ERWINAZE

Jazz Pharmaceuticals, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ERWINAZE safely and effectively.  See full prescribing information for ERWINAZE. ERWINAZE (asparaginase ) for injection, intramuscular useInitial U.S. Approval: 2011RECENT MAJOR CHANGESWarnings and Precautions (5.1)                                                     2/2014Warnings and Precautions (5.3)                                                     2/2014INDICATIONS AND USAGEERWINAZE (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/m2 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/m2 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.CONTRAINDICATIONS •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) Side EffectsMost 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. or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 ERWINAZE INDICATIONS AND USAGE
• 2 ERWINAZE DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dose
  • 2.2 Preparation Instructions
  • 2.3 Administration Instructions
• 3 DOSAGE FORMS AND STRENGTHS
• 4 ERWINAZE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hypersensitivity Reactions
  • 5.2 Pancreatitis
  • 5.3 Glucose Intolerance
  • 5.4 Thrombosis and Hemorrhage
• 6 ERWINAZE ADVERSE REACTIONS
  • 6.1 Clinical Studies
  • 6.2 Immunogenicity
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 ERWINAZE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

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.

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.
• 4.Dissolve contents by gentle mixing or swirling. Do not shake or invert vial.
• 5.When reconstituted, ERWINAZE should be a clear, colorless solution. Discard the reconstituted solution if any visible particles or protein aggregates are present.
• 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(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 vial

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

Grade 3 and 4 hypersensitivity reactions after the use of ERWINAZE have occurred in 5% of patients in clinical trials. Anaphylaxis after the use of ERWINAZE has occurred in 0.8% of patients in clinical trials [seeAdverse 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.

5.2 Pancreatitis

Pancreatitis has been reported with ERWINAZE therapy in 4% of patients in clinical trials [seeAdverse 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.

5.3 Glucose Intolerance

Glucose intolerance has been reported with ERWINAZE therapy in 4% of patients in clinical trials [seeAdverse Reactions ( 6.1 )] and, in some cases, may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.

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 [seeWarnings and Precautions (5.1)]
• •Pancreatitis [see Warnings and Precautions (5.2)]
• •Glucose intolerance [see Warnings and Precautions (5.3)]
• •Thrombosis and hemorrhage [seeWarnings 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.