Label: ERWINAZE- asparaginase erwinia chrysanthemi injection, powder, lyophilized, for solution
- NDC Code(s): 57902-249-01, 57902-249-05
- Packager: Jazz Pharmaceuticals, Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: Biologic Licensing Application
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- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ERWINAZE ® safely and effectively. See full prescribing information for ERWINAZE.
ERWINAZE (asparaginase Erwinia chrysanthemi)
for injection, intramuscular use
Initial U.S. Approval: 2011
INDICATIONS AND USAGE
ERWINAZE (asparaginase Erwinia chrysanthemi) is an asparagine specific enzyme 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. (1)
DOSAGE AND ADMINISTRATION
- To substitute for a dose of pegaspargase: The recommended dose is 25,000 International Units/m 2 administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase. (2.1)
- To substitute for a dose of native E. coli asparaginase: The recommended dose is 25,000 International Units/m 2 administered intramuscularly for each scheduled dose of native E. coli asparaginase. (2.1)
- Limit the volume of reconstituted ERWINAZE at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites. (2.3)
DOSAGE FORMS AND STRENGTHS
• 10,000 International Units lyophilized powder per vial. (3)
- History of serious hypersensitivity reactions to ERWINAZE, including anaphylaxis ( 4)
- History of serious pancreatitis with prior L-asparaginase therapy ( 4)
- History of serious thrombosis with prior L-asparaginase therapy ( 4)
- History of serious hemorrhagic events with prior L-asparaginase therapy ( 4)
WARNINGS AND PRECAUTIONS
If the following occur, discontinue ERWINAZE:
Serious hypersensitivity reactions, including anaphylaxis ( 5.1 )
Severe or hemorrhagic pancreatitis ( 5.2 )
- Glucose intolerance can occur and, in some cases, may be irreversible. Perform appropriate monitoring and treat hyperglycemia with insulin, as necessary ( 5.3 )
- Thrombosis, hemorrhage: discontinue ERWINAZE until resolved ( 5.4)
Most common adverse reactions (1% or greater) are: systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea. (6)
To report SUSPECTED ADVERSE REACTIONS, contact EUSA Pharma (USA) Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
See 17 for PATIENT COUNSELING INFORMATION.
- FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
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.Close
- 2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
To substitute for a dose of pegaspargase:
The recommended dose is 25,000 International Units/m2 administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase.
To substitute for a dose of native E. coli asparaginase:
The recommended dose is 25,000 International Units/m2 administered intramuscularly for each scheduled dose of native E. coli asparaginase within a treatment.
2.2 Preparation Instructions
1. Visually inspect the ERWINAZE powder for foreign particulate matter and discoloration prior to reconstitution. Discard vial if present.
2. Reconstitute the contents of each vial by slowly injecting 1 or 2 mL of preservative free sterile sodium chloride (0.9%) injection (USP) against the inner vial wall.
3. Do not forcefully inject solution for reconstitution directly onto or into the powder. When reconstituted with 1 mL the resultant concentration is 10,000 International Units per mL. When reconstituted with 2 mL the resultant concentration is 5,000 International Units per mL.
6. Calculate the dose needed and the volume needed to obtain the calculated dose.
7. Withdraw the volume containing the calculated dose from the vial into a polypropylene syringe within 15 minutes of reconstitution. Do not freeze or refrigerate reconstituted solution and administer within 4 hours or discard [see How Supplied/Storage and Handling (16)].
2.3 Administration Instructions
1. Inject ERWINAZE solution intramuscularly.
2. Limit the volume of reconstituted ERWINAZE at a single injection site to 2 mL; if reconstituted dose to be administered is greater than 2 mL, use multiple injection sites.
3. If a partial vial is used, do not save or reuse the unused drug for later administration. Discard unused portions.
- 3 DOSAGE FORMS AND STRENGTHS
Lyophilized powder 10,000 International Units per vialClose
- 4 CONTRAINDICATIONS
- History of serious hypersensitivity reactions to ERWINAZE, including anaphylaxis
- History of serious pancreatitis with prior L-asparaginase therapy
- History of serious thrombosis with prior L-asparaginase therapy
- History of serious hemorrhagic events with prior L-asparaginase therapy
- 5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
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 has been reported with ERWINAZE therapy 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.
5.4 Thrombosis and Hemorrhage
Serious thrombotic events, including sagittal sinus thrombosis 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: 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.
- 6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Hypersensitivity reactions [see Warnings and Precautions (5.1)]
- Pancreatitis [see Warnings and Precautions (5.2)]
- Glucose intolerance [see Warnings and Precautions (5.3)]
- Thrombosis and hemorrhage [see Warnings and Precautions (5.4)]
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.
6.1 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 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 (14)].
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.
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.
- 7 DRUG INTERACTIONS
No formal drug interaction studies between ERWINAZE and other drugs have been performed.Close
- 8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C
There are no adequate and well-controlled studies of ERWINAZE in pregnant women. In embryofetal development studies in rats and rabbits, asparaginase Erwinia chrysanthemi produced embryofetal toxicities and fetal abnormalities. ERWINAZE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 500, 1000, or 2000 IU/kg) and rabbits (at 10, 25, and 40 IU/kg). In rats given 2000 IU/kg (approximately 50% of the recommended human dose, adjusted for body surface area), maternal toxicity of decreased body weight gain was observed, as well as a fetal finding of increased incidence of partially undescended thymic tissue.
In rabbits, maternal toxicity consisting of decreased body weight was observed at 40 IU/kg (approximately 2% of the recommended human dose, adjusted for body surface area). Increased post-implantation loss, a decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of ≥10 IU/kg (approximately 0.5% of the recommended human dose, adjusted for body surface area).
8.3 Nursing Mothers
It is not known whether ERWINAZE is secreted in human milk. Because many drugs are secreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ERWINAZE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
[see Clinical Studies (14)].
- 10 OVERDOSAGE
There are no known cases of overdose with ERWINAZE.Close
- 11 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).
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Asparaginase Erwinia chrysanthemi catalyzes the deamidation of asparagine to aspartic acid and ammonia, resulting in a reduction in circulating levels of asparagine. The mechanism of action of ERWINAZE is thought to be based on the inability of leukemic cells to synthesize asparagine due to lack of asparagine synthetase activity, resulting in cytotoxicity specific for leukemic cells that depend on an exogenous source of amino acid asparagine for their protein metabolism and survival.
The pharmacokinetics of ERWINAZE has not been characterized. The serum trough concentrations of asparaginase Erwinia chrysanthemi were determined in 48 ALL patients aged ≥ 2 year to ≤ 18 years enrolled in Study 1 [see Clinical Studies (14)]. Following administration of ERWINAZE 25,000 International Units/m2 intramuscularly on a Monday, Wednesday, and Friday schedule for 6 doses, 100% of patients in course 1 achieved serum trough asparaginase concentrations ≥ 0.1 International Units/mL at either 48-hour (n=35) or 72-hour (n=13) post dose 3. Eighty percent (28/35) of those evaluated at 48 hours and 38% (5/13) evaluated at 72 hours had serum asparaginase activity levels ≥ 0.4 International Units/mL [see Clinical Studies (14)].
- 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term carcinogenicity studies in animals have been performed with asparaginase Erwinia chrysanthemi. No studies that assess the mutagenic potential of asparaginase Erwinia chrysanthemi have been conducted.
In a fertility and early embryonic development study in rats, asparaginase Erwinia chrysanthemi had no effect on male or female fertility when administered intramuscularly at doses of up to 2000 IU/kg (approximately 50% of the recommended human dose, when adjusted for total body surface area) every other day for a total of 35 doses. Findings in males included decreased sperm count at doses of more than 500 IU/kg (approximately 12% of the recommended human dose).
- 14 CLINICAL STUDIES
The safety and efficacy of ERWINAZE was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial. Additional safety data was obtained in the ERWINAZE Master Treatment Protocol (EMTP), an expanded access program [see Adverse Reactions (6)]. Study 1 enrolled patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was determination of the proportion of patients who achieved a serum trough asparaginase level greater than or equal to 0.1 International Units/mL. Serum trough asparaginase activity ≥ 0.1 International Units/mL has been demonstrated to correlate with asparagine depletion (asparagine < 0.4 mcg/mL or 3 µM) and to serum levels that predict clinical efficacy. Patients received ERWINAZE 25,000 International Units/m2 intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol.
Fifty-eight patients were enrolled in Study 1, of these 48 were evaluable for the main outcome measure based on availability of pharmacokinetic samples in course 1. The median age was 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.
Study 1 met its main outcome measure of demonstrating that greater than 50% of the patients achieved the pre-specified trough asparaginase activity level of ≥ 0.1 International Units/mL at 48 or 72 hours following the third dose. Results for the main outcome measure and for an exploratory analysis using a higher cut-off (trough serum asparaginase activity levels ≥ 0.4 International Units/mL are presented in Table 3 [see Clinical Pharmacology (12.3)].Close
- 16 HOW SUPPLIED/STORAGE AND HANDLING
ERWINAZE is a sterile, white lyophilized powder supplied in a clear 3 mL glass vial. Each carton of ERWINAZE (NDC 57902-249-05) contains 5 vials. Each single vial (NDC 57902-249-01) contains 10,000 International Units asparaginase Erwinia chrysanthemi.
Store unused or unopened vials and cartons at 36°F to 46°F (2°C to 8°C). Protect from light. Do not use ERWINAZE after the expiration date on the vial.Close
- 17 PATIENT COUNSELING INFORMATION
- Instruct patients on the risk of allergic reactions, including anaphylaxis. Describe the symptoms of allergic reactions, including anaphylaxis, and instruct the patient to seek medical advice immediately if they experience such symptoms.
- Instruct patients on the risk of pancreatitis and to seek medical advice immediately if they experience abdominal pain.
- Instruct patients on the risk of hyperglycemia and glucose intolerance. Advise patients to seek medical advice if they experience excessive thirst or any increase in the volume or frequency of urination.
- Instruct patients on the risk of thrombosis and hemorrhage and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain.
- PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANELClose
5 Vials NDC 57902-249-05
asparaginase Erwinia chrysanthemi
For injection, Intramuscular Use
10,000 International Units per Vial
RX Only Single Use Vials. Discard unused portion
- INGREDIENTS AND APPEARANCE
asparaginase injection, powder, lyophilized, for solution
Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57902-249 Route of Administration INTRAMUSCULAR DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ASPARAGINASE ERWINIA CHRYSANTHEMI (ASPARAGINASE) ASPARAGINASE 10000 [iU] in 1 mL Inactive Ingredients Ingredient Name Strength DEXTROSE 5 mg in 1 mL SODIUM CHLORIDE 0.5 mg in 1 mL Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:57902-249-05 5 in 1 CARTON 1 NDC:57902-249-01 1 mL in 1 VIAL, GLASS Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125359 11/18/2011 Labeler - Jazz Pharmaceuticals, Inc. (135926363) Establishment Name Address ID/FEI Business Operations AndersonBrecon (UK) 762771269 PACK(57902-249) Establishment Name Address ID/FEI Business Operations PUBLIC HEALTH ENGLAND 233388961 MANUFACTURE(57902-249)