Gemtuzumab Ozogamicin

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. Monitor blood counts and chemistries at least three times per week through recovery from treatment-related toxicities. Management of some adverse reactions [see Warnings and Precautions (5) , Adverse Reactions (6) ] may require dose interruptions or permanent discontinuation of MYLOTARG. Table 1 shows the dose modification guidelines for hematologic and nonhematologic toxicities. Table 1. Dosage Modifications for Hematologic and Nonhematologic Toxicities Hematologic and Nonhematologic Toxicities Recommended Action Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; VOD=veno-occlusive disease; ULN=upper limit of normal. For patients receiving MYLOTARG in combination therapy Persistent thrombocytopenia • Adults: If platelet count does not recover to greater than or equal to 100 Gi/L within 14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following previous cycle), discontinue MYLOTARG (do not administer MYLOTARG in the consolidation cycles). • Pediatrics: Patients should have a platelet count of 75 Gi/L before the next cycle (induction or intensification). Persistent neutropenia • Adults: If neutrophil count does not recover to greater than 0.5 Gi/L within 14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following previous cycle), discontinue MYLOTARG (do not administer MYLOTARG in the consolidation cycles). • Pediatrics: Patients should have a neutrophil count of 1 Gi/L before the next cycle (induction or intensification). For all patients receiving MYLOTARG (Monotherapy or in Combination) VOD • Discontinue MYLOTARG [see Warnings and Precautions (5.1) ] . Total bilirubin greater than 2 × ULN, or AST and/or ALT greater than 2.5 × ULN • Delay treatment with MYLOTARG until recovery of total bilirubin to less than or equal to 2 × ULN and AST and ALT to less than or equal to 2.5 × ULN prior to each dose. • Omit scheduled dose if delayed more than 2 days between sequential infusions. Infusion-related reactions • Interrupt the infusion and institute appropriate medical management. • Administer acetaminophen, diphenhydramine and/or methylprednisolone, if needed [see Dosage and Administration (2.1) ] • Provide supportive care measures as needed. • For mild, moderate or severe infusion-related reactions, once symptoms resolve, consider resuming the infusion at no more than half the rate at which the reaction occurred. Repeat the procedure above in the event of recurrence of symptoms. • Permanently discontinue MYLOTARG upon occurrence of a severe infusion reaction or for any life-threatening infusion reaction [see Warnings and Precautions (5.2) ] . Other severe or life-threatening non-hematologic toxicities • Delay treatment with MYLOTARG until recovery to a severity of no more than mild. • Omit scheduled dose if delayed more than 2 days between sequential infusions. 2.4 Instructions for Reconstitution, Dilution, and Administration Use appropriate aseptic technique for the reconstitution and dilution procedures. Protect the reconstituted and diluted MYLOTARG solution from light. Reconstitution • MYLOTARG is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 • Calculate the dose (mg) and number of vials of MYLOTARG required. • Prior to reconstitution, allow drug product vials to reach room temperature (up to 30°C) for approximately 5 minutes. • Reconstitute each vial with 5 mL of Sterile Water for Injection, USP to obtain a concentration of 1 mg/mL of MYLOTARG that delivers 4.5 mL (4.5 mg). • Gently swirl the vial to aid dissolution. DO NOT SHAKE. • Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-like particles. • MYLOTARG contains no bacteriostatic preservatives. • If the reconstituted solution cannot be used immediately, it may be stored in the original vial for up to 16 hours in a refrigerator (2°C to 8°C; 36°F to 46°F) or up to 3 hours at room temperature (up to 30°C). PROTECT FROM LIGHT. DO NOT FREEZE . Dilution • Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial(s) using a syringe. PROTECT FROM LIGHT. Discard any unused reconstituted solution left in the vial. Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to the following instructions: • Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted MYLOTARG solution to a syringe with 0.9% Sodium Chloride Injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT. • Doses greater than or equal to 3.9 mg are to be diluted in a syringe or a polyvinyl chloride (PVC) with di(2-ethylhexyl)phthalate (DEHP), non-PVC polyolefin, or ethylene vinyl acetate intravenous infusion bag in an appropriate volume of 0.9% Sodium Chloride Injection to ensure a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT. • Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE. • Following dilution with 0.9% Sodium Chloride Injection, MYLOTARG solution should be infused immediately. If not used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C to 8°C; 36°F to 46°F) and for up to 6 hours at room temperature (up to 30°C). The allowed time at room temperature (up to 30°C) includes the time required for preparation of the diluted solution, equilibration, if needed, and the 2 hours needed to administer to the patient. PROTECT FROM LIGHT and DO NOT FREEZE. Administration • Use an in-line 0.2 micron polyethersulfone (PES) filter for infusion of MYLOTARG. • Protect the intravenous bag from light using a light-blocking cover during infusion. The infusion line does not need to be protected from light. • Infuse the diluted solution over 2 hours using an infusion set made of polyvinyl chloride (PVC) with DEHP, PVC non-DEHP, polyethylene, or polyurethane. The infusion must be completed prior to the end of the allowed 6-hour storage of the diluted solution at room temperature (up to 30°C). • Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.

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 than or equal to 3 (n, %) Hypophosphatemia 117 75 (64%) 127 52 (41%) Hypokalemia 127 73 (57%) 133 41 (31%) Hyponatremia 129 57 (44%) 134 36 (27%) Alkaline phosphatase increased 120 16 (13%) 128 7 (5%) Aspartate aminotransferase increased 126 18 (14%) 132 11 (8%) Alanine aminotransferase increased 124 13 (10%) 132 20 (15%) Blood bilirubin increased 119 9 (8%) 126 5 (4%) Study AAML0531 The safety evaluation of MYLOTARG in combination with chemotherapy in pediatric patients is based on data from AAML0531 [see Clinical Studies (14.1) ] in randomized and treated patients (N = 520 MYLOTARG and chemotherapy and N = 517 chemotherapy alone). In the MYLOTARG arm of this study, 520 patients received Induction 1 and 326 patients received Intensification 2. Safety data collected included only Grade 3 and 4 nonhematologic adverse events, deaths, VOD/SOS, and prolongation of neutropenia and thrombocytopenia. Table 5 shows the Grade 3 or 4 adverse reactions (≥5%) in the MYLOTARG + chemotherapy or chemotherapy alone arms in patients with newly-diagnosed de novo AML in AAML0531. In the MYLOTARG + chemotherapy arm, fatal adverse reactions (by grouped terms) were infection (14 [3%]), multi-organ failure (5 [1%]), anemia (1 [<1%]), and hemorrhage (3 [<1%]). In the chemotherapy arm, fatal adverse reactions included infection (7 [1%]), multi-organ failure (6 [1%]), hepatic failure (1 [<1%]), hypotension (3 [<1%]), and hemorrhage (3 [<1%]). Table 5. Grade 3 and Higher Adverse Reactions (≥5%) in Patients with Newly-Diagnosed De Novo AML in AAML0531 During Treatment Cycles with MYLOTARG Induction 1 Intensification 2 MYLOTARG + Chemotherapy N = 520 n (%) Chemotherapy alone N = 517 n (%) MYLOTARG + Chemotherapy N = 326 n (%) Chemotherapy alone N = 304 n (%) Infection Grouped term consisting of multiple preferred terms 186 (36%) 181 (35%) 220 (67%) 211 (69%) Febrile neutropenia 167 (32%) 157 (30%) 79 (24%) 68 (22%) Decreased appetite 78 (15%) 79 (15%) 61 (19%) 36 (12%) Hyperglycemia 59 (11%) 55 (11%) 36 (11%) 28 (9%) Mucositis 55 (11%) 64 (12%) 25 (8%) 15 (5%) Hypoxia 35 (7%) 26 (5%) 19 (6%) 22 (7%) Hemorrhage 36 (7%) 19 (4%) 19 (6%) 9 (3%) Transaminase Increased 33 (6%) 24 (5%) 23 (7%) 13 (4%) Diarrhea 21 (4%) 36 (7%) 15 (5%) 10 (3%) Nausea 21 (4%) 18 (4%) 23 (7%) 10 (3%) Hypotension 16 (3%) 26 (5%) 28 (9%) 23 (8%) The addition of MYLOTARG to chemotherapy was associated with a higher incidence of prolonged thrombocytopenia and neutropenia particularly when used in Intensification 2. During Intensification 2, prolonged thrombocytopenia (platelets <50 Gi/L lasting past cycle Day 42 in the absence of active leukemia) was reported in 64% (190/297) of patients in the MYLOTARG + chemotherapy arm compared with 55% (146/264) in the chemotherapy alone arm. Prolonged neutropenia (neutrophils <0.5 Gi/L lasting past cycle Day 42 in the absence of active leukemia) occurred in 47% (142/300) versus 43% (118/275) of patients, respectively. The prolonged cytopenias were associated with more deaths in remission in the MYLOTARG + chemotherapy arm (29 [5%]) compared to the chemotherapy alone arm (15 [3%]). VOD events were reported in 25 (5%) patients in the MYLOTARG + chemotherapy arm as well as 25 (5%) of the chemotherapy alone arm. VOD was fatal in 2 (<1%) and 7 (1%) patients in the MYLOTARG + chemotherapy arm and chemotherapy alone arm, respectively. Monotherapy for Newly-Diagnosed CD33-positive AML The safety evaluation of MYLOTARG (6 mg/m 2 then 3 mg/m 2 , with 7 days between the doses) as monotherapy is based on a randomized, open-label, Phase 3 trial of MYLOTARG (N=118) versus best supportive care (BSC) (N=119) in patients with previously untreated AML who were considered ineligible for intensive chemotherapy in Study AML-19 [see Clinical Studies (14.1) ]. The overall incidence of any Grade adverse reactions reported in AML-19 was 87% in the MYLOTARG arm and 90% in the BSC arm. The incidence of Grade greater than or equal to 3 adverse reactions was 61% in the MYLOTARG arm and 68% in the BSC arm. Death due to any Adverse Event was reported in the MYLOTARG arm of 19 (17%) compared to the BSC arm of 23 (20%). Table 6. Selected Adverse Reactions in AML-19 MYLOTARG n=111 Best Supportive Care n=114 Any Grade Grade ≥3 Any Grade Grade ≥3 Liver 57 (51%) 8 (7%) 52 (46%) 7 (6%) Fatigue 51 (46%) 13 (12%) 69 (61%) 24 (21%) Infection 49 (44%) 39 (35%) 48 (42%) 39 (34%) Cardiac 31 (28%) 7 (6%) 37 (33%) 16 (14%) Bleeding 28 (25%) 14 (13%) 34 (30%) 14 (12%) Febrile neutropenia 20 (18%) 20 (18%) 27 (24%) 27 (24%) Metabolic 18 (16%) 4 (4%) 17 (15%) 7 (6%) Renal 7 (6%) 4 (4%) 9 (8%) 5 (4%) Monotherapy for Relapsed or Refractory CD33-positive AML The adverse reactions described in this section reflect exposure to MYLOTARG 3 mg/m 2 on Days 1, 4 and 7 as monotherapy in 57 patients with relapsed AML treated on MyloFrance-1 [see Clinical Studies (14.1) ] . All 57 (100%) patients received the 3 planned doses of MYLOTARG. During the treatment period, Grade 3 treatment-emergent adverse events (TEAEs) that occurred in greater than 1% patients included sepsis (32%), fever (16%), rash (11%), pneumonia (7%), bleeding (7%), mucositis (4%), pain (4%), diarrhea (2%), headaches (2%), tachycardia (2%), and lung edema (2%). No Grade 4 toxicity was observed. All grade TEAEs that occurred in greater than 15% of patients included fever (79%), infection (42%), increased AST (40%), bleeding (23%), nausea and vomiting (21%), constipation (21%), mucositis (21%), headache (19%), increased ALT (16%), and rash (16%). No infectious deaths occurred. Grade 1 or 2 hyperbilirubinemia developed in 4 (7%) patients. No episodes of VOD occurred. Seven patients received HSCT after MYLOTARG treatment. Three patients received an allogeneic BMT and 4 patients were treated with autologous BMT. No patients developed VOD following HSCT. 6.2 Postmarketing Experience The following adverse drug reactions have been identified during post-approval use of MYLOTARG. 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. Gastrointestinal Disorders: Neutropenic colitis including fatal events Infections and Infestations: fungal lung infections including Pulmonary mycosis and Pneumocystis jirovecii pneumonia ; and bacterial infections including Stenotrophomonas infection Renal and Urinary Disorders: Hemorrhagic cystitis Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonia 6.3 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity of MYLOTARG was not studied in clinical trials using the recommended dose regimens.

12.3 Pharmacokinetics There are no clinical PK data for the fractionated regimen. When gemtuzumab ozogamicin is administered at 9 mg/m 2 (2 doses, 14 days apart), the C max following the first dose for patients who received 9 mg/m 2 gemtuzumab ozogamicin was 3.0 mg/L and increased to 3.6 mg/L after the second dose. Distribution N-acetyl gamma calicheamicin dimethyl hydrazide is approximately 97% bound to human plasma proteins in vitro. Population PK analyses found the total volume of distribution of hP67.6 antibody (sum of V1 [6.31 L] and V2 [15.1 L]) to be approximately 21.4 L in patients. Elimination The clearance (CL) value of hP67.6 from plasma was 0.35 L/h after the first dose and 0.15 L/h after the second dose, a decrease of roughly 60%. The terminal plasma half-life (t ½ ) for hP67.6 was 62 hours after the first dose and 90 hours after the second dose. Metabolism In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolized, primarily via nonenzymatic reduction of the disulfide moiety. Specific Populations Age, race, sex, mild or moderate renal impairment (creatinine clearance [CLcr] 30–89 mL/min calculated by the Cockcroft-Gault equation) or mild hepatic impairment had no clinically significant effect on the pharmacokinetics of gemtuzumab ozogamicin. The pharmacokinetics of gemtuzumab ozogamicin in patients with severe renal impairment (CLcr 15–29 mL/min) or moderate (total bilirubin greater than 1.5× to 3.0× ULN) and severe hepatic impairment (total bilirubin greater than 3× ULN) is unknown. Drug Interaction Studies No clinical drug interaction studies have been performed. In Vitro Studies At clinically relevant concentrations, gemtuzumab ozogamicin had a low potential to: • Inhibit CYP450 Enzymes : CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. At clinically relevant concentrations, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to: • Inhibit CYP450 Enzymes : CYP1A2, CYP2B6 , CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. • Induce CYP450 Enzymes : CYP1A2, CYP2B6, and CYP3A4. • Inhibit UGT Enzymes : UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7. • Inhibit Drug Transporters : P-gp (P-glycoprotein), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3.