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ERWINASE®

SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT_

ERWINASE®, 10,000 Units/vial, Lyophilisate for solution for injection.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Crisantaspase (Asparaginase from Erwinia chrysanthemi; Erwinia L-asparaginase), 10,000 Units/vial.

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM_

Lyophilisate for solution for injection.

White lyophilised powder in a vial.

4.    CLINICAL PARTICULARS_

4.1    Therapeutic indications

Erwinase is used in combination with other anti-neoplastic agents to treat acute lymphoblastic leukaemia. It may also be used in other neoplastic conditions where depletion of asparagine might be expected to have a useful effect. Patients receiving treatment with L-asparaginase from Escherichia coli, and who develop hypersensitivity to that enzyme may be able to continue treatment with Erwinase as the enzymes are immunologically distinct.

4.2    Posology and method of administration Posology

For all patients the usual dose is 6,000 Units/m² body surface area (200 Units/kg of body weight), three times a week for three weeks.

Therapy may be further intensified according to protocol. Reference to current Medical Research Council protocols on leukaemia therapy should be made for information on dose, route and frequency of treatment.

Method of administration

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

4.3    Contraindications

Previous allergic reaction to Erwinia asparaginase.

Previous episode of acute pancreatitis related to L-asparaginase therapy.

Breast-feeding (see section 4.6).

4.4    Special warnings and precautions for use Warnings: Anaphylactic reactions have been observed after the use of Erwinase. Facilities should be made available for management of an anaphylactic reaction, should it occur, during administration.

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 reactions occurring.

Posterior Reversible Encephalopathy Syndrome (PRES) may occur rarely during treatment with any asparaginase (see section 4.8). This syndrome 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.

Careful monitoring before and during therapy is necessary:

•    Serum amylase, lipase and/or insulin levels should be monitored to exclude hyperglycaemia and severe pancreatitis. Hyperglycaemia may be treated with insulin, if needed.

•    Routine clotting screening may be performed before treatment initiation. If significant symptomatic coagulopathy occurs withhold L-asparaginase treatment until resolved then continue according to protocol.

•    Hepatic function tests should be monitored regularly during therapy.

4.5    Interaction with other medicinal products and other forms of interaction

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

Concomitant use of L-asparaginase and drugs affecting liver function may increase the risk of a change in liver parameters (e.g. increase of ASAT, ALAT, bilirubin).

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

Concomitant use of prednisone and L-asparaginase may increase the risk of a change in clotting parameters (e.g. a decrease in fibrinogen and ATI 11 levels).

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

4.6    Fertility, pregnancy and lactation

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 clearly necessary. Lactation: it is not known whether Crisantaspase (Erwinia L-asparaginase) is excreted in human breast milk. The excretion of Crisantaspase (Erwinia L-asparaginase) has not been studied in animals. Because potential serious adverse reactions may occur in nursing infants, breast-feeding is contra-indicated.

4.7    Effects on ability to drive and use machines None known.

4.8    Undesirable effects

Adverse effects reported spontaneously and in the literature, from patients treated with L-asparaginase as part of their chemotherapy regime, are listed in the table below. Adverse effects are categorised by system organ class and frequency. The two most frequent adverse reactions are:

Hypersensitivity, including urticaria, laryngeal oedema, bronchospasm, hypotension or even anaphylactic shock. In case of 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. Pancreatic disorders - acute pancreatitis occurs in <10% of cases. There have been isolated reports of pseudocyst formation up to four months after last treatment, so appropriate testing (e.g. ultrasound) may need to be considered beyond last treatment. In very rare cases, haemorrhagic or necrotising pancreatitis occurs, with fatal consequences. L-asparaginase can affect endocrine pancreatic function. Hyperglycaemia is the most commonly reported undesired effect and is readily controlled with administration of insulin. Isolated cases of diabetic ketoacidosis have been reported.

Nervous system and cardiac disorders are often secondary to other adverse effects (e.g. thrombo-embolism) or synergistic to the effects of other chemotherapy drugs (e.g. delayed methotrexate clearance).

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

Undesirable effects are generally reversible.

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”.

Isolated cases reported in the literature or spontaneously have been classified as “Rare” or “Very Rare”.

ERWINASE®

Package leaflet: Information for the patient    10,000 Units

Powder for solution for injection    (Asparaginase from Erwinia chrysanthemi, Erwinia L-asparaginase)

What is in this leaflet:

1.    What Erwinase is and what it is used for

2.    What you need to know before you receive Erwinase

3.    How to receive Erwinase

4.    Possible side effects

5.    How to store Erwinase

6.    Contents of the pack and other information

1. What ERWINASE is and what it is used for

How does Erwinase work

Erwinase is an anti-blood-cell-cancer treatment. It works by lowering the levels of asparagine in your body, a substance the cancer cells need to survive.

What this medicine is used for

Erwinase is used for the treatment of a cancer of the white blood cells called Acute Lymphoblastic Leukaemia. It may also be used to treat other cancers where lower levels of asparagine might have a useful effect.

Erwinase may be used alone or with other treatments.

2. What you need to know before you receive ERWINASE

You should not receive Erwinase if :

■    you are allergic (hypersensitive) to the active substance (Erwinia L-asparaginase) or any of the other ingredients of Erwinase (see section 6.)

■    you have had a bad reaction to treatment with Erwinase on a previous occasion.

■    you have history of pancreas problems (acute pancreatitis).

■    you are pregnant or trying to get pregnant.

■    you are breast-feeding.

Warnings and precautions

Talk to your doctor or pharmacist or nurse before using Erwinase.

Your body may become sensitive to the active substance after repeated treatments. It could be the cause of allergic reactions (see section 4. Possible side effects).

Blood and urine tests

Treatment with Erwinase can sometimes affect the results of certain blood or urine tests. Your doctor will be aware of this and may carry out routine blood tests before and during your treatment to check for any changes.

Posterior reversible encephalopathy syndrome (characterised by headache, confusion, seizures and visual loss) may require blood-pressure lowering medicines and in case of seizure, anti-epileptic treatment.

Other medicines and Erwinase

Tell your doctor or your pharmacist if you are taking, have recently taken, or might take any other medicines.

Please tell your doctor or your pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Your doctor or your nurse will not mix Erwinase with other medicines in the same infusion.

However you will probably be given other medicines before, during or after Erwinase treatment as part of your course of therapy.

Pregnancy and breast feeding

■    You must not use this medicine if you are pregnant. Tell your doctor straightaway if you are pregnant, become pregnant during treatment with this medicine, or plan to become pregnant in the near future.

■    You must not breast-feed your baby during your treatment with Erwinase.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Erwinase is not known to affect your ability to drive or operate machines. However, as in all cases, you should not drive if you feel unwell or if your doctor has advised you not to drive.

Erwinase contains sodium and glucose

Erwinase contains the following ingredients :

■    sodium (less than 23 mg per dose). You can consider this medicine as essentially sodium free if you are on a salt-free or low-salt diet.

■    glucose. If you are diabetic, please note that each bottle of Erwinase contains 5 mg glucose

3. How to receive ERWINASE

Dosage

Your doctor will decide what dose to administer, how often you will be given Erwinase and for how long. It varies according to your body weight, your specific condition being treated, and your response to therapy.

Method of administration

Erwinase can be given to you in one of the following ways:

a)    Into a vein (intravenous use).

b)    Into a muscle (intramuscular use).

c)    Just under the skin (subcutaneous use).

Erwinase should be injected by your doctor or your nurse.

Your treatment will normally be given without interruption. If your dose is large, it may be given at two different sites.

If you receive more Erwinase than you should

If you are concerned that you have been given too much Erwinase, contact your doctor or another healthcare professional immediately.

If you don’t receive Erwinase

If you are concerned that you have missed a dose, contact your doctor or another healthcare professional immediately.

If you have any further questions on this product, ask your doctor or pharmacist.

4. Possible side effects

5. How to store ERWINASE

Like all medicines, Erwinase can cause side effects, although not everybody gets them. Erwinase will be given under strict medical supervision and your doctor may give you other medicines to treat these side effects. Most of the side effects will stop once you stop taking Erwinase.

The most common side effects experienced by patients treated with Erwinase are:

Allergic reactions: You may develop the following symptoms: redness or inflammation of the skin, decrease in blood pressure, swelling of the face and/or the throat and difficulty breathing. You may require emergency treatment and should seek medical advice immediately. Erwinase treatment should be discontinued.

Coagulation disorders: Asparaginase can increase the risk of your blood clotting, which may block major blood vessels in the brain or heart, or may cause bleeding.

Common (may affect up to 1 in 10 people) side effects include:

Fits (convulsions), drowsiness, confusion, dizziness, tiredness or headache.

Pancreas disorders with increase of the blood glucose level or other changes in blood tests. Diarrhoea.

Pale skin.

Unusual blood test results in liver enzymes.

High temperature, chills, generalised pain, swelling of legs and injection site reactions (pain, redness, bruising, swelling)

Uncommon (may affect up to 1 in 100 people) side effects include:

Difficulty breathing or stopping breathing. Increase in blood levels of sugars and lipids (fats).

Runny nose.

Rare (may affect up to 1 in 1,000 people) side effects include:

Liver failure.

Complication of diabetes.

Depressed level of consciousness or coma. Difficulty speaking, difficulty swallowing, impaired movement.

Heart attack, usually secondary to other adverse effects.

Posterior reversible encephalopathy syndrome (a condition characterized by headache, confusion, seizures and visual loss).

Very rare (may affect up to 1 in 10,000 people) side effects include:

Severe inflammation of the pancreas.

Muscle pain, joint pain.

Low white blood cells as manifested by increased susceptibility to infection.

Other side effects with unknown frequency include: High blood levels of ammonia.

High or low blood pressure, flushing.

Nausea, vomiting, abdominal pain.

Liver disorders.

Pain in arms and legs.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed (see the details below).

By reporting side effects you can help provide more information on the safety of this medicine.

Keep out of the reach and sight of children.

Erwinase will be stored in a refrigerator (2°C to 8°C) by the hospital and must not be used after the expiry date which is stated on the label. The expiry date refers to the last day of the month.

6. Contents of the pack and other information

What Erwinase contains

The active substance is Erwinia L-asparaginase. Each vial contains 10,000 Units Erwinia L-asparaginase.

The other ingredients are sodium chloride and glucose monohydrate.

What Erwinase looks like and contents of the pack

Erwinase comes as a white powder in a glass bottle. Each pack contains 5 glass bottles of powder.

Marketing Authorisation Holder

Porton Biopharma Limited Manor Farm Road,

Porton Down, Salisbury, SP4 0JG United Kingdom

Manufacturer

AndersonBrecon (UK) Ltd Hay on Wye, Hereford, HR3 5PG,

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Local representative

Jazz Pharmaceuticals UK Limited Pharmacovigilance and Medical information Tel:+44 8450305089 e-mail: medinfo-uk@jazzpharma.com

This Leaflet was last revised in September 2016

Erwinase is a registered trademark of Porton Biopharma Limited.

NOT/ERW/EN/072/09

United Kingdom

Yellow Card Scheme

We bsite: www. m hra.gov.uk/yellowcard

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 the national reporting system listed (see below).

United Kingdom

Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

No specific measures are recommended.

5. PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents ATC code: L01XX02

Asparagine is 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. Neoplastic cells associated with Acute Lymphoblastic Leukaemia (ALL), Acute Myeloid Leukaemia (AML) and Non-Hodgkin’s Lymphoma (especially the lymphoblastic form) are lacking asparagine synthetase activity and are dependent upon exogenous asparagine.

The anti-tumour activity of L-asparaginase is a result of the sustained depletion of exogenous asparagine. L-asparaginase catalyses the deamination of asparagine to aspartic acid with the release of ammonia. The biochemical reaction may be depicted schematically as follows:

Erwinia L-asparaginase

Asparagine -► Aspartate + NH₃

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 as follows:

Erwinia L-asparaginase

Glutamine -► Glutamate + NH₃

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

5.2    Pharmacokinetic properties

The half-life of Erwinase after i.v. infusion is 6.4 ± 0.5 hours. The half-life of Erwinase after i.m. infusion is about 16 hours. 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 pM) and to serum levels that predict clinical efficacy.

With repeated use, the drug may be bound by specific antibodies and eliminated.

IM study:

The serum trough concentrations of crisantaspase were determined in 48 ALL patients aged >2year to <18 years enrolled in a single-arm study, multi-centre, open-label, safety and clinical pharmacology trial AALL07P2. 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 U/mL.

Following intramuscular administration at a dose of 25,000 U/m² for the first course, serum asparaginase activity is maintained above 0.1 U/mL at 48 hours post-dose in 92.5% of patients, and at least at 0.1 U/mL after 72 hours in 88.5% of patients.

IV Study:

The serum trough asparaginase activity was determined in 24 ALL patients aged >1 year to <17 years enrolled in a single-arm, multi-centre, open-label, pharmacokinetic study 100EUSA12. The primary objective of the study was to determine the proportion of patients with 2-day nadir (trough) serum asparaginase activity levels (48-hour levels taken after the fifth dose) that were >0.1 U/mL in the first 2 weeks of Erwinase treatment (three times per week IV) in patients with ALL/LBL who had developed hypersensitivity to native E. coli asparaginase, pegaspargase, or calaspargase pegol. Following intravenous administration over 1 hour at a dose of 25,000 U/m² for the first course, serum asparaginase activity was maintained >0.1 U/mL at 48 hours post-dose 5 (primary endpoint) in 83% of patients, and >0.1 U/mL 72 hours post dose 6 (secondary endpoint) in 43% of patients.

5.3 Pre-clinical safety data

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.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium Chloride Glucose Monohydrate

6.2    Incompatibilities

See section 4.5 "Interactions with other medicinal products and other forms of interaction".

6.3    Shelf-life

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

Shelf-life following reconstitution according to directions:

15 minutes in the original container, 8 hours in a glass or polypropylene syringe. (See section 6.6 "Special precautions for disposal and other handling").

6.4    Special precautions for storage Store in a refrigerator (+2°C to +8°C).

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.

6.6    Special precautions for disposal and other handling

The contents of each vial should be reconstituted in 1 ml to 2 ml of sodium chloride (0.9%) solution for injection. Slowly add the reconstitution solution 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. 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 8 hours.

Erwinase is not a cytotoxic drug (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.

7.    MARKETING AUTHORISATION HOLDER_

Porton Biopharma Limited,Manor Farm Road, Porton Down, Salisbury, SP4 0JG, United Kingdom

8.    MARKETING AUTHORISATION NUMBER(S)

PL44403/0002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

First authorisation:    19 July 1985

Latest renewal:    May 2006

10. DATE OF REVISION OF THE SPC

September 2016 Local representative:

Jazz Pharmaceuticals UK Limited

Pharmacovigilance and Medical information

Tel:+44 8450305089

e-mail: medinfo-uk@jazzpharma.com

Erwinase is a registered trademark of Porton Biopharma Limited.

NOT/ERW/EN/072/09

Jazz Pharmaceuticals’