PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 0.9 mg Vial Label. PfizerNDC 0008-0100-01 Rx only BESPONSA(TM)(inotuzumab ozogamicin) for Injection 0.9 mg/vialFor Intravenous Infusion OnlyNo PreservativesSingle-dose vial.Discard unused portion.. PRINCIPAL DISPLAY PANEL 0.9 mg Vial Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients.

ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the label:Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)] Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)] Myelosuppression [see Warnings and Precautions (5.3)] Infusion related reactions [see Warnings and Precautions (5.4)] QT interval prolongation [see Warnings and Precautions (5.5)] Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)] Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)] Myelosuppression [see Warnings and Precautions (5.3)] Infusion related reactions [see Warnings and Precautions (5.4)] QT interval prolongation [see Warnings and Precautions (5.5)] The most common (>= 20%) adverse reactions are thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia. (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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions described in this section reflect exposure to BESPONSA in 164 patients with relapsed or refractory ALL who participated in randomized clinical study of BESPONSA versus Investigators choice of chemotherapy (fludarabine cytarabine granulocyte colony-stimulating factor [FLAG], mitoxantrone cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (INO-VATE ALL Trial [NCT01564784]) [see Clinical Studies (14)].Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18-78 years), 56% were male, 68% had received prior treatment regimen for ALL, 31% had received prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black. In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range: 0.1-26.4 weeks), with median of treatment cycles started in each patient. In patients who received Investigators choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1-15.6 weeks), with median of treatment cycle started in each patient.In patients who received BESPONSA, the most common (>= 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.In patients who received BESPONSA, the most common (>= 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue. In patients who received BESPONSA, the most common (>= 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (>= 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (>= 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following HSCT after completion of treatment [see Warnings and Precautions (5.1)]. Table shows the adverse reactions with >= 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigators choice of chemotherapy.Table 6. Adverse Reactions With >= 10% IncidenceOnly adverse reactions with >= 10% incidence in the BESPONSA arm are included. in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigators Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)Body System Adverse ReactionBESPONSA(N=164)FLAG, MXN/Ara-C, or HIDAC(N=14319 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.)All Grades>= Grade 3All Grades>= Grade 3%%%%Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle Day within 42 days after the last dose of BESPONSA, but prior to the start of new anticancer treatment (including HSCT).Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.Severity grade of adverse reactions were according to NCI CTCAE version 3.0.Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine cytarabine granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.Infections InfectionInfection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. 48287654Blood and lymphatic system disorders ThrombocytopeniaThrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia. 51426159 NeutropeniaNeutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased. 49484543 AnemiaAnemia includes the following reported preferred terms: Anemia and Hemoglobin decreased. 36245947 LeukopeniaLeukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased. 35334342 Febrile neutropenia26265353 LymphopeniaLymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia. 18162726Metabolism and nutrition disorders Decreased appetite121132Nervous system disorders HeadacheHeadache includes the following reported preferred terms: Headache, Migraine, and Sinus headache. 282271Vascular disorders HemorrhageHemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage. 335285Gastrointestinal disorders Nausea312460 Abdominal painAbdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain. 233231 Diarrhea171381 Constipation160240 Vomiting151240 StomatitisStomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis. 132263Hepatobiliary disorders Hyperbilirubinemia215176General disorders and administration site conditions FatigueFatigue includes the following reported preferred terms: Asthenia and Fatigue. 355253 Pyrexia323426 Chills110110Investigations Transaminases increasedTransaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia. 267135 Gamma-glutamyltransferase increased211084 Alkaline phosphatase increased13270Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).Table shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigators choice of chemotherapy.Table 7. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigators Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) BESPONSAFLAG, MXN/Ara-C, or HIDAC All GradesGrade 3/4All GradesGrade 3/4Laboratory AbnormalityLaboratory abnormalities were summarized up to the end of treatment 42 days but prior to the start of new anti-cancer therapy. N%%N%%Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0.Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine cytarabine granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events.HematologyPlatelet count decreased161987614210099Hemoglobin decreased161944014210070Leukocytes decreased16195821429998Neutrophil count decreased16094861309388Lymphocytes (absolute) decreased16093711279791ChemistryGGT increased14867181116817AST increased160714134384ALP increased158571133523ALT increased161494137464Blood bilirubin increased161365138356Lipase increased139321390202Hyperuricemia158163122110Amylase increased14315210291. 6.2Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to inotuzumab ozogamicin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In clinical studies of BESPONSA in patients with relapsed or refractory ALL, the immunogenicity of BESPONSA was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera tested positive for anti-inotuzumab ozogamicin antibodies, cell-based luminescence assay was performed to detect neutralizing antibodies. In clinical studies of BESPONSA in patients with relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment.

BOXED WARNING SECTION.

WARNING: HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE (VOD) (ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME and INCREASED RISK OF POST-HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITY. WARNING: HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE (VOD) (ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME and INCREASED RISK OF POST- HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITYSee full prescribing information for complete boxed warning.Hepatotoxicity, including fatal and life-threatening VOD occurred in patients who received BESPONSA. (5.1)A higher post-HSCT non-relapse mortality rate occurred in patients receiving BESPONSA (5.2). Hepatotoxicity, including fatal and life-threatening VOD occurred in patients who received BESPONSA. (5.1). higher post-HSCT non-relapse mortality rate occurred in patients receiving BESPONSA (5.2). HEPATOTOXICITY, INCLUDING VODHepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing alkylating agents and last total bilirubin level >= upper limit of normal (ULN) before HSCT were significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and greater number of BESPONSA treatment cycles. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Hepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing alkylating agents and last total bilirubin level >= upper limit of normal (ULN) before HSCT were significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and greater number of BESPONSA treatment cycles. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. INCREASED RISK OF POST-HSCT NON-RELAPSE MORTALITYThere was higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in higher Day 100 post-HSCT mortality rate [see Warnings and Precautions (5.2)].. There was higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in higher Day 100 post-HSCT mortality rate [see Warnings and Precautions (5.2)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In toxicity studies, rats were dosed weekly for or 26 weeks with inotuzumab ozogamicin at doses up to 4.1 mg/m2 and 0.73 mg/m2, respectively. After 26 weeks of dosing, rats developed hepatocellular adenomas in the liver at 0.73 mg/m2 (approximately times the exposure in patients at the maximum recommended dose, based on AUC).Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice that received single doses >=1.1 mg/m2. This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin dimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in an in vitro bacterial reverse mutation (Ames) assay.In female fertility and early embryonic development study, female rats were administered daily intravenous doses of inotuzumab ozogamicin up to 0.11 mg/m2 for weeks before mating through Day of pregnancy. An increase in the proportion of resorptions and decrease in the number of viable embryos and gravid uterine weights were observed at the 0.11 mg/m2 dose level (approximately times the exposure in patients at the maximum recommended dose, based on AUC). Additional findings in female reproductive organs occurred in repeat-dose toxicology studies and included decreased ovarian and uterine weights, and ovarian and uterine atrophy. Findings in male reproductive organs occurred in repeat-dose toxicology studies and included decreased testicular weights, testicular degeneration, hypospermia, and prostatic and seminal vesicle atrophy. Testicular degeneration and hypospermia were nonreversible following 4-week nondosing period. In the chronic studies of 26-weeks duration, adverse effects on reproductive organs occurred at >=0.07 mg/m2 in male rats and at 0.73 mg/m2 in female monkeys [see Use in Specific Populations (8.3)].

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Inotuzumab ozogamicin is CD22-directed antibody-drug conjugate (ADC). Inotuzumab recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is cytotoxic agent that is covalently attached to the antibody via linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death. 12.2 Pharmacodynamics. During the treatment period, the pharmacodynamic response to BESPONSA was characterized by the depletion of CD22-positive leukemic blasts.. Cardiac ElectrophysiologyIn randomized clinical study in patients with relapsed or refractory ALL, increases in QTcF of >= 60 msec from baseline were measured in 4/162 patients (3%) in the BESPONSA arm and 3/124 patients (2%) in the Investigators choice of chemotherapy arm. Increases in QTcF of 500 msec were observed in none of the patients in the BESPONSA arm and 1/124 patients (1%) in the Investigators choice of chemotherapy arm. Central tendency analysis of the QTcF interval changes from baseline showed that the highest mean (upper bound of the 2-sided 90% CI) for QTcF was 15.3 (21.1) msec, which was observed at Cycle 4/Day 1/1 hour in the BESPONSA arm [see Warnings and Precautions (5.5)]. 12.3 Pharmacokinetics. The mean Cmax of inotuzumab ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ngh/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4. Following administration of multiple doses, 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4. DistributionN-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L. EliminationThe pharmacokinetics of inotuzumab ozogamicin was well characterized by 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h and the terminal half-life (t 1/2 was 12.3 days. Following administration of multiple doses, 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4. MetabolismIn vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. In humans, N-acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation.. Specific PopulationsThe effect of intrinsic factors on inotuzumab ozogamicin pharmacokinetics was assessed using population pharmacokinetic analysis unless otherwise specified. Age (18 to 92 years of age), sex, and race (Asian versus non-Asian [Caucasian, Black, and Unspecified]) had no clinically significant effect on the pharmacokinetics of inotuzumab ozogamicin. Body surface area was found to significantly affect inotuzumab ozogamicin disposition. BESPONSA is dosed based on body surface area [see Dosage and Administration (2.1)]. Patients with Renal ImpairmentThe clearance of inotuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr; based on the Cockcroft-Gault formula] 60-89 mL/min; n=237), moderate renal impairment (CLcr 30-59 mL/min; n=122), or severe renal impairment (CLcr 15-29 mL/min; n=4) was similar to patients with normal renal function (CLcr >=90 mL/min; n=402). The safety and efficacy of inotuzumab ozogamicin in patients with end stage renal disease with or without hemodialysis is unknown.. Patients with Hepatic ImpairmentThe clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin <=ULN and AST ULN, or total bilirubin >1.0-1.5 ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST <=ULN; n=611). There is insufficient data in patients with moderate and severe hepatic impairment (total bilirubin >1.5 ULN).. Drug Interactions. In vitro. Effect of Metabolic Pathways and Transporter Systems on BESPONSA N-acetyl-gamma-calicheamicin dimethylhydrazide is substrate of P-glycoprotein (P-gp).. Effect of BESPONSA on Metabolic Pathways and Transporter SystemsAt clinically relevant concentrations, N-acetyl-gamma-calicheamicin dimethylhydrazide had low potential to:Inhibit cytochrome P450 (CYP 450) 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, 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.At clinically relevant concentrations, inotuzumab ozogamicin had low potential to: Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.. Inhibit cytochrome P450 (CYP 450) 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, 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.. Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.. Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.

CLINICAL STUDIES SECTION.

14. CLINICAL STUDIES. Patients With Relapsed or Refractory ALL INO-VATE ALLThe safety and efficacy of BESPONSA were evaluated in INO-VATE ALL (NCT01564784) randomized (1:1), open-label, international, multicenter study in patients with relapsed or refractory ALL. Patients were stratified at randomization based on duration of first remission (< 12 months or >= 12 months, salvage treatment (Salvage or 2) and patient age at randomization (< 55 or >= 55 years). Eligible patients were >= 18 years of age with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. All patients were required to have >= 5% bone marrow blasts and to have received or previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least tyrosine kinase inhibitor and standard chemotherapy. Table shows the dosing regimen used to treat patients.Among all 326 patients who were randomized to receive BESPONSA (N=164) or Investigators choice of chemotherapy (N=162), 215 patients (66%) had received prior treatment regimen for ALL and 108 patients (33%) had received prior treatment regimens for ALL. The median age was 47 years (range: 18-79 years), 276 patients (85%) had Philadelphia chromosome-negative ALL, 206 patients (63%) had duration of first remission 12 months, and 55 patients (17%) had undergone HSCT prior to receiving BESPONSA or Investigators choice of chemotherapy. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics. All evaluable patients had B-cell precursor ALL that expressed CD22, with >= 90% of evaluable patients exhibiting >= 70% leukemic blast CD22 positivity prior to treatment, as assessed by flow cytometry performed at central laboratory. The efficacy of BESPONSA was established on the basis of CR, the duration of CR, and proportion of MRD-negative CR (< x 10-4 of bone marrow nucleated cells by flow cytometry) in the first 218 patients randomized. CR, duration of remission (DoR), and MRD results in the initial 218 randomized patients were consistent with those seen in all 326 randomized patients.Among the initial 218 randomized patients, 64/88 (73%) and 21/88 (24%) of responding patients per EAC achieved CR/CRi in Cycles and 2, respectively, in the BESPONSA arm, and 29/32 (91%) and 1/32 (3%) of responding patients per EAC achieved CR/CRi in Cycles and 2, respectively, in the Investigators choice of chemotherapy arm. Table shows the efficacy results from this study.Table 8. Efficacy Results in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigators Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) CRCR, per EAC, was defined as 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets >= 100 109/L and absolute neutrophil counts [ANC] >= x 109/L) and resolution of any extramedullary disease. CRiCRi, per EAC, was defined as 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets 100 109/L and/or ANC 1 109/L) and resolution of any extramedullary disease. CR/CRi BESPONSA(N=109)HIDAC, FLAG, or MXN/Ara-C(N=109)BESPONSA(N=109)HIDAC, FLAG or MXN/Ara-C(N=109)BESPONSA(N=109)HIDAC, FLAG, or MXN/Ara-C(N=109)Abbreviations: CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; DoR=duration of remission; EAC=Endpoint Adjudication Committee; FLAG=fludarabine cytarabine granulocyte colony-stimulating factor; HIDAC=high-dose cytarabine; HR=hazard ratio; MRD=minimal residual disease; MXN/AraC=mitoxantrone cytarabine; N/n=number of patients; OS=overall survival; PFS=progression-free survival. Responding (CR/CRi) patientsn (%)[95% CI]39 (35.8)[26.8-45.5]19 (17.4)[10.8-25.9]49 (45.0)[35.4-54.8]13 (11.9)[6.5-19.5]88 (80.7)[72.1-87.7]32 (29.4)[21.0-38.8]p-value1-sided p-value using Chi-squared test. <0.0001DoRDoR, based on later cutoff date than the CR/CRi, was defined for patients who achieved CR/CRi per Investigators assessment as time since first response of CR or CRi+ per Investigators assessment to the date of PFS event or censoring date if no PFS event was documented. n391845148432Median, months[95% CI]8.0[4.9-10.4]4.9[2.9-7.2]4.6[3.7-5.7]2.9[0.6-5.7]5.4[4.2-8.0]3.5[2.9-6.6]MRD-negativityMRD-negativity was defined by flow cytometry as leukemic cells comprising 1 10-4 (< 0.01%) of bone marrow nucleated cells. n356343699RateRate was defined as the number of patients who achieved MRD negativity divided by the total number of patients who achieved CR/CRi per EAC. (%)[95% CI]35/39 (89.7)[75.8-97.1]6/19 (31.6)[12.6-56.6]34/49 (69.4)[54.6-81.7]3/13 (23.1)[5.0-53.8]69/88 (78.4)[68.4-86.5]9/32 (28.1)[13.7-46.7]Among the initial 218 patients, as per EAC assessment, 32/109 patients (29%) in the BESPONSA arm achieved complete remission with partial hematologic recovery (CRh; defined as <5% blasts in the bone marrow, ANC 0.5 109/L, and platelet counts 50 109/L but not meeting full recovery of peripheral blood counts) versus 6/109 patients (6%) in the Investigators choice of chemotherapy arm, and 71/109 patients (65%) in the BESPONSA arm achieved CR/CRh versus 25/109 patients (23%) in the Investigators choice of chemotherapy arm.Overall, 79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the Investigators choice of chemotherapy arm had follow-up HSCT.Figure shows the analysis of overall survival (OS). The analysis of OS did not meet the pre-specified boundary for statistical significance. Figure 1. Kaplan-Meier Curve for Overall Survival (Intent-to-Treat Population) Figure 1.

CONTRAINDICATIONS SECTION.

4. CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11. DESCRIPTION. Inotuzumab ozogamicin is CD22-directed antibody-drug conjugate (ADC) consisting of components: 1) the recombinant humanized immunoglobulin class subtype (IgG4) kappa antibody inotuzumab, specific for human CD22, 2) N-acetyl-gamma-calicheamicin that causes double-stranded DNA breaks, and 3) an acid-cleavable linker composed of the condensation product of 4-(4-acetylphenoxy)-butanoic acid (AcBut) and 3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide) that covalently attaches N-acetyl-gamma-calicheamicin to inotuzumab. Inotuzumab ozogamicin has an approximate molecular weight of 160 kDa. The average number of calicheamicin derivative molecules conjugated to each inotuzumab molecule is approximately with distribution from 2-8. Inotuzumab ozogamicin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the semisynthetic calicheamicin derivative is produced by microbial fermentation followed by synthetic modification. BESPONSA (inotuzumab ozogamicin) for Injection is supplied as sterile, white to off-white, preservative-free, lyophilized powder for intravenous administration. Each single-dose vial delivers 0.9 mg inotuzumab ozogamicin. Inactive ingredients are polysorbate 80 (0.36 mg), sodium chloride (2.16 mg), sucrose (180 mg), and tromethamine (8.64 mg). After reconstitution with mL of Sterile Water for Injection, USP, the final concentration is 0.25 mg/mL of inotuzumab ozogamicin with deliverable volume of 3.6 mL (0.9 mg) and pH of approximately 8.0. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION. Pre-medicate with corticosteroid, antipyretic, and antihistamine prior to all infusions. (2.2) Dosing regimens for Cycle and subsequent cycles, depending on the response to treatment, are shown below. See full prescribing information for dosing details. (2) Day 1Day 8Day 15Dosing regimen for Cycle 1All patients: Dose0.8 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length21 daysFor patients who achieve CR or CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21). Dosing regimen for subsequent cycles depending on response to treatmentPatients who have achieved CR or CRi: Dose0.5 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length28 daysPatients who have not achieved CR or CRi: Dose0.8 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length28 days See full prescribing information for instructions on reconstitution of lyophilized powder, and preparation and administration of reconstituted drug. (2.4). Pre-medicate with corticosteroid, antipyretic, and antihistamine prior to all infusions. (2.2) Dosing regimens for Cycle and subsequent cycles, depending on the response to treatment, are shown below. See full prescribing information for dosing details. (2) Day 1Day 8Day 15Dosing regimen for Cycle 1All patients: Dose0.8 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length21 daysFor patients who achieve CR or CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21). Dosing regimen for subsequent cycles depending on response to treatmentPatients who have achieved CR or CRi: Dose0.5 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length28 daysPatients who have not achieved CR or CRi: Dose0.8 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length28 days See full prescribing information for instructions on reconstitution of lyophilized powder, and preparation and administration of reconstituted drug. (2.4). 2.1Recommended Dosage. Pre-medicate before each dose [see Dosage and Administration (2.2)]. For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m2 per cycle, administered as divided doses on Day (0.8 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Cycle is weeks in duration, but may be extended to weeks if the patient achieves complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity. For subsequent cycles: In patients who achieve CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m2 per cycle, administered as divided doses on Day (0.5 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are weeks in duration. ORIn patients who do not achieve CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m2 per cycle given as divided doses on Day (0.8 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are weeks in duration. Patients who do not achieve CR or CRi within cycles should discontinue treatment. For patients proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment with BESPONSA is cycles. third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after cycles [see Warnings and Precautions (5.1)]. For patients not proceeding to HSCT, additional cycles of treatment, up to maximum of cycles, may be administered. Table shows the recommended dosing regimens.Table 1. Dosing Regimen for Cycle and Subsequent Cycles Depending on Response to TreatmentDay 1Day 8+/- days (maintain minimum of days between doses). Day 15 Abbreviations: CR=complete remission; CRi=complete remission with incomplete hematologic recovery.Dosing regimen for Cycle 1All patients: DoseDose is based on the patients body surface area (m2). 0.8 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length21 daysFor patients who achieve CR or CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21). Dosing regimen for subsequent cycles depending on response to treatmentPatients who have achieved CRCR is defined as 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets >= 100 109/L and absolute neutrophil counts [ANC] >= x 109/L) and resolution of any extramedullary disease. or CRiCRi is defined as 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets 100 109/L and/or ANC 1 109/L) and resolution of any extramedullary disease. Dose 0.5 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length28 days7-day treatment-free interval starting on Day 21. Patients who have not achieved CR or CRi: Dose 0.8 mg/m2 0.5 mg/m2 0.5 mg/m2 Cycle length28 days Pre-medicate before each dose [see Dosage and Administration (2.2)]. For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m2 per cycle, administered as divided doses on Day (0.8 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Cycle is weeks in duration, but may be extended to weeks if the patient achieves complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity. For subsequent cycles: In patients who achieve CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m2 per cycle, administered as divided doses on Day (0.5 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are weeks in duration. ORIn patients who do not achieve CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m2 per cycle given as divided doses on Day (0.8 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are weeks in duration. Patients who do not achieve CR or CRi within cycles should discontinue treatment. In patients who achieve CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m2 per cycle, administered as divided doses on Day (0.5 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are weeks in duration. OR. In patients who do not achieve CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m2 per cycle given as divided doses on Day (0.8 mg/m2), Day (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are weeks in duration. Patients who do not achieve CR or CRi within cycles should discontinue treatment.. For patients proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment with BESPONSA is cycles. third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after cycles [see Warnings and Precautions (5.1)]. For patients not proceeding to HSCT, additional cycles of treatment, up to maximum of cycles, may be administered. 2.2Recommended Pre-medications and Cytoreduction. Premedication with corticosteroid, antipyretic, and antihistamine is recommended prior to dosing. Patients should be observed during and for at least hour after the end of infusion for symptoms of infusion related reactions [see Warnings and Precautions (5.4)].For patients with circulating lymphoblasts, cytoreduction with combination of hydroxyurea, steroids, and/or vincristine to peripheral blast count of less than or equal to 10,000/mm3 is recommended prior to the first dose. Premedication with corticosteroid, antipyretic, and antihistamine is recommended prior to dosing. Patients should be observed during and for at least hour after the end of infusion for symptoms of infusion related reactions [see Warnings and Precautions (5.4)].. For patients with circulating lymphoblasts, cytoreduction with combination of hydroxyurea, steroids, and/or vincristine to peripheral blast count of less than or equal to 10,000/mm3 is recommended prior to the first dose. 2.3Dose Modification. Modify the dose of BESPONSA for toxicities (see Tables 2-4). BESPONSA doses within treatment cycle (i.e., Days and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within cycle are recommended for non-hematologic toxicities. If the dose is reduced due to BESPONSA-related toxicity, the dose must not be re-escalated. Table 2. BESPONSA Dose Modifications for Hematologic ToxicitiesCriteriaBESPONSA Dose Modification(s)Abbreviation: ANC=absolute neutrophil count.If prior to BESPONSA treatment ANC was greater than or equal to x 109/LIf ANC decreases, then interrupt the next cycle of treatment until recovery of ANC to greater than or equal to x 109/L. Discontinue BESPONSA if low ANC persists for greater than 28 days and is suspected to be related to BESPONSA.If prior to BESPONSA treatment platelet count was greater than or equal to 50 109/LPlatelet count used for dosing should be independent of blood transfusion. If platelet count decreases, then interrupt the next cycle of treatment until platelet count recovers to greater than or equal to 50 109/L. Discontinue BESPONSA if low platelet count persists for greater than 28 days and is suspected to be related to BESPONSA.If prior to BESPONSA treatment ANC was less than x 109/L and/or platelet count was less than 50 109/L If ANC or platelet count decreases, then interrupt the next cycle of treatment until at least one of the following occurs: -ANC and platelet counts recover to at least baseline levels for the prior cycle, or-ANC recovers to greater than or equal to x 109/L and platelet count recovers to greater than or equal to 50 109/L, or-Stable or improved disease (based on most recent bone marrow assessment) and the ANC and platelet count decrease is considered to be due to the underlying disease (not considered to be BESPONSA-related toxicity). Table 3. BESPONSA Dose Modifications for Non-hematologic Toxicities Non-hematologic ToxicityDose Modification(s)Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; VOD=venoocclusive disease.VOD or other severe liver toxicity Permanently discontinue treatment [see Warnings and Precautions (5.1)].Total bilirubin greater than 1.5 ULN and AST/ALT greater than 2.5 ULNInterrupt dosing until recovery of total bilirubin to less than or equal to 1.5 ULN and AST/ALT to less than or equal to 2.5 ULN prior to each dose unless due to Gilberts syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 ULN or AST/ALT does not recover to less than or equal to 2.5 ULN [see Warnings and Precautions (5.1)].Infusion related reactionInterrupt the infusion and institute appropriate medical management. Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue treatment [see Warnings and Precautions (5.4)].Non-hematologic toxicity greater than or equal to Grade 2Severity grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Interrupt treatment until recovery to Grade or pre-treatment grade levels prior to each dose. Table 4.BESPONSA Dose Modifications Depending on Duration of Dosing Interruption Due to Non-Hematologic Toxicity ToxicitiesDuration of Dose Interruption Due to ToxicityDose Modification(s)Less than days (within cycle) Interrupt the next dose (maintain minimum of days between doses).Greater than or equal to daysOmit the next dose within the cycle. Greater than or equal to 14 daysOnce adequate recovery is achieved, decrease the total dose by 25% for the subsequent cycle. If further dose modification is required, then reduce the number of doses to per cycle for subsequent cycles. If 25% decrease in the total dose followed by decrease to doses per cycle is not tolerated, then permanently discontinue treatment.Greater than 28 days Consider permanent discontinuation of treatment.. -ANC and platelet counts recover to at least baseline levels for the prior cycle, or. -ANC recovers to greater than or equal to x 109/L and platelet count recovers to greater than or equal to 50 109/L, or. -Stable or improved disease (based on most recent bone marrow assessment) and the ANC and platelet count decrease is considered to be due to the underlying disease (not considered to be BESPONSA-related toxicity). 2.4Instructions for Reconstitution, Dilution, and Administration. Protect the reconstituted and diluted BESPONSA solutions from light. Do not freeze the reconstituted or diluted solution. The maximum time from reconstitution through the end of administration should be less than or equal to hours, with less than or equal to hours between reconstitution and dilution. Reconstitution:BESPONSA is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Calculate the dose (mg) and number of vials of BESPONSA required. Reconstitute each vial with mL of Sterile Water for Injection, USP, to obtain concentration of 0.25 mg/mL of BESPONSA that delivers 3.6 mL (0.9 mg). Gently swirl the vial to aid dissolution. DO NOT SHAKE. Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution should be clear to opalescent, colorless to slightly yellow, and essentially free of visible foreign matter. See Table for storage times and conditions for the reconstituted solution.. BESPONSA is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Calculate the dose (mg) and number of vials of BESPONSA required. Reconstitute each vial with mL of Sterile Water for Injection, USP, to obtain concentration of 0.25 mg/mL of BESPONSA that delivers 3.6 mL (0.9 mg). Gently swirl the vial to aid dissolution. DO NOT SHAKE. Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution should be clear to opalescent, colorless to slightly yellow, and essentially free of visible foreign matter. See Table for storage times and conditions for the reconstituted solution.. Dilution:Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to the patients body surface area. Withdraw this amount from the vial(s) using syringe. Discard any unused reconstituted BESPONSA solution left in the vial.Add reconstituted solution to an infusion container with 0.9% Sodium Chloride Injection, USP, to make total volume of 50 mL. An infusion container made of polyvinyl chloride (PVC) (di(2-ethylhexyl)phthalate [DEHP]- or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) is recommended.Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.See Table for storage times and conditions for the diluted solution. Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to the patients body surface area. Withdraw this amount from the vial(s) using syringe. Discard any unused reconstituted BESPONSA solution left in the vial.. Add reconstituted solution to an infusion container with 0.9% Sodium Chloride Injection, USP, to make total volume of 50 mL. An infusion container made of polyvinyl chloride (PVC) (di(2-ethylhexyl)phthalate [DEHP]- or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) is recommended.. Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.. See Table for storage times and conditions for the diluted solution. Administration:See Table for storage times and conditions for prior to and during administration of the diluted solution.Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-,or hydrophilic polysulfone (HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE). Infuse the diluted solution for hour at rate of 50 mL/h at room temperature (20-25C; 68-77F). Infusion lines made of PVC (DEHP- or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.Do not mix BESPONSA or administer as an infusion with other medicinal products. Table shows the storage times and conditions for reconstitution, dilution, and administration of BESPONSA.Table 5. Storage Times and Conditions for Reconstituted and Diluted BESPONSA Solution Maximum time from reconstitution through end of administration less than or equal to hoursWith less than or equal to hours between reconstitution and dilution. Diluted SolutionReconstituted SolutionAfter Start of DilutionAdministrationBESPONSA contains no bacteriostatic preservatives. Use reconstituted solution immediately or after being refrigerated (2-8C; 36-46F) for up to hours. PROTECT FROM LIGHT. DO NOT FREEZE. Use diluted solution immediately or after storage at room temperature (20-25C; 68-77F) for up to hours or being refrigerated (2-8C; 36-46F) for up to hours. PROTECT FROM LIGHT. DO NOT FREEZE. If the diluted solution is refrigerated (2-8C; 36-46F), allow it to equilibrate at room temperature (20-25C; 68-77F) for approximately hour prior to administration. Administer diluted solution within hours of reconstitution as 1-hour infusion at rate of 50 mL/h at room temperature (20-25C; 68-77F). PROTECT FROM LIGHT.. See Table for storage times and conditions for prior to and during administration of the diluted solution.. Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-,or hydrophilic polysulfone (HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE). Infuse the diluted solution for hour at rate of 50 mL/h at room temperature (20-25C; 68-77F). Infusion lines made of PVC (DEHP- or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.

DOSAGE FORMS & STRENGTHS SECTION.

3. DOSAGE FORMS AND STRENGTHS. For Injection: 0.9 mg as white to off-white lyophilized powder in single-dose vial for reconstitution and further dilution.. For injection: 0.9 mg lyophilized powder in single-dose vial for reconstitution and further dilution. (3).

DRUG INTERACTIONS SECTION.

7. DRUG INTERACTIONS. Drugs That Prolong the QT IntervalConcomitant use of BESPONSA with drugs known to prolong the QT interval or induce Torsades de Pointes may increase the risk of clinically significant QTc interval prolongation [see Clinical Pharmacology (12.2)]. Discontinue or use alternative concomitant drugs that do not prolong QT/QTc interval while the patient is using BESPONSA. When it is not feasible to avoid concomitant use of drugs known to prolong QT/QTc, obtain ECGs and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment [see Warnings and Precautions (5.5)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingBased on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA.. Contraception. FemalesAdvise females of reproductive potential to avoid becoming pregnant while receiving BESPONSA. Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for at least months after the last dose [see Nonclinical Toxicology (13.1)].. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for at least months after the last dose [see Nonclinical Toxicology (13.1)].. Infertility. FemalesBased on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].. MalesBased on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. In the INO-VATE ALL trial, 30/164 patients (18%) treated with BESPONSA were >= 65 years of age. No differences in responses were identified between older and younger patients. Based on population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16. HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. BESPONSA (inotuzumab ozogamicin) for Injection is supplied as white to off-white lyophilized powder in single-dose vial for reconstitution and further dilution. Each vial delivers 0.9 mg inotuzumab ozogamicin. Each carton (NDC 0008-0100-01) contains one single-dose vial.. 16.2 Storage and Handling. Refrigerate (2-8C; 36-46F) BESPONSA vials and store in the original carton to protect from light. Do not freeze.BESPONSA is cytotoxic drug. Follow applicable special handling and disposal procedures.1.

INDICATIONS & USAGE SECTION.

1. INDICATIONS AND USAGE. BESPONSA is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). BESPONSA is CD22-directed antibody-drug conjugate (ADC) indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). (1).

INFORMATION FOR PATIENTS SECTION.

17. PATIENT COUNSELING INFORMATION. Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome) Inform patients that liver problems, including severe, life-threatening, or fatal VOD, and increases in liver tests may develop during BESPONSA treatment. Inform patients that they should seek immediate medical advice if they experience symptoms of VOD, which may include elevated bilirubin, rapid weight gain, and abdominal swelling that may be painful. Inform patients that they should carefully consider the benefit/risk of BESPONSA treatment if they have prior history of VOD or serious ongoing liver disease [see Warnings and Precautions (5.1)].. Increased Risk of Post-HSCT Non-Relapse MortalityInform patients that there is an increased risk of post-HSCT non-relapse mortality after receiving BESPONSA, that the most common causes of post-HSCT non-relapse mortality included infection and VOD. Advise patients to report signs and symptoms of infection [see Warnings and Precautions (5.2)].. MyelosuppressionInform patients that decreased blood counts, which may be life-threatening, may develop during BESPONSA treatment and that complications associated with decreased blood counts may include infections, which may be life-threatening or fatal, and bleeding/hemorrhage events. Inform patients that signs and symptoms of infection, bleeding/hemorrhage, or other effects of decreased blood counts should be reported during treatment with BESPONSA [see Warnings and Precautions (5.3)]. Infusion Related Reactions Advise patients to contact their health care provider if they experience symptoms such as fever, chills, rash, or breathing problems during the infusion of BESPONSA [see Warnings and Precautions (5.4)].. QT Interval ProlongationInform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and the use of all medications to their healthcare provider [see Warnings and Precautions (5.5)].. Embryo-Fetal ToxicityAdvise males and females of reproductive potential to use effective contraception during BESPONSA treatment and for at least and months after the last dose, respectively [see Use in Specific Populations (8.3)]. Advise females of reproductive potential to avoid becoming pregnant while receiving BESPONSA. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with BESPONSA. Inform the patient of the potential risk to the fetus [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].. LactationAdvise women against breastfeeding while receiving BESPONSA and for months after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk Summary There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with BESPONSA and for at least months after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Inotuzumab ozogamicin is CD22-directed antibody-drug conjugate (ADC). Inotuzumab recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is cytotoxic agent that is covalently attached to the antibody via linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

NONCLINICAL TOXICOLOGY SECTION.

13. NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In toxicity studies, rats were dosed weekly for or 26 weeks with inotuzumab ozogamicin at doses up to 4.1 mg/m2 and 0.73 mg/m2, respectively. After 26 weeks of dosing, rats developed hepatocellular adenomas in the liver at 0.73 mg/m2 (approximately times the exposure in patients at the maximum recommended dose, based on AUC).Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice that received single doses >=1.1 mg/m2. This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin dimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in an in vitro bacterial reverse mutation (Ames) assay.In female fertility and early embryonic development study, female rats were administered daily intravenous doses of inotuzumab ozogamicin up to 0.11 mg/m2 for weeks before mating through Day of pregnancy. An increase in the proportion of resorptions and decrease in the number of viable embryos and gravid uterine weights were observed at the 0.11 mg/m2 dose level (approximately times the exposure in patients at the maximum recommended dose, based on AUC). Additional findings in female reproductive organs occurred in repeat-dose toxicology studies and included decreased ovarian and uterine weights, and ovarian and uterine atrophy. Findings in male reproductive organs occurred in repeat-dose toxicology studies and included decreased testicular weights, testicular degeneration, hypospermia, and prostatic and seminal vesicle atrophy. Testicular degeneration and hypospermia were nonreversible following 4-week nondosing period. In the chronic studies of 26-weeks duration, adverse effects on reproductive organs occurred at >=0.07 mg/m2 in male rats and at 0.73 mg/m2 in female monkeys [see Use in Specific Populations (8.3)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. During the treatment period, the pharmacodynamic response to BESPONSA was characterized by the depletion of CD22-positive leukemic blasts.. Cardiac ElectrophysiologyIn randomized clinical study in patients with relapsed or refractory ALL, increases in QTcF of >= 60 msec from baseline were measured in 4/162 patients (3%) in the BESPONSA arm and 3/124 patients (2%) in the Investigators choice of chemotherapy arm. Increases in QTcF of 500 msec were observed in none of the patients in the BESPONSA arm and 1/124 patients (1%) in the Investigators choice of chemotherapy arm. Central tendency analysis of the QTcF interval changes from baseline showed that the highest mean (upper bound of the 2-sided 90% CI) for QTcF was 15.3 (21.1) msec, which was observed at Cycle 4/Day 1/1 hour in the BESPONSA arm [see Warnings and Precautions (5.5)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The mean Cmax of inotuzumab ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ngh/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4. Following administration of multiple doses, 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4. DistributionN-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L. EliminationThe pharmacokinetics of inotuzumab ozogamicin was well characterized by 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h and the terminal half-life (t 1/2 was 12.3 days. Following administration of multiple doses, 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4. MetabolismIn vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction. In humans, N-acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation.. Specific PopulationsThe effect of intrinsic factors on inotuzumab ozogamicin pharmacokinetics was assessed using population pharmacokinetic analysis unless otherwise specified. Age (18 to 92 years of age), sex, and race (Asian versus non-Asian [Caucasian, Black, and Unspecified]) had no clinically significant effect on the pharmacokinetics of inotuzumab ozogamicin. Body surface area was found to significantly affect inotuzumab ozogamicin disposition. BESPONSA is dosed based on body surface area [see Dosage and Administration (2.1)]. Patients with Renal ImpairmentThe clearance of inotuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr; based on the Cockcroft-Gault formula] 60-89 mL/min; n=237), moderate renal impairment (CLcr 30-59 mL/min; n=122), or severe renal impairment (CLcr 15-29 mL/min; n=4) was similar to patients with normal renal function (CLcr >=90 mL/min; n=402). The safety and efficacy of inotuzumab ozogamicin in patients with end stage renal disease with or without hemodialysis is unknown.. Patients with Hepatic ImpairmentThe clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin <=ULN and AST ULN, or total bilirubin >1.0-1.5 ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST <=ULN; n=611). There is insufficient data in patients with moderate and severe hepatic impairment (total bilirubin >1.5 ULN).. Drug Interactions. In vitro. Effect of Metabolic Pathways and Transporter Systems on BESPONSA N-acetyl-gamma-calicheamicin dimethylhydrazide is substrate of P-glycoprotein (P-gp).. Effect of BESPONSA on Metabolic Pathways and Transporter SystemsAt clinically relevant concentrations, N-acetyl-gamma-calicheamicin dimethylhydrazide had low potential to:Inhibit cytochrome P450 (CYP 450) 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, 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.At clinically relevant concentrations, inotuzumab ozogamicin had low potential to: Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.. Inhibit cytochrome P450 (CYP 450) 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, 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.. Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.. Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.

PREGNANCY SECTION.

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)], BESPONSA can cause embryo-fetal harm when administered to pregnant woman. There are no available data on BESPONSA use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were >= 0.4 times the exposure in patients at the maximum recommended dose, based on AUC [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to fetus.Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.. Data. Animal Data In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m2 during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at >= 0.11 mg/m2 (approximately times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC). In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m2 (approximately times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At dose of 0.15 mg/m2, slight maternal toxicity was observed in the absence of any effects on embryo-fetal development.

REFERENCES SECTION.

15. REFERENCES. OSHA Hazardous Drugs. OSHA. [Accessed on May 2017, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]. OSHA Hazardous Drugs. OSHA. [Accessed on May 2017, from http://www.osha.gov/SLTC/hazardousdrugs/index.html].

SPL UNCLASSIFIED SECTION.

HEPATOTOXICITY, INCLUDING VODHepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing alkylating agents and last total bilirubin level >= upper limit of normal (ULN) before HSCT were significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and greater number of BESPONSA treatment cycles. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Hepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing alkylating agents and last total bilirubin level >= upper limit of normal (ULN) before HSCT were significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and greater number of BESPONSA treatment cycles. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Refrigerate (2-8C; 36-46F) BESPONSA vials and store in the original carton to protect from light. Do not freeze.BESPONSA is cytotoxic drug. Follow applicable special handling and disposal procedures.1.

USE IN SPECIFIC POPULATIONS SECTION.

8. USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 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)], BESPONSA can cause embryo-fetal harm when administered to pregnant woman. There are no available data on BESPONSA use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were >= 0.4 times the exposure in patients at the maximum recommended dose, based on AUC [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to fetus.Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.. Data. Animal Data In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m2 during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at >= 0.11 mg/m2 (approximately times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC). In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m2 (approximately times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At dose of 0.15 mg/m2, slight maternal toxicity was observed in the absence of any effects on embryo-fetal development.. 8.2 Lactation. Risk Summary There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with BESPONSA and for at least months after the last dose. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingBased on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)]. Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA.. Contraception. FemalesAdvise females of reproductive potential to avoid becoming pregnant while receiving BESPONSA. Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for at least months after the last dose [see Nonclinical Toxicology (13.1)].. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for at least months after the last dose [see Nonclinical Toxicology (13.1)].. Infertility. FemalesBased on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].. MalesBased on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use. In the INO-VATE ALL trial, 30/164 patients (18%) treated with BESPONSA were >= 65 years of age. No differences in responses were identified between older and younger patients. Based on population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3)].. 8.6Hepatic Impairment. Based on population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0-1.5 ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611). In patients with moderate (total bilirubin greater than 1.5-3 ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than x ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced [see Clinical Pharmacology (12.3)]. No adjustment to the starting dose is required when administering BESPONSA to patients with total bilirubin less than or equal to 1.5 ULN and AST/ALT less than or equal to 2.5 ULN [see Dosage and Administration (2.3)]. There is limited safety information available in patients with total bilirubin greater than 1.5 ULN and/or AST/ALT greater than 2.5 ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 ULN and AST/ALT to less than or equal to 2.5 ULN prior to each dose unless due to Gilberts syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 ULN or AST/ALT does not recover to less than or equal to 2.5 ULN [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.

5. WARNINGS AND PRECAUTIONS. Myelosuppression: Monitor complete blood counts; for signs and symptoms of infection; bleeding/hemorrhage; or other effects of myelosuppression during treatment; manage appropriately. (5.3)Infusion related reactions: Monitor for infusion related reactions during and for at least hour after infusion ends. (5.4)QT interval prolongation: Obtain electrocardiograms (ECGs) and electrolytes at baseline and monitor during treatment. Monitor more frequently when using concomitant mediations known to prolong QT interval. (5.5) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.6). Myelosuppression: Monitor complete blood counts; for signs and symptoms of infection; bleeding/hemorrhage; or other effects of myelosuppression during treatment; manage appropriately. (5.3). Infusion related reactions: Monitor for infusion related reactions during and for at least hour after infusion ends. (5.4). QT interval prolongation: Obtain electrocardiograms (ECGs) and electrolytes at baseline and monitor during treatment. Monitor more frequently when using concomitant mediations known to prolong QT interval. (5.5) Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.6). 5.1Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome). In the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD was observed in 23/164 patients (14%) in the BESPONSA arm during or following treatment or following HSCT after completion of treatment. VOD was reported up to 56 days after the last dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days). In the BESPONSA arm, among the 79 patients who proceeded to subsequent HSCT, VOD was reported in 18/79 patients (23%), and among all 164 patients treated, VOD was reported in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total bilirubin level greater than or equal to the ULN before HSCT are significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and greater number of BESPONSA treatment cycles. Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following treatment with BESPONSA.Monitor closely for signs and symptoms of VOD; these may include elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Due to the risk of VOD, for patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is cycles; third cycle may be considered for those patients who do not achieve CR or CRi and MRD negativity after cycles [see Dosage and Administration (2.1)]. For patients who proceed to HSCT, monitor liver tests closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice.In the INO-VATE ALL trial, increases in liver tests were reported. Grade 3/4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively. In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. Elevations of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA [see Dosage and Administration (2.3)].. 5.2Increased Risk of Post-Transplant Non-Relapse Mortality. In the INO-VATE ALL trial, higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared to the Investigators choice of chemotherapy arm, resulting in higher Day 100 post-HSCT mortality rate.Overall, 79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the Investigators choice of chemotherapy arm had follow-up HSCT. The post-HSCT non-relapse mortality rate was 31/79 (39%) and 8/35 (23%) in the BESPONSA arm compared to the Investigators choice of chemotherapy arm, respectively. In the BESPONSA arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events that occurred post-HSCT were fatal. In the BESPONSA arm, among patients with ongoing VOD at time of death, patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, patients died due to infection, and patient died due to MOF and infection). Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD [see Warnings and Precautions (5.1, 5.3)].. 5.3Myelosuppression In the INO-VATE ALL trial, myelosuppression was observed in patients receiving BESPONSA [see Adverse Reactions (6.1)]. Thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade thrombocytopenia and neutropenia were reported in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade thrombocytopenia and neutropenia were reported in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, was reported in 43/164 patients (26%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to 50,000/mm3 was later than 45 days after the last dose in 15/164 patients (9%) who received BESPONSA and 3/162 patients (2%) who received Investigators choice of chemotherapy.Complications associated with myelosuppression (including infections and bleeding/hemorrhagic events) were observed in patients receiving BESPONSA [see Adverse Reactions (6.1)]. Infections, including serious infections, some of which were life-threatening or fatal, were reported in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8/164 patients (5%). Bacterial, viral, and fungal infections were reported.Hemorrhagic events were reported in 54/164 patients (33%). Grade or hemorrhagic events were reported in 8/164 patients (5%). One Grade (fatal) hemorrhagic event (intra-abdominal hemorrhage) was reported in 1/164 patients (1%). The most common hemorrhagic event was epistaxis which was reported in 24/164 patients (15%).Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with BESPONSA. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with BESPONSA. Management of severe infection, bleeding/hemorrhage, or other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA [see Dosage and Administration (2.3)]. 5.4Infusion Related Reactions. In the INO-VATE ALL trial, infusion related reactions were observed in patients who received BESPONSA. Infusion related reactions (all Grade 2) were reported in 4/164 patients (2%). Infusion related reactions generally occurred in Cycle shortly after the end of the BESPONSA infusion and resolved spontaneously or with medical management. Premedicate with corticosteroid, antipyretic, and antihistamine prior to dosing [see Dosage and Administration (2.2)]. Monitor patients closely during and for at least hour after the end of infusion for the potential onset of infusion related reactions, including symptoms such as fever, chills, rash, or breathing problems. Interrupt infusion and institute appropriate medical management if an infusion related reaction occurs. Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue BESPONSA [see Dosage and Administration (2.3)].. 5.5QT Interval Prolongation. In the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericias formula (QTcF) of >= to 60 msec from baseline were measured in 4/162 patients (3%). No patients had QTcF values greater than 500 msec [see Clinical Pharmacology (12.2)]. Grade QT prolongation was reported in 2/164 patients (1%). No >= Grade QT prolongation or events of Torsade de Pointes were reported [see Adverse Reactions (6.1)]. Administer BESPONSA with caution in patients who have history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval [see Drug Interactions (7)], and in patients with electrolyte disturbances [see Drug Interactions (7)]. Obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment [see Drug Interactions (7), Clinical Pharmacology (12.2)]).. 5.6Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to pregnant woman. In animal studies, inotuzumab ozogamicin caused embryo-fetal toxicities, starting at dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for at least months after the final dose of BESPONSA. Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for at least months after the last dose of BESPONSA. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with BESPONSA [see Use in Specific Populations (8.1, 8.3) Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].