ERWINASE 10 000 UNITS/VIAL LYOPHILISATE FOR SOLUTION FOR INJECTION
Active substance(s): CRISANTASPASE
ERWINASE®, 10,000 Units/vial, Lyophilisate for solution for
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
4.2 Posology and method of administration
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
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.
Previous allergic reaction to Erwinia asparaginase.
Previous episode of acute pancreatitis related to
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,
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
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
4.5 Interaction with other medicinal products and
other forms of interaction
Asparaginase must not be mixed with any other drugs prior to
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
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).
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
4.7 Effects on ability to drive and use machines
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
In rare cases, a posterior reversible encephalopathy syndrome
(PRES) has been observed during therapy with asparaginasecontaining 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”.
Package leaflet: Information for the patient
Powder for solution for injection
What is in this leaflet:
1. What Erwinase is and what it is used for
2. What you need to know before you receive
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.
Infections and infestations:
Infections and life-threatening sepsis.
Blood and lymphatic system disorders:
Very Common: Coagulation abnormalities - decreased
levels of clotting factor, antithrombin III,
protein C, protein S and fibrinogen (1).
Coagulation abnormalities associated with
bleeding or thrombotic complications,
Neutropenia, febrile neutropenia and
Immune system disorders:
Hypersensitivity or systemic allergic
Erwinase may be used alone or with other
2. What you need to know before you
Metabolic and nutrition disorders:
Elevation of serum amylases and lipase.
Hyperlipidaemia(1) and hyperglycaemia.
Nervous system disorders:
(grand mal, partial seizures)(2), headache.
Dysphasia, dysphagia, paresis and
encephalopathy(3), CNS depression and
coma. Posterior Reversible Encephalopathy
Myocardial infarction – secondary to other
Thrombosis of peripheral, pulmonary or
central nervous system blood vessels and
Hypertension, flushing(4) and hypotension(4).
Respiratory, thoracic and mediastinal disorders:
Laryngeal oedema(4), respiratory arrest,
hypoxia, rhinitis and bronchospasm(4).
Gastrointestinal system disorders:
Diarrhoea and acute pancreatitis.
Haemorrhagic or necrotising pancreatitis.
Nausea, vomiting and abdominal pain.
(Asparaginase from Erwinia chrysanthemi, Erwinia L-asparaginase)
Read all of this leaflet carefully before you
start receiving this medicine because it
contains important information for you.
- Keep this leaflet. You may need to read it
- If you have any further questions, ask your
doctor or your pharmacist.
- If you get any side effects, talk to your doctor
or pharmacist or nurse. This includes any
possible side effects not listed in this leaflet.
See section 4.
DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
SUMMARY OF PRODUCT CHARACTERISTICS
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
you are pregnant or trying to get pregnant.
you are breast-feeding.
Warnings and precautions
Talk to your doctor or pharmacist or nurse before
Your body may become sensitive to the active
substance after repeated treatments. It could be the
cause of allergic reactions (see section 4. Possible
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
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
Other medicines and Erwinase
Tell your doctor or your pharmacist if you are taking,
have recently taken, or might take any other
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
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
Method of administration
Erwinase can be given to you in one of the following
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
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
If you have any further questions on this product,
ask your doctor or pharmacist.
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.
Keep out of the reach and sight of children.
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
Common (may affect up to 1 in 10 people) side
- Fits (convulsions), drowsiness, confusion,
dizziness, tiredness or headache.
- Pancreas disorders with increase of the blood
glucose level or other changes in blood tests.
- 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
- Difficulty breathing or stopping breathing.
- Increase in blood levels of sugars and lipids
- Runny nose.
Rare (may affect up to 1 in 1,000 people) side
- Liver failure.
- Complication of diabetes.
- Depressed level of consciousness or coma.
- Heart attack, usually secondary to other adverse
- Posterior reversible encephalopathy syndrome
(a condition characterized by headache,
confusion, seizures and visual loss).
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
What Erwinase contains
The active substance is Erwinia L-asparaginase.
Each vial contains 10,000 Units Erwinia
The other ingredients are sodium chloride and
What Erwinase looks like and contents of the
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
AndersonBrecon (UK) Ltd
Hay on Wye, Hereford, HR3 5PG,
For any information about this medicine, please
contact the local representative of the Marketing
Jazz Pharmaceuticals UK Limited
Pharmacovigilance and Medical information
This Leaflet was last revised in September 2016
Erwinase is a registered trademark of
Porton Biopharma Limited.
As a consequence of inhibition of protein
Convulsions may be associated with cases of
thrombosis or metabolic encephalopathy.
As a consequence of excessive ammonia
production induced by the action of
L-asparaginase on endogenous asparagine
These symptoms are commonly associated
with hypersensitivity reactions.
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).
Yellow Card Scheme
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:
Glutamate + NH3
Glutamine may lead to alternative asparagine synthesis and
therefore glutamine depletion may complement asparagine
depletion. However, exact potential of this glutaminase activity
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.
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.
Yellow Card Scheme
Elevation of bilirubin, ALT, AST, alkaline
phosphatase and cholesterol levels, liver
Not known: Hepatomegaly,
increased BSP retention.
Skin and sub-cutaneous tissue disorders:
Rashes, urticaria, pruritis, erythema, facial
oedema and swelling lips(4).
Musculoskeletal and connective tissue disorders:
Myalgia and reactive arthritis.
Not known: Pain in extremities.
Pyrexia, chills, swelling of limbs, pain in
extremities and injection site reactions
(including pain, erythema, purpura and swelling
at injection site), generalised pain.
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:
Very rare (may affect up to 1 in 10,000 people) side
- Severe inflammation of the pancreas.
- Muscle pain, joint pain.
- Low white blood cells as manifested by
increased susceptibility to infection.
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.
DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
4. Possible side effects
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.
With repeated use, the drug may be bound by specific
antibodies and eliminated.
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.
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
See section 4.5 "Interactions with other medicinal products and
other forms of interaction".
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
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
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)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE
19 July 1985
10. DATE OF REVISION OF THE SPC
Jazz Pharmaceuticals UK Limited
Pharmacovigilance and Medical information
Erwinase is a registered trademark of Porton Biopharma Limited.
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.