Product name

Erwinaze®- asparaginase injection, powder, lyophilized, for solution

Erwinase® 10,000 IU/vial Powder for solution for injection/infusion

Indication

1 Indications and Usage

ERWINAZE 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.

4 Clinical Particulars

4.1 Therapeutic indications

Erwinase is indicated as a component of a chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukaemia (ALL) who have developed hypersensitivity to E. coli-derived asparaginase.

Erwinase is indicated in paediatric patients from the age of 4 months and in adults.

2.3 Administration Instructions

Administer ERWINAZE in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis.

ERWINAZE solution can be administered by intramuscular injection or by intravenous infusion.

• For intramuscular use, 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.
• For intravenous use, infuse ERWINAZE in 100 mL of normal saline over 1 to 2 hours. Do not infuse other intravenous drugs through the same intravenous line while infusing ERWINAZE.

Method of administration

Erwinase solution can be given by intravenous infusion or intramuscular injection.

For IM injection the volume of reconstituted solution administered at a single injection site should not exceed 2 mL. Multiple injection sites should be used if this volume is exceeded.

For IV infusion, the reconstituted solution should be further diluted in 100 mL of normal saline and administered over 1 to 2 hours.

For further instructions on reconstitution of the medicinal product before administration, see section 6.6.

Description

3 DOSAGE FORMS AND STRENGTHS

For injection: 10,000 International Units as a lyophilized powder in a single-dose vial for reconstitution

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).

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Crisantaspase (L-asparaginase from Erwinia chrysanthemi), 10,000 International units/vial.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for injection/infusion.

White lyophilised powder in a vial.

6.1 List of excipients

Sodium Chloride (0.5 mg)

Glucose Monohydrate (5.0 mg)

Contraindications

4 CONTRAINDICATIONS

ERWINAZE is contraindicated in patients with a history of:

• Serious hypersensitivity reactions to ERWINAZE, including anaphylaxis
• Serious pancreatitis with prior L-asparaginase therapy
• Serious thrombosis with prior L-asparaginase therapy
• Serious hemorrhagic events with prior L-asparaginase therapy

4.3 Contraindications

• History of severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Current or past severe pancreatitis associated with L‑asparaginase therapy
• Current pancreatitis not associated with L‑asparaginase therapy

5.4 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.

Coagulation Disorders

Administration of L-asparaginase, including Erwinase, leads to decreased synthesis of coagulant, anticoagulant, and fibrinolytic proteins, abnormal coagulation times, and clinical coagulation abnormalities that can cause serious thromboembolic and bleeding events (see section 4.8).

Routine clotting screening should be performed before treatment initiation and monitored during treatment. Preventive measures must be considered.

If significant symptomatic coagulopathy occurs in addition to other clinically indicated interventions withhold Erwinase treatment until resolved. Treatment may then continue according to protocol, if the benefit of continued administration is considered to outweigh the risk from re-exposure.

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 in other studies or to other asparaginase Erwinia chrysanthemi products may be misleading.

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 anti-drug antibody (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

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

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 crisantaspase with the incidence of antibodies to other products may be misleading.

In a study with Erwinase treatment by IM administration (Study ALL07P2), 6 of 56 (11%) patients treated with Erwinase developed antibodies to crisantaspase. Of these 6 ADA positive patients, one experienced a hypersensitivity reaction (2%, 1 of 56). None of these 6 patients had neutralising antibodies.

In a study with Erwinase treatment by IV administration (Study 100EUSA12), 4 of 30 (13.3%) patients treated with Erwinase developed anti-crisantaspase antibodies. Of these 4 patients, 3 experienced hypersensitivity reactions (10%, 3 of 30). None of these 4 patients had neutralising antibodies

Neutralising antibodies

As with other L-asparaginase preparations, development of specific neutralising antibodies has been reported with repeated dosing and is associated with reduced L-asparaginase activity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Drug interactions

Note: The following information is provided in the USPI under section 12.3 Pharmacokinetics

Drug Interaction Studies

No formal drug interaction studies between ERWINAZE and other drugs have been performed

4.5 Interaction with other medicinal products and other forms of interaction

No formal medicinal product interaction studies have been performed.

Asparaginase must not be mixed with any other medicinal products prior to administration.

In addition concomitant use of L-asparaginase and medicinal products affecting liver function may increase the risk of a change in liver parameters (e.g. increase of ASAT, ALAT, bilirubin).

Since an indirect interaction between components of the oral contraception and asparaginase cannot be ruled out, oral contraceptives are not considered sufficiently safe in such clinical situation. Another method than oral contraception should be used in women of childbearing potential (see section 4.6).

• Methotrexate, cytarabine

L-asparaginase may diminish or abolish methotrexate’s and cytarabine’s effect on malignant cells; this effect persists as long as plasma asparagine levels are suppressed. Accordingly, do not use methotrexate or cytarabine with, or following L-asparaginase, while asparagine levels are below normal.

Alternatively, administration of L-asparaginase after methotrexate or cytarabine results in a synergistic effect. The extent to which these affect the overall effectiveness of established treatment protocols is not known.

• Prednisone

Concomitant use of prednisone and L-asparaginase may increase the risk of a change in clotting parameters (e.g. a decrease in fibrinogen and ATIII levels).

• Vincristine

Administration of vincristine concurrently with or immediately before treatment with L-asparaginase may be associated with increased toxicity and increased risk of anaphylaxis.

8.5 Geriatric Use

Clinical studies of ERWINAZE did not include geriatric patients.

e. Other special populations

No special individual populations of patients have been identified in which the safety profile differs from that defined above.

Overdosage

There are no corresponding clinical data for Erwinaze USPI

4.9 Overdose

There is no known antidote for asparaginase overdoses. No data are available on the elimination (peritoneal or by haemodialysis) of the product. Patients who accidentally receive an overdose of L-asparaginase should be monitored closely and receive any appropriate symptomatic and supportive treatment.

12.3 Pharmacokinetics

Based on a population PK model, the mean (%CV) half-life of intravenous ERWINAZE was 7.51 (23.9%) hours in contrast to a mean (%CV) half-life of 15.6 (20%) hours reported for intramuscular ERWINAZE. These differences in PK between intravenous and intramuscular ERWINAZE are reflected in the proportion of patients with 2-day and 3-day nadir serum asparaginase activity (NSAA) levels of asparaginase Erwinia chrysanthemi ≥ 0.1 or 0.4 IU/mL [see Clinical Studies (14)].

Following administration of ERWINAZE 25,000 International Units/m2 intramuscularly to 48 ALL patients aged ≥ 2 years to ≤ 18 years in Study 1 on a Monday, Wednesday, and Friday schedule for 6 doses, 100% of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at either 48 hours (n=35) or 72 hours (n=13) post dose 3. Eighty percent (28/35) of those evaluated at 48 hours and 38% (5/13) evaluated at 72 hours had nadir serum asparaginase activity levels ≥ 0.4 International Units/mL [see Clinical Studies (14)].

Following intravenous administration of ERWINAZE 25,000 International Units/m2 to 24 evaluable patients (aged ≥ 1 year to ≤ 17 years) in Study 2 on a Monday, Wednesday, and Friday schedule, 83% (20/24) and 43% (9/21) of patients who completed Course 1 achieved NSAA levels ≥ 0.1 International Units/mL at 48 hours post-dose 5 and 72 hours post dose 6, respectively. Twenty-nine percent (7/24) of those evaluated at 48 hours and no patients (0/21) evaluated at 72 hours had nadir serum asparaginase activity levels ≥ 0.4 International Units/mL [see Clinical Studies (14)].

Drug Interaction Studies

No formal drug interaction studies between ERWINAZE and other drugs have been performed

5.2       Pharmacokinetic properties

Based on a population PK model, the mean (%CV) half-life of crisantaspase is 7.5 (24%) hours after intravenous infusion in contrast to 15.6 (20%) hours after intramuscular injection. L-asparaginase penetrates through to the cerebrospinal fluid to a small degree and is also found in lymph.

Serum trough asparaginase activity ≥ 0.1 U/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.

Clinical trials

Study 1 (AALL07P2) was a single-arm, multicentre, open-label, safety and clinical pharmacology trial, which enrolled ALL patients who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was the proportion of patients who achieved a serum trough asparaginase level      ≥ 0.1 IU/mL, which correlates with asparagine depletion and predicts clinical efficacy. Patients received Erwinase 25,000 IU/m2 intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase.

Out of 58 patients enrolled, 48 were evaluable for the main outcome measure in the first treatment course. The median age was 11 years (2 to 18 years) and 59% were male.

Study 2 (100EUSA12) was a single-arm, multicentre pharmacokinetic study in patients with ALL/LBL who had developed hypersensitivity to native E. coli asparaginase, pegaspargase, or calaspargase pegol. Patients received Erwinase 25,000 IU/m2 intravenously 3 days per week for up to 30 weeks. The main outcome measure was the proportion of patients with 2-day nadir serum asparaginase activity (NSAA) levels after the fifth dose ≥ 0.1 IU/mL.

Out of 30 patients enrolled, 24 were evaluable for the main outcome measure in the first treatment course. The median age was 7 years (1-17 years) and 63% were male.

The results of the two studies are presented in the table below.

Proportion of patients with sustained asparaginase activity

Neutralising antibodies

As with other L-asparaginase preparations, development of specific neutralising antibodies has been reported with repeated dosing and is associated with reduced L-asparaginase activity.

Cerebrospinal fluid activity

After IM administration of 25,000 IU/m2 Erwinase per week for 16 weeks, CSF L-asparagine levels were undetectable 3 days after last administration in 5 of 8 children (62.5%), and in 2 of 8 children (25%) after both the 5th and 6th administration during reinforced re-induction therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 12000 IU/m2 (approximately 0.50 times the maximum recommended human dose) every other day for a total of 35 doses. Findings in males included decreased sperm count at doses of more than 3000 IU/m2 (approximately 0.12 times the maximum recommended human dose).

5.3 Preclinical safety data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Reproduction and development toxicity

Embryotoxicity studies with Erwinia L-asparaginase have given evidence of teratogenic potential in rabbits. In addition, pre-clinical experience with other asparaginase preparations has shown teratogenic potential in rats, mice and rabbits with doses in the therapeutic ranges.

In a fertility and early embryonic development study in rats, IM administration of crisantaspase had no effect on male and female fertility at doses approximately 50% of the recommended human dose (based on body surface area). However, a 12 to 15% decrease in sperm count was observed at doses approximately 12 to 50% of the recommended human dose.

Carcinogenicity

Non-clinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of crisantaspase. Crisantaspase is an enzyme for which the structure and well documented activity do not suggest any carcinogenic or mutagenic potential.

Clinical data

14 CLINICAL STUDIES

The efficacy of ERWINAZE for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. Coli-derived asparaginase as a component of a multi-agent chemotherapeutic regimen was established in Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial. Additional safety data were 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)].

The safety and efficacy of intravenous administration were determined in Study 2 by characterizing the PK of a 25,000 International Units/m2 ERWINAZE dose given 3 days per week on a Monday, Wednesday, and Friday schedule for up to 30 weeks. This open-label, single-arm, multicenter PK study enrolled 30 patients. The main outcome measure was determination of the proportion of patients with 2-day NSAA levels (48-hour levels taken after the fifth dose) ≥ 0.1 International Unit/mL in the first 2 weeks of ERWINAZE treatment.

Of the thirty patients enrolled, 24 were evaluable for the main outcome measure based on the pharmacokinetic samples in Course 1. The median age was 7 years (1-17 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).

In Study 2, serum asparaginase activity of asparaginase Erwinia chrysanthemi was determined in 24 evaluable patients (aged ≥ 1 year to ≤17 years) following intravenous administration of ERWINAZE 25,000 International Units/m2. Five minutes after the 60-minute infusion in Course 1, the mean asparaginase activity level was 12.65 ± 3.16 International Unit/mL post-dose 1 and 12.11 ± 3.11 International Unit/mL post dose 4. The main study objective was met with an asparaginase activity level of ≥ 0.1 International Units/mL 48 hours after the fifth dose observed in 83% of patients. The 72-hour post dose 6 asparaginase activity level of ≥ 0.1 International Unit/mL was the secondary endpoint, with 43% of patients achieving this endpoint. Results are presented in Table 3 [see Clinical Pharmacology (12.3)].

5.2       Pharmacokinetic properties

Based on a population PK model, the mean (%CV) half-life of crisantaspase is 7.5 (24%) hours after intravenous infusion in contrast to 15.6 (20%) hours after intramuscular injection. L-asparaginase penetrates through to the cerebrospinal fluid to a small degree and is also found in lymph.

Serum trough asparaginase activity ≥ 0.1 U/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.

Clinical trials

Study 1 (AALL07P2) was a single-arm, multicentre, open-label, safety and clinical pharmacology trial, which enrolled ALL patients who were unable to continue to receive pegaspargase due to hypersensitivity reactions. The main outcome measure was the proportion of patients who achieved a serum trough asparaginase level      ≥ 0.1 IU/mL, which correlates with asparagine depletion and predicts clinical efficacy. Patients received Erwinase 25,000 IU/m2 intramuscularly for two weeks (total 6 doses) as a replacement for each scheduled dose of pegaspargase.

Out of 58 patients enrolled, 48 were evaluable for the main outcome measure in the first treatment course. The median age was 11 years (2 to 18 years) and 59% were male.

Study 2 (100EUSA12) was a single-arm, multicentre pharmacokinetic study in patients with ALL/LBL who had developed hypersensitivity to native E. coli asparaginase, pegaspargase, or calaspargase pegol. Patients received Erwinase 25,000 IU/m2 intravenously 3 days per week for up to 30 weeks. The main outcome measure was the proportion of patients with 2-day nadir serum asparaginase activity (NSAA) levels after the fifth dose ≥ 0.1 IU/mL.

Out of 30 patients enrolled, 24 were evaluable for the main outcome measure in the first treatment course. The median age was 7 years (1-17 years) and 63% were male.

The results of the two studies are presented in the table below.

Proportion of patients with sustained asparaginase activity

Cerebrospinal fluid activity

After IM administration of 25,000 IU/m2 Erwinase per week for 16 weeks, CSF L-asparagine levels were undetectable 3 days after last administration in 5 of 8 children (62.5%), and in 2 of 8 children (25%) after both the 5th and 6th administration during reinforced re-induction therapy.

Supply, storage and handling

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.

6.5      Nature and contents of container

Type 1 clear neutral glass vials of 3 ml nominal capacity, closed with 13 mm halobutyl freeze-drying stoppers and aluminium overseals, containing a white lyophilised solid.

Pack size: 5 vials.

6.4     Special precautions for storage

Store in a refrigerator (+2°C to +8°C).

For storage conditions of the reconstituted medicinal product, see section 6.3.

17 PATIENT COUNSELING INFORMATION

Hypersensitivity

Inform patients of the risk of allergic reactions, including anaphylaxis. Instruct patients on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms [see Warnings and Precautions (5.1)].

Pancreatitis

Instruct patients on the risk of pancreatitis and to seek medical advice immediately if they experience abdominal pain [see Warnings and Precautions (5.2)].

Glucose Intolerance

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 [see Warnings and Precautions (5.3)].

Thrombosis

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 [see Warnings and Precautions (5.4)].

Pregnancy and Lactation

Advise female patients of reproductive potential to use effective contraceptive methods while receiving ERWINAZE and for at least 3 months after the last dose. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during ERWINAZE treatment [see Use in Specific Populations (8.3)]. Advise lactating women not to breastfeed during treatment with ERWINAZE and for at least 3 months after the last dose [see Use in Specific Populations (8.2)].

There is no corresponding section for Erwinase SmPC