Erwinaze

Name: Erwinaze

What special precautions should I follow?

Before taking asparaginase Erwinia chrysanthemi,

  • tell your doctor and pharmacist if you are allergic to asparaginase Erwinia chrysanthemi, any other medications, or any of the ingredients in asparaginase Erwinia chrysanthemi powder. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you have or have ever had pancreatitis (swelling of the pancreas), blood clots, or severe bleeding, especially if these happened during treatment with asparaginase (Elspar) or pegaspargase (Oncaspar). Your doctor probably will not want you to receive asparaginase Erwinia chrysanthemi.
  • tell your doctor if you have or have ever had diabetes.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while receiving asparaginase Erwinia chrysanthemi, call your doctor.

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to asparaginase Erwinia chrysanthemi.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Description

ERWINAZE (asparaginase Erwinia chrysanthemi) contains an asparagine specific enzyme derived from Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme consisting of four identical subunits, each having a molecular weight of about 35 kDa. The activity of ERWINAZE is expressed in terms of International Units.

ERWINAZE is supplied as a sterile, lyophilized, white powder in vials. Each vial contains 10,000 International Units of asparaginase Erwinia chrysanthemi, and the following inactive ingredients: glucose monohydrate (5.0 mg), sodium chloride (0.5 mg).

Indications

ERWINAZE (asparaginase Erwinia chrysanthemi) is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase.

Side effects

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, transaminases abnormal, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.

Clinical Studies

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 (intramuscular administration), the ERWINAZE Master Treatment Protocol (EMTP), an expanded access program (both intramuscular, intravenous, and other or unknown administration), and Study 2, a single-arm, multi-center, open-label, pharmacokinetic (PK) study trial of intravenous administration of ERWINAZE.

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].

Study 2 enrolled 30 patients [29 were being treated for ALL and one for lymphoblastic lymphoma (LBL)] following allergy to native E. coli asparaginase or pegaspargase. Patients received ERWINAZE 25,000 International Units/m²/dose, administered by intravenous infusion on a Monday, Wednesday, and Friday schedule (6 doses) as a replacement for doses remaining on their original treatment plan. The Study 2 population included patients with a median age of 7 years (1 to 17 years); 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native or Indian) [see Clinical Studies].

The EMTP trial 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 (0 to 76 years), 63% were male, 91% with leukemia, 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. The route of administration was intramuscular n=852, intravenous n=29, other or unknown n= 59. 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 and Study 2, safety information was prospectively and systematically collected. In Study 1, all Grades of adverse events were reported for 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, and cerebral venous thrombosis) and only Grade 3 and 4 events were reported for other adverse events. In Study 2 all adverse events of all Grades were prospectively collected. In the EMTP trial, 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 incidence of non-hematologic, non-infectious, adverse events (all Grades) in Study 1, Study 2, and the EMTP trial is provided in Table 1.

Table 1: Per Patient Incidence of Non-Hematologic and Non-Infectious* Adverse Events**

Type of Event Description of Event (Collated Term) Study 1 (IM)
N=58
Study 2 (IV)
N=30
EMTP (IM&IV)
N=940
Allergic Reactions Total 8 (14%) 11 (37%) 149 (16%)
Hypersensitivity (systemic) 8 (14%) 11 (37%) 128 (14%)
Local Reactions 0 0 31 (3%)
Liver Abnormalities Total 7 (12%) 4 (13%) 42 (4%)
Elevated transaminase 6 (10%) 4 (13%) 33 (4%)
Hyperbilirubinemia 6 (10%) 0 8 ( < 1%)
Hyperammonemia 0 0 7 ( < 1%)
Hyperglycemia Hyperglycemia 7 (12%) 5 (17%) 35 (4%)
Gastrointestinal Symptoms Not Associated with Pancreatitis Total 3 (5%) 6 (20%) 39 (4%)
Nausea 2 (3%) 6 (20%) 23 (2%)
Vomiting 3 (5%) 5 (17%) 28 (3%)
Abdominal Pain/ Discomfort 1 (2%) 0 13 (1%)
Pancreatitis Pancreatitis 1 (2%) 2 (7%) 37 (4%)
Fever Fever 2 (3%) 3 (10%) 36 (4%)
Clinical Coagulation Abnormalities Total 1 (2%) 2 (7%) 27 (3%)
Thrombosis*** 1 (2%) 2 (7%) 20 (2%)
Hemorrhagic Disorder 0 0 9 (1%)
Mucositis Mucositis 0 2 (7%) 11 (1%)
Diarrhea Diarrhea 0 1 (3%) 10 (1%)
*Hematologic and infectious adverse events observed in these studies are not included in this table. Patients were enrolled in uncontrolled trials and were receiving multi-agent myelosuppressive chemotherapy making causality unclear.
** Type of Event reported in more than 1% in EMTP trial
***Including pulmonary embolism and cerebrovascular accident

The incidence of Grade 3 or greater non-hematologic, non-infectious adverse reactions occurring with ERWINAZE in Study 1, Study 2 and EMTP trial is provided in Table 2.

Table 2: Incidence of Non-Hematologic, Non-Infectious, Grade 3 and 4 Adverse Reactions

Description of Event-Collated Term Study 1 (IM)
N=58
Study 2 (IV)
N=30
EMTP (IM&IV)
N=940
Allergic Reactions 5 (9%) 1 (3%) 42 (4%)
-Hypersensitivity (systemic, Grade 3) 5 (9%) 1 (3%) 34 (4%)
-Anaphylactic Reaction (Grade 4) 0 0 8 ( < 1%)
Hyperglycemia 1 (2%) 1 (3%) 33 (4%)
Liver Abnormalities 3 (5%) 0 7 ( < 1%)
-Transaminases Abnormal 3 (5%) 0 6 ( < 1%)
-Hyperbilirubinemia 0 0 1 ( < 1%)
Pancreatitis 0 2 (7%) 8 ( < 1%)
Clinical Coagulation Abnormalities 0 0 9 ( < 1%)
-Thrombosis* 0 0 8 ( < 1%)
-Hemorrhagic Disorder 0 0 1 ( < 1%)
Gastrointestinal Symptoms Not Associated with Pancreatitis 1 (2%) 2 (7%) 6 ( < 1%)
-Abdominal Pain/Discomfort 1 (2%) 1 (3%) 3 ( < 1%)
-Nausea 1 (2%) 1 (3%) 3 ( < 1%)
-Vomiting 1 (2%) 1 (3%) 3 ( < 1%)
*Including pulmonary embolism and cerebrovascular accident

Immunogenicity

As with most therapeutic proteins, patients may develop anti-drug antibodies (ADA) to ERWINAZE.

In a study with ERWINAZE treatment by intramuscular administration (Study 1), 6 of 56 (11%) patients treated with ERWINAZE developed antibodies to ERWINAZE. Of these 6 ADA positive patients, one experienced a hypersensitivity reaction during Study 1 (2%, 1 of 56). None of these 6 patients had neutralizing antibodies.

In a study with ERWINAZE treatment by intravenous administration (Study 2), 4 of 30 (13.3%) patients treated with ERWINAZE developed anti-ERWINAZE antibodies. Of these 4 patients who developed anti-ERWINAZE antibodies, 3 experienced hypersensitivity reactions (10%, 3 of 30) during the study. None of these 4 patients had neutralizing antibodies.

The presence of ADA to ERWINAZE is associated with a higher risk of hypersensitivity reactions in patients who received ERWINAZE through intravenous infusion compared to intramuscular administration of ERWINAZE.

Immunogenicity assays are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ERWINAZE with the incidence of antibodies to other products may be misleading.

Erwinaze Overdose

Because this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.
 

Introduction

Antineoplastic agent; enzyme derived from Erwinia chrysanthemi (formerly Erwinia carotovora; also known as Pectobacterium chrysanthemi).1 6

Uses for Erwinaze

Acute Lymphocytic Leukemia (ALL)

Component of combination chemotherapy for treatment of ALL in patients who are hypersensitive to E. coli-derived asparaginase (native [nonconjugated] asparaginase [Escherichia coli] or pegaspargase; asparaginase [Escherichia coli] no longer commercially available in the US); designated an orphan drug by FDA for this use.1 2 4 6 7 8 9

Interactions for Erwinaze

No formal drug interaction studies to date.1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Asparaginase (Erwinia chrysanthemi)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IM use

10,000 units

Erwinaze

EUSA

How is this medicine (Erwinaze) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as a shot into a muscle or as an infusion into a vein over a period of time.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
  • Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Chest pain or pressure.
  • Swelling, warmth, numbness, change of color, or pain in a leg or arm.
  • Coughing up blood.
  • Shortness of breath.
  • Very bad headache.
  • Any unexplained bruising or bleeding.
  • Fever.

Warnings and Precautions

Hypersensitivity Reactions

Grade 3 and 4 hypersensitivity reactions after the use of Erwinaze have occurred in 5% of patients in clinical trials [see Adverse Reactions (6.1)].

Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. If a serious hypersensitivity reaction occurs, discontinue Erwinaze and initiate appropriate therapy.

Pancreatitis

Pancreatitis has been reported in 4% of patients in clinical trials [see Adverse Reactions (6.1)].

Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Discontinue Erwinaze for severe or hemorrhagic pancreatitis manifested by abdominal pain > 72 hours and amylase elevation ≥ 2.0 x ULN. Severe pancreatitis is a contraindication to additional asparaginase administration. In the case of mild pancreatitis, hold Erwinaze until the signs and symptoms subside and amylase levels return to normal. After resolution, treatment with Erwinaze may be resumed.

Glucose Intolerance

Glucose intolerance has been reported in 5% of patients receiving Erwinaze in clinical trials [see Adverse Reactions (6.1)]. In some cases glucose intolerance may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.

Thrombosis and Hemorrhage

Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism have been reported with both E. coli and Erwinia-derived L-asparaginase therapy. The following coagulation proteins were decreased in the majority of patients after a 2-week course of Erwinaze by intramuscular administration: fibrinogen, protein C activity, protein S activity, and anti-thrombin III. Discontinue Erwinaze for a thrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment with Erwinaze may be resumed.

In Summary

Common side effects of Erwinaze include: anaphylaxis. Other side effects include: pancreatitis and severe hypersensitivity. See below for a comprehensive list of adverse effects.

For Healthcare Professionals

Applies to asparaginase erwinia chrysanthemi: injectable powder for injection

General

Most common adverse reactions were systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.[Ref]

Hypersensitivity

Very common (10% or more): Systemic hypersensitivity (14%)
Very rare (less than 0.01%): Anaphylaxis[Ref]

Gastrointestinal

Common (1% to 10%): Pancreatitis, vomiting, nausea, abdominal pain/discomfort, diarrhea, serum amylases increased, serum lipase increased[Ref]

Nervous system

Common (1% to 10%): Lethargy, somnolence, confusion, dizziness, neurotoxicity, convulsions, headache
Rare (less than 0.1%): Dysphasia, dysphagia, CNS depression, coma[Ref]

Dermatologic

Common (1% to 10%): Rash, urticarial, pruritus, erythema, facial edema[Ref]

Hepatic

Common (1% to 10%): Transaminases abnormal, hyperbilirubinemia, alkaline phosphatase increased, cholesterol increased
Rare (less than 0.1%): Hepatic failure
Frequency not reported: Hepatomegaly, cholestatic jaundice[Ref]

Hematologic

Common (1% to 10%): Hypofibrinogenemia, asymptomatic coagulopathy
Very rare (less than 0.01%): Neutropenia, febrile neutropenia, thrombocytopenia
Frequency not reported: clotting factor decreased, antithrombin III decreased, protein C decreased, protein S decreased, fibrinogen decreased[Ref]

Cardiovascular

Common (1% to 10%): Thrombosis, pallor
Very rare (less than 0.01%): Hemorrhage
Frequency not reported: Hypertension[Ref]

Metabolic

Common (1% to 10%): Hyperglycemia
Uncommon (0.1% to 1%): Hyperlipidemia
Rare (0.01% to 0.1%): Diabetic ketoacidosis
Very rare (less than 0.01%): Hyperammonemia[Ref]

Local

Common (1% to 10%): Local reactions[Ref]

Other

Common (1% to 10%): Fever[Ref]

Musculoskeletal

Very rare (less than 0.01%): Myalgia, reactive arthritis
Frequency not reported: Extremity pain[Ref]

Immunologic

Very rare (less than 0.01%): Life-threatening sepsis[Ref]

Some side effects of Erwinaze may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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