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 )
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 )
5.1Hepatotoxicity, 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.
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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) ] .
5.2Increased 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) ] .
5.3Myelosuppression
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%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to > 50,000/mm 3 was later than 45 days after the final dose in 15/164 patients (9%) who received BESPONSA and 3/162 patients (2%) who received Investigator's choice of chemotherapy. Complications associated with myelosuppression (including infections and bleeding/hemorrhage) occurred in patients receiving BESPONSA [see Adverse Reactions (6.1) ] .
Infections, including serious infections, some of which were life-threatening or fatal, occurred in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, occurred in 8/164 patients (5%). Bacterial, viral, and fungal infections occurred. Hemorrhage occurred in 54/164 patients (33%). Grade 3 or 4 hemorrhage occurred in 8/164 patients (5%), including a fatality in 1/164 patients (1%) (intra-abdominal hemorrhage).
The most common type of hemorrhage was epistaxis which occurred in 24/164 patients (15%). In pediatric patients in Study WI203581 (ITCC-059), Grade 3 or 4 thrombocytopenia occurred in 24/53 (45%) patients. Grade 3 or 4 neutropenia occurred in 21/53 (40%) patients. Infections occurred in 23/53 (43%) patients, and hemorrhage occurred in 22/53 (42%) patients. The most common types of hemorrhage were hematoma in 8/53 (15%), mouth hemorrhage in 6/53 (11%), and epistaxis in 6/53 (11%) patients [see Adverse Reactions (6.1) ] .
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. Based on the severity of myelosuppression, reduce dose, temporarily withhold, or permanently discontinue BESPONSA [see Dosage and Administration (2.3) ].
5.4Infusion Related Reactions
BESPONSA can cause infusion related reactions. In
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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) ] .
Pregnancy and breastfeeding
8.1Pregnancy 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.
Adverse reactions
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 .
6.1Clinical 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. 35 33 43 42 Febrile neutropenia 26 26 53 53 Lymphopenia Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia. 18 16 27 26 Metabolism and nutrition disorders Decreased appetite 12 1 13 2 Nervous system disorders Headache Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache. 28 2 27 1 Vascular disorders Hemorrhage Hemorrhage 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. 33 5 28 5 Gastrointestinal disorders Nausea 31 2 46 0 Abdominal pain Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain. 23 3 23 1 Diarrhea 17 1 38 1 Constipation 16 0 24 0 Vomiting 15 1 24 0 Stomatitis Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis. 13 2 26 3 Hepatobiliary disorders Hyperbilirubinemia 21 5 17 6 General disorders and administration site conditions Fatigue Fatigue includes the following reported preferred terms: Asthenia and Fatigue. 35 5 25 3 Pyrexia 32 3 42 6 Chills 11 0 11 0 Investigations Transaminases increased Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanin
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
INOTUZUMAB OZOGAMICIN 0.9/MG/VIAL
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA761040.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Besponsa
Active substance
inotuzumab ozogamicin
Drug class
CD22 (Clusters of Differentiation 22) inhibitors
Dosage form
Powder, for injection solution, lyophilized powder
