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

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.

Posology

The recommended dosage is 20,000 or 25,000 IU/m2 body surface area administered three times a week (e.g., Monday/Wednesday/Friday).

Therapy should be adjusted according to local treatment protocols.

Method of administration

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

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

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

• 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

In order to improve traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded (or stated) in the patient file.

Hypersensitivity reactions

Administration of Erwinase can cause hypersensitivity reactions (infusion/injection reactions), including reactions presenting as anaphylaxis.

Severe reactions are common.

Reactions have occurred following the first or subsequent administrations.

There is little or no cross-reactivity between crisantaspase and E. coli-derived L-asparaginase. Reactions include

• reactions limited to the area at or near the site of IM or IV administration, and

• other reactions, including

Reactions can begin during or immediately following administration. In the majority of patients, local and non-local reactions occur within the first 24 hours. Later onset of reactions has been reported two days or later after IM administration.

Facilities should be made available for management of an anaphylactic reaction, should it occur, during administration. If a severe reaction occurs, Erwinase must be discontinued (see section 4.3).

Careful observation is required on re-exposure to L-asparaginase after any time interval (e.g. between induction and consolidation), which may increase the risk of anaphylactic and hypersensitivity reactions occurring.

Pancreatitis

Treatment with L-asparaginase, including Erwinase, can cause pancreatitis. L-asparaginase-induced pancreatitis can be limited to biochemical and/or radiologic manifestations, progress to pancreatitis with clinical symptoms, and be severe (see section 4.8).

Fatal outcome of pancreatitis due to L-asparaginase products, including Erwinase, has been reported.

Patients must be closely monitored for signs and symptoms of pancreatic toxicity and instructed to promptly report potential symptoms of pancreatitis. If pancreatitis is suspected based on clinical symptoms, serum amylase and lipase should be determined. In patients treated with L-asparaginase, increases of serum amylase and lipase may be delayed, mild or absent.

Erwinase must be permanently discontinued in case of severe pancreatitis (see section 4.3). Hypertriglyceridemia, if marked, can contribute to the development of pancreatitis (see section 4.8).

There have been isolated reports of first onset of clinical pancreatitis and detection of pancreatic pseudocyst formation several months after the last administration of L-asparaginase. Patients must be monitored for late-occurring signs of pancreatitis.

Development of chronic pancreatitis as well as persistent pancreatic insufficiency (exocrine insufficiency with, e.g., malabsorption; persistent glucose intolerance/diabetes mellitus) has been reported with L- asparaginase treatment.

Glucose Intolerance

Treatment with L-asparaginase, including Erwinase, can cause glucose intolerance and potentially severe hyperglycemia.

In some patients, ketoacidosis has been reported.

Patients must be monitored for developing hyperglycemia and potential complications.

Administration of insulin and possibly discontinuation of L-asparaginase treatment may be necessary to manage hyperglycemia.

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.

Hepatic Effects

Treatment with L-asparaginase, including Erwinase, can cause or worsen hepatic injury/dysfunction (including increase in transaminases and bilirubin, hepatic steatosis and hepatic failure). In addition, L- asparaginase reduces hepatic protein synthesis, leading to, e.g. hypoalbuminemia (see also Coagulation Disorders and section 4.8).

Hepatic function tests should be monitored regularly during therapy (See section 4.5).

In case of severe hepatic adverse reactions, discontinuation of Erwinase should be considered until complete or near-complete (CTCAE Grade 1) recovery. Treatment must be re-instituted only under very close monitoring.

Neurological Disorders

CNS toxicity, including encephalopathy, seizures and CNS depression as well as Posterior Reversible Encephalopathy Syndrome (PRES) may occur rarely during treatment with any asparaginase, including Erwinase (see section 4.8).

PRES is characterised in magnetic resonance imaging (MRI) by reversible (from a few days to months) lesions/oedema, primarily in the posterior region of the brain. Symptoms of PRES essentially include elevated blood pressure, seizures, headaches, changes in mental state and acute visual impairment (primarily cortical blindness or homonymous hemianopsia).It is unclear whether the PRES is caused by asparaginase, concomitant treatment or the underlying diseases. PRES is treated symptomatically, including measures to treat any seizures. Discontinuation or dose reduction of concomitantly administered immunosuppressive medicinal products may be necessary. Expert advice should be sought.

Since hyperammonemia, if present, may cause or contribute to CNS toxicity, consider measuring serum ammonia in patients with CNS toxicity. In symptomatic patients initiate treatment as appropriate.

Fatal outcome of L-asparaginase-induced CNS toxicity has been reported.

Renal Impairment

Renal impairment may be caused or aggravated by the chemotherapy regimen. Renal function and serum uric acid levels should be monitored.

Immunosuppression, Infections

L-asparaginase has been reported to have immunosuppressive activity in animal experiments.

This should be considered because Erwinase is used concomitantly with other agents that can reduce immune response and increase the risk for infections.

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.

Pregnancy

There are no adequate data from the use of crisantaspase (Erwinia L-asparaginase) in pregnant women. Limited reports in humans of the use of E.coli asparaginase in combination with other antineoplastics during pregnancy did not provide sufficient data to conclude. However, based on effects on embryonal/foetal development shown in pre-clinical studies (see section 5.3),

Erwinase should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should use effective contraception and avoid becoming pregnant while being treated with asparaginase-containing chemotherapy.

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. A method other than oral contraceptives should be used in women of childbearing potential.

Men should use effective contraceptive measures and be advised to not father a child while receiving asparaginase.

The time period following treatment with asparaginase when it is safe to become pregnant or father a child is unknown. As a precautionary measure it is recommended to wait for three months after completion of treatment. However, treatment with other chemotherapeutic agents should also be taken into consideration.

Breastfeeding

It is not known whether crisantaspase (Erwinia L-asparaginase) is excreted in human breast milk. Potential serious adverse reactions may occur in nursing infants, therefore Erwinase should be discontinued during breastfeeding.

Fertility

There are no human data on the effect of crisantaspase on fertility. In rats, crisantaspase did not affect male and female fertility. However, a decrease in sperm count was observed in male rats (see section 5.3). The relevance of this finding to humans is not known.

Erwinase may have a minor influence on the ability to drive and use machines. Dizziness, somnolence and other central nervous system effects may occur following administration of Erwinase (see section 4.8).

a. Summary of the safety profile

The two most frequent adverse reactions are:

• Hypersensitivity, including urticaria, fever, arthralgia angioedema, bronchospasm, hypotension or even anaphylactic shock. In case of severe systemic hypersensitivity reaction, treatment should be discontinued immediately and withdrawn.

• Coagulation abnormalities (e.g. thromboses), due to protein synthesis impairment, are the second most frequent class of adverse reactions. Thromboses of peripheral, pulmonary or central nervous system blood vessels have been reported, potentially fatal or with residual delayed affects dependent upon the location of the occlusion. Other risk factors contributing to coagulation abnormalities include the disease itself, concomitant steroid therapy and central venous catheters.

Undesirable effects are generally reversible.

b. Tabulated list of adverse reactions

The adverse reaction data presented in Table 1 have been identified from 3 clinical studies (100EUSA12, AALL07P2, and Erwinase Master Treatment Protocol [EMTP]) with Erwinase in 1028 patients (primarily pediatric patients), the majority having acute lymphoblastic leukemia, as well as post-marketing experience with Erwinase and other L-asparaginase preparations in pediatric and adult patients.

Some of the adverse reactions listed below are known to be associated with multi-agent chemotherapeutic regimens (e.g., reactions resulting from bone marrow depression, and infections), and the contributory role of Erwinase is not clear. In individual cases of other adverse reactions, other medicinal products of the regimen may have contributed.

Frequency definitions: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10000 to <1/1000) and very rare (<1/10000).When no valid estimate of the incidence rate for an adverse event from available data can be calculated, the frequency of such ADR has been classified as “ Not known” .

c. Description of selected adverse reactions

Posterior reversible encephalopathy syndrome

In rare cases, a posterior reversible encephalopathy syndrome (PRES) has been observed during therapy with asparaginase-containing regimens.

Immunogenicity

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

In a study with Erwinase treatment by IM administration (Study AALL07P2), 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.

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.

d. Pediatric population

Compared with children, the incidence of hepatic and pancreatic toxicities and of venous thromboembolic events may be increased in adolescents and young adults.

e. Other special populations

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

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.

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.

Pharmacotherapeutic group: other antineoplastic agents ATC code: L01XX02

Mechanism of action

L-asparaginase catalyses the deamination of asparagine to aspartic acid with the release of ammonia.

Asparagine is an amino acid found incorporated into most proteins, and protein synthesis is halted in its absence, thereby inhibiting RNA and DNA synthesis with a resulting halt to cellular proliferation.

As lymphoblastic cells are lacking asparagine synthetase activity they are dependent upon exogenous asparagine. The anti-tumour activity of L-asparaginase is a result of the sustained depletion of exogenous asparagine.

It has also been noted that asparaginase, in addition to its asparaginase activity, has significant glutaminase activity. It catalyses the deamination of glutamine in glutamic acid with the release of ammonia.

Glutamine may lead to alternative asparagine synthesis and therefore glutamine depletion may complement asparagine depletion. However, exact potential of this glutaminase activity remains unknown.

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 μ M) 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

a. Trough sampling time is post-dose 3 at 48 and 72

b. Trough sampling time is post-dose 5 at 48 hours and post-dose 6 for 72 hours

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.

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.

Sodium Chloride

Glucose Monohydrate

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Accordingly, other intravenous medicinal products must not be infused through the same intravenous line while infusing Erwinase.

Shelf life of product as packed for sale: 3 years.

Shelf life following reconstitution according to directions: 15 minutes in the original container. Chemical and physical stability of the reconstituted solution when stored in a glass or transparent polypropylene syringe at a temperature below 25 ° C was demonstrated for up to 4 hours.

From a microbiological perspective, the reconstituted solution for injection must be used immediately unless the method of dilution excludes the risk of microbiological contamination. If the reconstituted solution is not used immediately, the duration and conditions of storage are the responsibility of the user.

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

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

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

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.

The contents of each vial should be reconstituted in 1 mL or 2 mL of sodium chloride (0.9%) solution for injection.

When reconstituted with 1 mL the resultant concentration is 10,000 IU/mL. When reconstituted with 2 mL the resultant concentration is 5,000 IU/mL

Slowly add the sodium chloride (0.9%) solution for injection against the inner vial wall, do not squirt directly onto or into the powder.

Allow the contents to dissolve by gentle mixing or swirling maintaining the vial in an upright position, avoiding contact of the solution with the stopper. Avoid froth formation due to excessive or vigorous shaking.

The solution should be clear without any visible particles. Fine crystalline or thread-like wisps of protein aggregates may be visible if shaking is excessive. If there are any visible particles or protein aggregates present the reconstituted solution should be rejected.

The solution should be administered within 15 minutes of reconstitution. If a delay of more than 15 minutes between reconstitution and administration is unavoidable, the solution should be withdrawn into a glass or polypropylene syringe for the period of the delay. The solution should be used within 4 hours.

Erwinase is not a cytotoxic medicinal product (such as vincristine or methotrexate) and does not require the special precautions needed for manipulating such agents. It should be handled in the same way as other therapeutic enzymes such as hyaluronidase.

Any unused product or waste material should be disposed of in accordance with local requirements.