The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Hypersensitivity reactions[see WARNINGS AND PRECAUTIONS]
- Pancreatitis [see WARNINGS AND PRECAUTIONS]
- Glucose intolerance [see WARNINGS AND PRECAUTIONS]
- Thrombosis and hemorrhage [see WARNINGS AND PRECAUTIONS]
The most common adverse reactions (incidence 1% or greater) with ERWINAZE treatment are systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.
Because clinical trials are conducted under controlled, but widely varying conditions, adverse reaction rates observed in clinical trials of ERWINAZE cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
The data presented below are based on information collected from Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial and the ERWINAZE Master Treatment Protocol (EMTP), an expanded access program. Study 1 enrolled 58 patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. Patients received 6 doses of ERWINAZE 25,000 International Units/m² intramuscularly on a Monday, Wednesday, and Friday schedule as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. The Study 1 population included patients with a median age of 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino. In Study 1, the number of ERWINAZE courses ranged from 1 to 9. In this study, 76% (44 of 58) completed all planned therapy. Fourteen (24%) patients stopped therapy prior to completion; seven due to allergic reactions, five due to physician or patient choice, one due to disease progression, and one due to discontinuation during frontline protocol. All other chemotherapy was continued according to the patient's prescribed treatment regimen [see Clinical Studies].
The EMTP trial had enrolled 1368 patients with ALL or lymphoblastic lymphoma who received ERWINAZE after developing systemic hypersensitivity to an E. coli-derived asparaginase. Of these 1368 patients, safety data were received for 940 patients with a median age of 9 years (1 to 76 years), 63% were male, 91% with leukemia, and 3% with lymphoma, and 6% with unknown disease information. Patients received ERWINAZE according to several schedules, and treatment center specifications with doses that ranged from 20,000 to 25,000 International Units/m² . In the EMTP trial, the planned number of doses of ERWINAZE ranged from 3 to 48 doses. Seventy-eight percent of patients (693 of 893) were able to receive all planned doses to complete their prescribed treatment regimen.
In Study 1, safety information included all reported adverse events with systematic collection of the following adverse events of special interest: allergy, pancreatitis, coagulopathy (hemorrhage, thrombosis or infarct), hyperbilirubinemia, hyperglycemia, hyperlipidemia, ketoacidosis, and CNS events (hemorrhage, thrombosis or infarction, cerebral venous thrombosis). EMTP safety data were derived from case report forms that collected adverse event information. The forms specifically requested information on occurrence of allergic reactions, thrombotic events, hemorrhagic events, hepatobiliary disorders, pancreatic disorders, and hyperglycemia.
The combined incidence of non-hematologic, non-infectious, adverse reactions (all Grades) occurring with ERWINAZE in Study 1 and the EMTP trial is provided in Table 1. The incidence of Grade 3 or greater non-hematologic, non-infectious adverse reactions occurring with ERWINAZE in each individual Study is provided in Table 2.
Table 1: Per Patient Combined Incidence of Non-Hematologic and Non-Infectious Adverse Events N=998 (Study 1 + EMTP)
|Type of Event||Specific Response||Total Patients
(N / % of total)
|Allergic Reactions||Total||163 (16%)|
|Systemic hypersensitivity||136 (14%)|
|Local Reactions||31 (3%)|
|Anaphylaxis||8 ( < 1%)|
|Liver Abnormalities||Total||45 (5%)|
|Abnormal Transaminases||40 (4%)|
|Gastrointestinal Symptoms Not Associated with Pancreatitis||Total||42 (4%)|
|Abdominal Pain/Discomfort||14 (1%)|
|Clinical Coagulation Abnormalities||Total||28 (3%)|
|Hemorrhagic||9 ( < 1%)|
|Hyperammonemia||Hyperammonemia||7 ( < 1%)|
|Headache||Headache||8 ( < 1%)|
|Seizure||Seizure||7 ( < 1%)|
Table 2: Per Patient Incidence of Non-Hematologic, Non-Infectious, Grade 3 and 4 Adverse Reactions
|Description of Event||Study 1
|Allergic Reactions||5 (9%)||42 (4%)|
|-Systemic Hypersensitivity||5 (9%)||34 (4%)|
|-Anaphylaxis||0||8 ( < 1%)|
|Hyperglycemia||1 (2%)||33 (4%)|
|Clinical Coagulation Abnormalities||0||9 ( < 1%)|
|-Thrombosis||0||8 ( < 1%)|
|-Hemorrhage||0||1 ( < 1%)|
|Pancreatitis||0||8 ( < 1%)|
|Liver Abnormalities||3 (5%)||7 ( < 1%)|
|-Abnormal Transaminases||3 (5%)||6 ( < 1%)|
|Hyperbilirubinemia||0||1 ( < 1%)|
|Gastrointestinal Symptoms Not Associated with Pancreatitis||1 (2%)||6 ( < 1%)|
|-Abdominal Pain/Discomfort||1 (2%)||3 ( < 1%)|
|-Nausea||1 (2%)||3 ( < 1%)|
|-Vomiting||1 (2%)||3 ( < 1%)|
|Fever||0||4 ( < 1%)|
|Diarrhea||0||3 ( < 1%)|
|Headache||0||2 ( < 1%)|
|Seizure||0||2 ( < 1%)|
There is a potential for immunogenicity with therapeutic proteins such as ERWINAZE. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ERWINAZE with the incidence of antibodies to other products may be misleading.
There is insufficient information to characterize the incidence of antibodies to ERWINAZE.