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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. Capillary Leak Syndrome [see Warnings and Precautions (5.1) ] Hemolytic Uremic Syndrome [see Warnings and Precautions (5.2) ] Renal Toxicity [see Warnings and Precautions (5.3) ] Infusion Related Reactions [see Warnings and Precautions (5.4) ] Electrolyte Abnormalities [see Warnings and Precautions (5.5) ] Most common (≥ 20%) adverse reactions are infusion related reactions, edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea. Most common (≥ 50%) laboratory abnormalities are creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, and hypophosphatemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Innate Pharma at 1-888-501-0998 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience As 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. The safety data described in this section reflect exposure to LUMOXITI in 80 patients with previously treated HCL in Study 1053 [see Clinical Studies (14) ] . Patients received LUMOXITI 0.04 mg/kg as an intravenous infusion over 30 minutes on Days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles or until disease progression or unacceptable toxicity. The median duration of treatment with LUMOXITI was 5.7 months (range: 0.9 to 6.7), with a median of 6 treatment cycles started in each patient. The most common non-laboratory adverse reactions (≥ 20%) of any grade were infusion related reactions, edema, nausea, fatigue, headache, pyrexia, constipation, anemia, and diarrhea. The most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS. The most common laboratory abnormalities (≥ 20%) of any grade were creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia, hemoglobin decreased, neutrophil count decreased, hyponatremia, blood bilirubin increased, hypokalemia, GGT increased, hypomagnesemia, platelet count decreased, hyperuricemia, and alkaline phosphate increased. Adverse reactions resulting in permanent discontinuation of LUMOXITI occurred in 15% (12/80) of patients. The most common adverse reaction leading to LUMOXITI discontinuation was HUS (5%). The most common adverse reaction resulting in dose delays, omissions, or interruptions was pyrexia (3.8%). Tables 4 and 5 present the frequency category of adverse reactions and key laboratory abnormalities observed in patients with relapsed or refractory HCL treated with LUMOXITI. Table 4: Adverse Reactions Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. in ≥ 20% (All Grades) of Patients with HCL in Study 1053 LUMOXITI N=80 All Grades (%) Grade 3 (%) General Disorders and Administration Site Conditions Edema peripheral 39 - Fatigue 34 - Pyrexia 31 1.3 Gastrointestinal Disorders Nausea 35 2.5 Constipation 23 - Diarrhea 21 - Injury, Poisoning, and Procedural Complications Infusion related reactions Infusion related reactions: includes patients who were reported to have one or more infusion event that may be infusion-related on the day of study drug infusion. 50 3.8 Nervous System Disorders Headache 33 - Blood and Lymphatic System Disorders Anemia 21 10 Fluid retention occurred in 63% (50/80) of patients treated with LUMOXITI in Study 1053, including Grade 3 in 1.3% (1/80) of patients. Fluid retention included all preferred terms of edema peripheral (39%), face edema (14%), abdominal distension (13%), weight increased (8%), pleural effusion (6%), edema (5%), peripheral swelling (5%), localized edema (3.8%), ascites (1.3%), fluid overload (1.3%), fluid retention (1.3%), and pericardial effusion (1.3%). Of the fifty patients with fluid retention, 29% of patients required diuretics. Ocular adverse events occurred, including: blurred vision (9%), dry eye (8%), cataracts (5%), ocular discomfort and/or pain (4%), ocular swelling/periorbital edema (4%), conjunctivitis (1.3%), conjunctival hemorrhage (1.3%), and ocular discharge (1.3%). Table 5: Laboratory Abnormalities Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and based on laboratory measurements worsening from baseline in ≥ 20% (All Grades) Reported in Patients with HCL in Study 1053 LUMOXITI N=80 All Grades (%) Grade 3 (%) Grade 4 (%) ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma glutamyl transferase Hematology Hemoglobin decreased 43 15 - Neutrophil count decreased 41 11 20 Platelet count decreased 21 11 3.8 Chemistry Creatinine increased 96 2.5 - ALT increased 65 3.8 - Hypoalbuminemia 64 1.3 - AST increased 55 1.3 - Hypocalcemia 54 - - Hypophosphatemia 53 14 - Hyponatremia 41 8.8 - Blood Bilirubin increased 30 1.3 - Hypokalemia 25 1.3 1.3 GGT increased 25 - - Hypomagnesemia 23 1.3 - Hyperuricemia 21 - 2.5 Alkaline phosphatase increased 20 - - 6.2 Immunogenicity 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 moxetumomab pasudotox-tdfk in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. The immunogenicity of LUMOXITI was evaluated using electrochemiluminescent (ECL)-based immunoassay to test for anti-moxetumomab pasudotox-tdfk antibodies (ADA). For patients whose serum tested positive for ADA, a cell-based assay was performed to detect neutralizing antibodies (nAb). In Study 1053, 59% (45/76) of patients tested positive for ADA prior to any treatment with moxetumomab pasudotox-tdfk. Seventy out of 80 subjects tested ADA positive at any point during the study and were subsequently tested for nAb. The results showed that 67 of 70 subjects were nAb-positive. Among these 67 patients who tested nAb-positive, 99% (66/67) had ADA specific to the PE38 binding domain, and 54% (36/67) also had ADA specific to the CD22 binding domain. In 41 out of 73 patients who had baseline and post-baseline ADA results, the median fold increase from baseline (Cycle 1, Day 1) in ADA titer was 3.75- (range: 0 to 240), 54- (range: 0 to 2560), 120- (range: 0 to 1920), and 128- (range: 0 to 2560) fold at Cycles 2, 3, 5, and end-of-treatment, respectively. Patients who tested positive for ADA had decreased systemic moxetumomab pasudotox-tdfk concentrations [see Clinical Pharmacology (12.3) ].