receiving MYLOTARG as a therapy for relapsed AML. In MyloFrance-1 (MYLOTARG 3 mg/m 2 on Days 1, 4 and 7), VOD events were reported in none of the 57 patients during or following treatment, or following HSCT after completion of MYLOTARG treatment. In AAML0531, VOD events were reported in 25/520 (5%) pediatric patients in the MYLOTARG arm. VOD was fatal in 2 patients. Among 187 pediatric patients who underwent HSCT in the MYLOTARG arm, VOD occurred within 30 days post-HSCT in 20 (11%) patients. Based on an analysis across trials, the risk of VOD was higher in adult patients who received higher doses of MYLOTARG as monotherapy, in patients with moderate or severe hepatic impairment prior to receiving MYLOTARG, in patients treated with MYLOTARG after HSCT, and in patients who underwent HSCT after treatment with MYLOTARG. Patients who had moderate/severe hepatic impairment prior to treatment with MYLOTARG were 8.7 times more likely to develop VOD compared to patients without moderate/severe hepatic impairment at baseline. Patients treated with MYLOTARG for relapse after HSCT were 2.6 times more likely to develop VOD compared to patients without prior HSCT. Patients who underwent HSCT following MYLOTARG treatment were 2.9 times more likely to develop VOD after HSCT compared to patients without HSCT following MYLOTARG treatment. Although no relationship was found between VOD and time of HSCT relative to higher MYLOTARG monotherapy doses, the ALFA-0701 study recommended an interval of 2 months between the last dose of MYLOTARG and HSCT. In MyloFrance-1, no patients underwent HSCT within 3.5 months of MYLOTARG therapy. Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose of MYLOTARG. After treatment with MYLOTARG, monitor frequently for signs and symptoms of VOD; these may include elevations in ALT, AST, total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, monitor liver tests frequently during the post-HSCT period, as appropriate. Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation of MYLOTARG [see Dosage and Administration (2.3) ] . In patients who experience VOD, discontinue MYLOTARG and treat according to…

4 CONTRAINDICATIONS MYLOTARG is contraindicated in patients with a history of hypersensitivity to the active substance in MYLOTARG or any of its components or to any of the excipients. Reactions have included anaphylaxis [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . Hypersensitivity to MYLOTARG or any of its components ( 4 ).

8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] , MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on MYLOTARG use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, gemtuzumab ozogamicin caused embryo-fetal toxicity, including structural abnormalities and alterations to growth, at maternal systemic exposures that were greater than or equal to 0.4 times the exposure in patients at the maximum recommended dose based on AUC (see Data ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 is 2–4% and 15–20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received daily intravenous doses up to 1.2 mg/m 2 /day gemtuzumab ozogamicin during the period of organogenesis. Embryo-fetal toxicities including fetal growth retardation as evidenced by decreased live fetal weights, incidence of fetal wavy ribs and delayed skeletal ossification were observed at greater than or equal to 0.15 mg/m 2 /day. Increased embryo-fetal lethality and fetal morphological anomalies (digital malformations, absence of the aortic arch, anomalies in the long bones in the forelimbs, misshapen scapula, absence of a vertebral centrum, and fused sternebrae) were observed at greater than or equal to 0.36 mg/m 2 /day. All doses with embryo-fetal effects were observed in the presence of maternal toxicity that included decreases in gestational body weight gain, food consumption, and gravid uterine weight. The lowest dose at which embryo-fetal effects were observed in rats (0.15 mg/m 2 /day) was 0.4 times the exposure in patients at the maximum recommended human dose, based on AUC.

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 …