Besponsa
Inotuzumab ozogamicin · Injection, Powder, Lyophilized, For Solution · Intravenous
• 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 VOD
• Hepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of…
Uses
1. INDICATIONS AND USAGE BESPONSA is indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older . BESPONSA is a CD22-directed antibody and cytotoxic drug conjugate indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older. ( 1 )
Dosage and administration
2. DOSAGE AND ADMINISTRATION
• Administer by intravenous infusion only. (2.1)
• Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions. ( 2.2 )
• Dosing regimens for Cycle 1 and subsequent cycles, depending on the response to treatment, are shown below. See full prescribing information for dosing details. ( 2 ) Day 1 Day 8 Day 15 Dosing regimen for Cycle 1 All patients: Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 21 days For patients who achieve a CR or a 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 treatment Patients who have achieved a CR or CRi: Dose 0.5 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days Patients who have not achieved a CR or CRi: Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days
• See full prescribing information for instructions on reconstitution of lyophilized powder, and preparation and administration of reconstituted drug. ( 2.4 ) 2.1 Recommended Dosage
• Pre-medicate before each dose [see Dosage and Administration (2.2) ] .
• Administer by intravenous infusion only.
• For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m 2 per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ). Cycle 1 is 3 weeks in duration, but may be extended to 4 weeks if the patient achieves a 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 a CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m 2 per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ). Subsequent cycles are 4 weeks in duration. OR
• In patients who do not achieve a CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m 2 per cycle given as 3 divided doses on Day 1 (0.8 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ). Subsequent cycles are 4 weeks in duration. Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
• For patients proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment with BESPONSA is 2 cycles. A third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles [see Warnings and Precautions (5.1) ] .
• For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered. Table 1 shows the recommended dosing regimens. Table 1. Dosing Regimen for Cycle 1 and Subsequent Cycles Depending on Response to Treatment Abbreviations: CR=complete remission; CRi=complete remission with incomplete hematologic recovery. Day 1 Day 8 +/- 2 days (maintain minimum of 6 days between doses). Day 15 Dosing regimen for Cycle 1 All patients: Dose Dose is based on the patient's body surface area (m 2 ). 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 21 days For patients who achieve a CR or a 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 treatment Patients who have achieved a CR CR 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 × 10 9 /L and absolute neutrophil counts [ANC] ≥ 1 × 10 9 /L) and resolution of any extramedullary disease. or CRi CRi 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 × 10 9 /L and/or ANC < 1 × 10 9 /L) and resolution of any extramedullary disease. : Dose 0.5 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days 7-day treatment-free interval starting on Day 21. Patients who have not achieved a CR or CRi : Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days 2.2 Recommended Pre-medications and Cytoreduction
• Premedication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing. Patients should be observed during and for at least 1 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 a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count of less than or equal to 10,000/mm 3 is recommended prior to the first dose. 2.3 Dosage Modifications for Adverse Reactions Modify the dose of BESPONSA for toxicities (see Tables 2–4). BESPONSA doses within a treatment cycle (i.e., Days 8 and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within a 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 Dosage Modifications for Hematologic Toxicities [see Warnings and Precautions (5.3) ] Criteria BESPONSA Dosage Modification(s) Abbreviation: ANC=absolute neutrophil count. If prior to BESPONSA treatment ANC was greater than or equal to 1 × 10 9 /L If ANC decreases, then interrupt the next cycle of treatment until recovery of ANC to greater than or equal to 1 × 10 9 /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 × 10 9 /L Platelet 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 × 10 9 /L .
Dosage forms and strengths
3. DOSAGE FORMS AND STRENGTHS For injection: 0.9 mg as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution. For injection: 0.9 mg lyophilized powder in a single-dose vial for reconstitution and further dilution. ( 3 )
Contraindications
4. CONTRAINDICATIONS None. None ( 4 )
Warnings and precautions
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 1 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 a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome) BESPONSA can cause hepatotoxicity, including VOD. In adult patients in the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD occurred in 23/164 patients (14%) in the BESPONSA arm during or following treatment or following a HSCT after completion of treatment. VOD occurred up to 56 days after the final 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 a subsequent HSCT, VOD occurred in 18/79 patients (23%), and among all 164 patients treated, VOD occurred 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 2 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 a 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. In Study WI203581 (ITCC-059) VOD occurred in 8/53 (15%) of pediatric patients treated with single agent BESPONSA. Among the 26 pediatric patients who underwent HSCT, VOD occurred in 5 (19%) patients [see Adverse Reactions (6.1) ] . Monitor closely for signs and symptoms of VOD including 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 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles [see Dosage and Administration (2.1) ] . For patients who proceed to HSCT, monitor liver tests at least weekly during the first month post-HSCT, then less frequently thereafter, according to standard medical practice. In adult patients in the INO-VATE ALL trial, increases in liver test abnormalities occurred. Grade 3 or 4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively. In pediatric patients in Study WI203581 (ITCC-059), liver test abnormalities occurred, with Grade 3 or 4 increases in AST, ALT, and blood bilirubin in 11/53 (21%), 11/53 (21%), and 5/53 (9%) of patients, respectively [see Adverse Reactions (6.1) ] . In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. Based on elevations of liver tests withhold, reduce dose, or permanently discontinue BESPONSA [see Dosage and Administration (2.3) ] . 5.2 Increased Risk of Post-Transplant Non-Relapse Mortality In adult patients in the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared to the Investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate. Overall, 79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the Investigator's choice of chemotherapy arm had a 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 Investigator's 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, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection). In pediatric patients in Study WI203581 (ITCC-059), 26/53 patients (49%) had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 7/26 (27%). Monitor for toxicities post-HSCT, including signs and symptoms of infection and VOD [see Warnings and Precautions (5.1 , 5.3) ] . 5.3 Myelosuppression BESPONSA can cause myelosuppression, including thrombocytopenia and neutropenia [see Adverse Reactions (6.1) ] . In adult patients in the INO-VATE ALL trial, thrombocytopenia and neutropenia occurred in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia occurred in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia occurred in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, occurred in 43/164 patients (26%).
Side effects
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) ] The most common (≥ 20%) adverse reactions, including laboratory abnormalities, in adult and pediatric patients are thrombocytopenia, pyrexia, neutropenia, infection, anemia, vomiting, leukopenia, hemorrhage, fatigue, nausea, febrile neutropenia, headache, transaminases increased, abdominal pain, and 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 . 6.1 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. Relapsed or Refractory B-cell Precursor ALL Adult Patients The safety of BESPONSA was evaluated in adult patients with relapsed or refractory B-cell precursor ALL in the INO-VATE ALL trial. The study was a randomized clinical study of BESPONSA (n=164) versus Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (n=143) [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 1 prior treatment regimen for ALL, 31% had received 2 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 a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1–15.6 weeks), with a median of 1 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 a HSCT after completion of treatment [see Warnings and Precautions (5.1) ]. Table 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy. Table 7. Adverse Reactions With ≥ 10% Incidence Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included. in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) Body System Adverse Reaction BESPONSA (N=164) FLAG, MXN/Ara-C, or HIDAC (N=143 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment. ) All Grades ≥ Grade 3 All Grades ≥ Grade 3 % % % % Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a 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 Infection Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. 48 28 76 54 Blood and lymphatic system disorders Thrombocytopenia Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia. 51 42 61 59 Neutropenia Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased. 49 48 45 43 Anemia Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased. 36 24 59 47 Leukopenia Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased.
Drug interactions
7. DRUG INTERACTIONS Drugs That Prolong the QT Interval Concomitant use of BESPONSA with drugs known to prolong the QT interval or induce Torsades de Pointes may increase the risk of a 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) ] .
Use in specific populations
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 a pregnant woman . There are no available data on BESPONSA use in pregnant women to inform a drug-associated risk. 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 ] . Advise patients of the potential risk to a fetus. 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/m 2 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/m 2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m 2 (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/m 2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m 2 , 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 child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with BESPONSA and for 2 months after the last dose. 8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for 8 months after the last dose [see Nonclinical Toxicology (13.1) ] . Males Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Females Based on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ] . Males Based on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL have been established. The use of BESPONSA for this indication is supported by evidence of safety and effectiveness in Study WI203581 (ITCC-059) [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . The study included patients in the following age groups: 2 patients 1 year to < 2 years old, 10 patients 2 years to < 6 years old, 20 patients 6 years to < 12 years old, and 20 patients 12 years to < 17 years old. Compared to adults, pediatric patients had a higher incidence of liver test abnormalities; with grade 3-4 increases in AST, ALT, and total bilirubin in 21%, 21%, and 9%, respectively, in pediatric patients treated with BESPONSA compared to 4%, 4%, and 5% in adults. The safety and effectiveness of BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established. 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 a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment Based on a 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 3 × 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 Gilbert's syndrome or hemolysis.
Pregnancy
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 a pregnant woman . There are no available data on BESPONSA use in pregnant women to inform a drug-associated risk. 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 ] . Advise patients of the potential risk to a fetus. 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/m 2 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/m 2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m 2 (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/m 2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m 2 , slight maternal toxicity was observed in the absence of any effects on embryo‑fetal development.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL have been established. The use of BESPONSA for this indication is supported by evidence of safety and effectiveness in Study WI203581 (ITCC-059) [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . The study included patients in the following age groups: 2 patients 1 year to < 2 years old, 10 patients 2 years to < 6 years old, 20 patients 6 years to < 12 years old, and 20 patients 12 years to < 17 years old. Compared to adults, pediatric patients had a higher incidence of liver test abnormalities; with grade 3-4 increases in AST, ALT, and total bilirubin in 21%, 21%, and 9%, respectively, in pediatric patients treated with BESPONSA compared to 4%, 4%, and 5% in adults. The safety and effectiveness of BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established.
Geriatric use
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 a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3) ] .
Description
11. DESCRIPTION Inotuzumab ozogamicin is a CD22-directed antibody and cytotoxic-drug conjugate (ADC) consisting of 3 components: 1) the recombinant humanized immunoglobulin class G subtype 4 (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 6 with a 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 a 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 4 mL of Sterile Water for Injection, USP, the final concentration is 0.25 mg/mL of inotuzumab ozogamicin with a deliverable volume of 3.6 mL (0.9 mg) and a pH of approximately 8.0. Chemical Structure
Mechanism of action
12.1 Mechanism of Action Inotuzumab ozogamicin is a CD22-directed antibody drug conjugate (ADC). Inotuzumab recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of 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.
How supplied
16. HOW SUPPLIED/STORAGE AND HANDLING How Supplied BESPONSA (inotuzumab ozogamicin) for injection is supplied as a white to off-white lyophilized powder in a 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. Storage and Handling Refrigerate (2-8°C; 36-46°F) BESPONSA vials and store in the original carton to protect from light. Do not freeze. BESPONSA is a hazardous drug. Follow applicable special handling and disposal procedures. 1
Patient information
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 a prior history of VOD or serious ongoing liver disease [see Warnings and Precautions (5.1) ] . Increased Risk of Post-HSCT Non-Relapse Mortality Inform 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) ] . Myelosuppression Inform 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 Prolongation Inform 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 Toxicity Advise males and females of reproductive potential to use effective contraception during BESPONSA treatment and for 5 and 8 months after the last dose, respectively [see Use in Specific Populations (8.3) ] . 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 (5.6) , Use in Specific Populations (8.1) ] . Lactation Advise women against breastfeeding while receiving BESPONSA and for 2 months after the last dose [see Use in Specific Populations (8.2) ].
Label text from the FDA structured product label by Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. (revised Feb 6, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Inotuzumab Ozogamicin in 1 product
Besponsa NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0008-0100 | Inotuzumab Ozogamicin .25 mg/mL Injection, Powder, Lyophilized, For Solution | Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. | BLA |
Frequently asked questions
What is Besponsa used for?
1. INDICATIONS AND USAGE BESPONSA is indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older . BESPONSA is a CD22-directed antibody and cytotoxic drug conjugate indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in…
What are the side effects of Besponsa?
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 the full label for the complete list.
Who makes Besponsa?
Besponsa is listed by 1 labeler in the FDA NDC directory, including Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc..