Adverse Reactions ( All Grades [%], ≥Grade 3 [%]) With ≥10 % Incidence a in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received SC ( N = 143 n ) were infection b ( 76 ; 54 ), thrombocytopenia c ( 61 ; 59 ), neutropenia d ( 45 ; 43 ), anemia e ( 59 ; 47 ), leukopenia f ( 43 ; 42 ), febrile neutropenia ( 53 ; 53 ), lymphopenia g ( 27 ; 26 ), decreased appetite ( 13 ; 2 ), headache h ( 27 ; 1 ), hemorrhage i ( 28 ; 5 ), nausea ( 46 ; 0 ), abdominal pain j ( 23 ; 1 ), diarrhea ( 38 ; 1 ), constipation ( 24 ; 0 ), vomiting ( 24 ; 0 ), stomatitis k ( 26 ; 3 ), hyperbilirubinemia ( 17 ; 6 ), fatigue l ( 25 ; 3 ), pyrexia ( 42 ;
6 ), chills ( 11 ; 0 ), transaminases increased m ( 13 ; 5 ), gamma-glutamyltransferase increased ( 8 ; 4 ), and alkaline phosphatase increased ( 7 ; 0 ).
Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the last 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 : N = number of patients ; NCI CTCAE = National Cancer Institute Common Toxicity Criteria for Adverse Events . a . Only adverse reactions with ≥10 % incidence in the BESPONSA arm are included . b . Infection also includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations . c . Thrombocytopenia also includes platelet count decreased . d . Neutropenia also includes the following reported preferred terms : neutrophil count decreased . e . Anemia also includes hemoglobin decreased . f . Leukopenia also includes monocytopenia and white blood cell count decreased . g . Lymphopenia also includes B-lymphocyte count decreased and lymphocyte count decreased . h . Headache also includes migraine and sinus headache . i . Hemorrhage also includes terms retrieved in the Standard MedDRA Query ( narrow ) for Hemorrhage terms ( excluding laboratory terms ), resulting in the following : 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 . j . Abdominal pain also includes abdominal pain lower , abdominal pain upper , abdominal tenderness , esophageal pain , and hepatic pain . k . Stomatitis also includes aphthous ulcer , mucosal inflammation , mouth ulceration , oral pain , and oropharyngeal pain . l . Fatigue also includes asthenia . m . Transaminases increased also includes Aspartate aminotransferase increased , Alanine aminotransferase increased , Hepatocellular injury , and Hypertransaminasemia . n . 19 patients randomized to FLAG , MXN / Ara-C , or HIDAC did not receive treatment .
Additional 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 %).
Lab abnormalities a ( N ; All Grades [%]; Grade 3 / 4 [%]) in patients with relapsed or refractory B-Cell precursor ALL who received BESPONSA were platelet count decreased ( 161 ; 98 ; 76 ), hemoglobin decreased ( 161 ; 94 ; 40 ), leukocytes decreased ( 161 ; 95 ; 82 ), neutrophil count decreased ( 160 ; 94 ; 86 ), lymphocytes ( absolute ) decreased ( 160 ; 93 ; 71 ), GGT increased ( 148 ; 67 ; 18 ), AST increased ( 160 ; 71 ; 4 ), ALP increased ( 158 ; 57 ; 1 ), ALT increased ( 161 ; 49 ; 4 ), blood bilirubin increased ( 161 ; 36 ; 5 ), lipase increased ( 139 ; 32 ; 13 ), hyperuricemia ( 158 ; 16 ; 3 ), amylase increased ( 143 ; 15 ; 2 ).
Lab abnormalities a ( N ; All Grades [%]; Grade 3 / 4 [%]) in patients with relapsed or refractory B-Cell precursor ALL who received SC were platelet count decreased ( 142 ; 100 ; 99 ), hemoglobin decreased ( 142 ; 100 ; 70 ), leukocytes decreased ( 142 ; 99 ; 98 ), neutrophil count decreased ( 130 ; 93 ; 88 ), lymphocytes ( absolute ) decreased ( 127 ; 97 ; 91 ), GGT increased ( 111 ; 68 ; 17 ), AST increased ( 134 ; 38 ; 4 ), ALP increased ( 133 ; 52 ; 3 ), ALT increased ( 137 ; 46 ; 4 ), blood bilirubin increased ( 138 ; 35 ; 6 ), lipase increased ( 90 ; 20 ; 2 ), hyperuricemia ( 122 ; 11 ; 0 ), amylase increased ( 102 ; 9 ; 1 ).
Abbreviations : ALP = alkaline phosphatase ; ALT = alanine aminotransferase ; AST = aspartate aminotransferase ; GGT = gamma-glutamyltransferase . a . Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy .
6.2 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 , a 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 antiinotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment .
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 . 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 .
8 . USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies , 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 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 . 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 a 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 / 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 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 2 months after the last dose . 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on its mechanism of action and findings from animal studies , BESPONSA can cause embryo-fetal harm when administered to a pregnant woman . Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA . Contraception Females Advise 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 8 months after the last dose . Males Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for at least 5 months after the last dose . Infertility Females Based on findings in animals , BESPONSA may impair fertility in females of reproductive potential . Males Based on findings in animals , BESPONSA may impair fertility in males of reproductive potential . 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 a population pharmacokinetic analysis in 765 patients , no adjustment to the starting dose is required based on age . 8.6 Hepatic Impairment Based on a population pharmacokinetic analysis , the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment ( total bilirubin ≤ ULN and AST > ULN , or total bilirubin > 1.0-1.5 x ULN and AST any level ; n = 150 ) was similar to patients with normal hepatic function ( total bilirubin / AST ≤ ULN ; n = 611 ). In patients with moderate ( total bilirubin > 1.5-3 x ULN and AST any level ; n = 3 ) and severe hepatic impairment ( total bilirubin > 3 x ULN and AST any level ; n = 1 ), inotuzumab ozogamicin clearance did not appear to be reduced . No adjustment to the starting dose is required when administering BESPONSA to patients with total bilirubin ≤ 1.5 x ULN and AST / ALT ≤ 2.5 x ULN . There is limited safety information available in patients with total bilirubin > 1.5 x ULN and / or AST / ALT > 2.5 x ULN prior to dosing . Interrupt dosing until recovery of total bilirubin to ≤ 1.5 x ULN and AST / ALT ≤ to 2.5 x ULN prior to each dose unless due to Gilbert ’ s syndrome or hemolysis . Permanently discontinue treatment if total bilirubin does not recover to ≤ 1.5 x ULN or AST / ALT does not recover to ≤ 2.5 x ULN .
17 . PATIENT COUNSELING INFORMATION
Hepatotoxicity , Including Hepatic VOD ( also known as SOS ) 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 . 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 . 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 lifethreatening 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 . 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 . 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 . Embryo-Fetal Toxicity Advise males and females of reproductive potential to use effective contraception during BESPONSA treatment and for at least 5 and 8 months after the last dose , respectively . 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 . Lactation Advise women against breastfeeding while receiving BESPONSA and for 2 months after the last dose .
This product ’ s label may have been updated . For current full prescribing information , please visit www . BESPONSA . com .
This brief summary is based on BESPONSA™ ( inotuzumab ozogamicin ) Prescribing Information LAB-0763-2.0 Revised March 2018 .
© 2018 Pfizer Inc . All rights reserved . April 2018