Israel - English - Ministry of Health
אירבה דרשמ י"ע עבקנ הז ןולע טמרופ ךיראתב תואירבה דרשמ י"ע רשואו קדבנ ונכותו תו
ןכדועו , ךיראתב תואירבה דרשמ תוארוהל םאתהב
SUMMARY OF PRODUCT CHARACTERISTICS
Name of the medicinal product:
KIDROLASE 10,000 I.U.
powder for solution for injection
Qualitative and quantitative composition
Composition of the powder (for one vial):
L-asparaginase 10,000 I.U.
For one bottle.
For the complete list of excipients, see section 6.1.
Powder for solution for injection.
- Acute lymphoblastic leukemia
- Acute myeloblastic leukemia
4.2. Posology and method of administration:
IV route (by infusion of an isotonic glucose or an isotonic sodium chloride
solution) or IM route:
500 to 1,000 IU per kg per day in children or 7,500 to 10,000 I.U./m
- initial therapy: every day for 6 to 21 days,
- maintenance therapy: 1 or 2 times per week,
- reinduction therapy: 3,000 I.U./m
/day IV x 5 days.
Intradermal skin test
Because of the occurrence of allergic reactions, an intradermal skin test should
be performed prior to the initial administration of KIDROLASE and when
KIDROLASE is given after an interval of a week or more has elapsed between
doses. The skin test solution may be prepared as follows: Reconstitute the
contents of a 10,000 I.U. vial with 5.0ml of diluent. From this solution (2,000
I.U./ml) withdraw 0.1 ml and inject it into another vial containing 9.9ml of diluent,
yielding a skin test solution of approximately 20.0 I.U./ml. Use 0.1 ml of this
solution (about 2.0 I.U.) for the intradermal skin test. The skin test site should be
observed for at least one hour for the appearance of a wheal or erythema either
of which indicates a positive reaction. An allergic reaction even to the skin test
dose in certain sensitized individuals may rarely occur. A negative skin test
reactoion does not preclude the possibility of the development of an allergic
Desensitization should be performed before administering the first dose of
KIDROLASE on initiation of therapy in positive reactors, and on retreatment of
any patient in whom such therapy is deemed necessary after carefully weighing
the increased risk of hypersensitivity reactions. Rapid desensitization of the
patient may be attempted with progressively increasing amounts of intravenously
administered KIDROLASE provided adequate precautions are taken to treat an
acute allergic reaction should it occur. One reported schedule begins with a total
of 1 I.U. given intravenously and doubles the dose every 10 minutes, provided no
reaction has occurred, until the accumulated total amount given equals the
planned doses for that day.
- Known hypersensitivity to the active substance or to any of the excipients listed
in section 6.1. Similarly, a hypersensitivity reaction during treatment
contraindicates the continuation of treatment.
- Hepatic failure
- pancreatitis (see section 4.4).
- In combination with a live attenuated vaccine and until at least six months after
stopping chemotherapy (see section 4.5).
4.4 Special Warnings and precautions for use
Kidrolase should only be used by physicians who specialize in this type of
Anaphylactic reactions have been observed after using Kidrolase.
Administration of this medicinal product must be performed in a healthcare
facility, in the presence of trained personnel and the resources necessary
to ensure treatment of an anaphylactic reaction that may occur during
Re-administering L-asparaginase after a period of time (for example,
between the induction phase and the consolidation phase) may increase
the risk of occurrence of an anaphylactic reaction. Close monitoring is
recommended in these conditions.
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
During reinduction, administer corticosteroid therapy for 24 to 48 hours to
prevent allergic reactions.
Close monitoring before and during treatment is necessary:
Blood lipase and blood glucose levels should be monitored to look
for pancreatitis or hyperglycaemia. Treatment must be discontinued
if there is an increase in blood lipase levels during treatment. This
treatment may exacerbate diabetes. Hyperglycaemia can be
treated with insulin, if needed.
Coagulation tests should be performed before treatment and
repeated during treatment before each injection of KIDROLASE (at
least aPTT, PT, fibrinogen assay, antithrombin III (AT III) assay).
Replacement therapy should be performed if fibrinogen is below 1
g/litre or if AT III is below 60%. If the fibrinogen or AT III levels do
not increase, or if a significant bleeding disorder appears, it is
preferable to temporarily interrupt treatment and it should not be
resumed until after laboratory parameters have returned to normal.
Regular liver function tests will be performed throughout the entire
duration of treatment, as will full blood counts.
Renal function and serum uric acid levels must be monitored.
This medicinal product is not recommended with phenytoin or fosphenytoin and
methotrexate. In patients treated with phenytoin, administration of an
anticonvulsant benzodiazepine should be considered to avoid a risk of seizures
related to a reduction of gastrointestinal absorption of phenytoin induced by
cytotoxic agents (see section 4.5).
4.5. Interactions with other medicinal products and other forms of
L-asparginase must not be mixed with other medicinal products before
e section 4.3):
Contraindicated combinations (se
Live attenuated vaccines:
Risk of fatal generalised vaccine disease.
Combination of a cytotoxic agent with a live attenuated vaccine (LAV) is
contraindicated during and for at least six months after stopping chemotherapy.
recommended (see section 4.4):
Phenytoin (and by extrapolation, fosphenytoin)
Risk of occurrence of seizures due to reduction of gastrointestinal absorption of
phenytoin by the cytotoxic agent or risk of increased toxicity or loss of efficacy of
the cytotoxic agent due to the increase of its hepatic metabolism by phenytoin or
L-asparginase may reduce or eliminate the effect of methotrexate on malignant
cells. Therefore, concomitant administration of L- asparginase and methotrexate
must be avoided.
Combinations to be used with caution:
Vitamin K antagonist
Increased thrombotic and haemorrhagic risk in cancer. Moreover, possible
interaction between VKAs and chemotherapy. INR to be monitored more
to take into consideration:
Immunosuppressants (cyclosporine, everolimus, tacrolimus, temsirolimus,
Excessive immunosuppression with a risk of lymphoproliferative syndrome.
4.6. Fertility, pregnancy and lactation
The data on use of L-asparaginase in pregnant women are limited.
Studies conducted in animals are insufficient for making conclusions about the
reproductive toxicity of KIDROLASE (see section 5.3).
KIDROLASE is not recommended during pregnancy and in women of
childbearing age who do not use contraception.
It is uncertain whether KIDROLASE is exerted in breast milk. Therefore,
breastfeeding is not recommended during treatment with KIDROLASE.
No fertility data are available.
4.7. Effects on the ability to drive a vehicle and operate machinery
4.8. Undesirable effects
The two most common adverse effects are:
Immediate hypersensitivity reactions, including urticaria, laryngeal
oedema, bronchospasm, hypotension and even anaphylactic shock. In
case of hypersensitivity reaction, treatment must be immediately and
definitively stopped (see section 4.3).
Thromboembolic events resulting from the effects of asparaginase on
clotting protein synthesis, are the second most common class of adverse
effects. They may be fatal or result in sequelae based on their location.
The disease itself and the presence of a central venous catheter
contribute to increasing thromboembolic risk.
Adverse effects are generally reversible.
The adverse effects spontaneously reported as well as those reported in the
literature in patients treated with L-asparaginase as part of their chemotherapy
protocol are listed in the table below. The adverse effects are classified by
system organ class and frequency.
The frequencies below are defined using the following convention:
Very common (≥ 1/10); Common (≥ 1/100 - < 1/10); Uncommon (≥ 1/1,000 - <
1/100); Rare (≥ 1/10,000 - < 1/1,000); Very rare (< 1/10,000), Not known.
Infections and infestations
Infections, Sepsis that may be fatal
Blood system and lymphatic disorders
Clotting disorders – prolonged PT and
aPTT, abnormal clotting factors (VII, IX,
X and VIII), decreased antithrombin III,
plasminogen, protein C, protein S and
; these disorders may be
the cause of haemorrhagic and
Leukopaenia, Neutropaenia, Febrile
Immune system disorders
Metabolism and nutrition disorders
Hypertriglyceridaemia, High blood
amylase levels, High blood lipase
levels, Hyperglycaemia, Decrease in
Nervous system disorders
Clinical signs of metabolic
encephalopathy such as
consciousness disorders with
confusion, Stupor, Episodes of
Posterior Reversible Encephalopathy
Embolic, venous or more rarely arterial
Respiratory, thoracic and mediastinal disorders
Acute pancreatitis, Diarrhoea,
Haemorrhagic or necrotising
Increase in bilirubin ALAT , ASAT,
GGT, alkaline phosphatases
Hepatomegaly, Cholestatic hepatitis,
hepatic steatosis, cytolytic hepatitis
Skin and subcutaneous tissue conditions
Urticaria, Pruritis, Erythema, Facial
oedema, Lip Swelling
Renal and urinary disorders
Reproductive system and hormonal disorders
General disorders and administration site conditions
Fever, Chills, Peripheral oedema, Pain
Fatigue, Malaise, Injection site reaction
(including injection site pain, erythema,
haematoma or oedema)
* See Description of selected adverse effects.
- Resulting from the inhibition of protein synthesis.
- Seizures may be associated with cases of thrombosis or metabolic
- Resulting from excessive ammonia production by the action of L-asparaginase
on endogenous asparagine and glutamine.
- These symptoms are commonly associated with hypersensitivity reactions.
Description of selected adverse effects
Pancreatic disorders – Acute pancreatitis occurs in less than 10% of cases.
Isolated cases of pseudocyst formation have been reported up to 4 months after
the last administration of treatment; relevant exams (e.g. ultrasound) may be
considered after the last administration of treatment. Very rare cases of
haemorrhagic or necrotising pancreatitis occur and may be fatal. L-asparaginase
may affect endocrine function. Hyperglycaemia is the most commonly reported
adverse effect and it is easy to control it by administering insulin. Rare cases of
diabetic ketoacidosis have been reported.
Nervous system disorders and cardiac disorders observed on Kidrolase are often
the result of a thromboembolic event or may be promoted by the concomitant
prescriptions of cancer drugs.
In rare cases, a posterior reversible encephalopathy syndrome (PRES) has been
observed during therapy with asparaginase-containing regimens.
on precautions for use, see section 4.4).
The frequency, type and severity of adverse effects should be the same in
children and adults.
Other special populations
No special patient populations have been identified in which the tolerability profile
of the medicinal product is expected to be different from the profile defined
Reporting suspected adverse effects
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.
Any suspected adverse events should be reported to the Ministry of Health
according to the National Regulation by using an online form:
No cases of overdose have been reported with E. coli asparaginase. In case of
an overdose, the patient must necessarily be placed under medical observation.
There is no known antidote for asparaginase overdoses. No data are available
on the elimination (peritoneal or by haemodialysis) of the product.
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: OTHER ANTINEOPLASTIC AGENT
ATC Code: L01XX02
L-asparaginase is a protein enzyme extracted from
destroyes asparagine by hydrolysis. This amino acid is a basic component of
cellular protein; leukemia cells, which cannot synthesise this amino acid
themselves, must use extracellular asparagine.
Given that extracellular aspargine is hydrolysed by L- asparginase, this
deficiency leads to the destruction of cells that are unable to endogenously
Given this particular mechanism of action, there is no cross-resistance with other
5.2. Pharmacokinetic properties
Asparginase is poorly distributed in tissue; its half-life is biphasic and varies
between 8 and 30 hours, depending on subjects; 24 hours after IV injection of
1,000 IU/kg, the plasma level is between 8 and 20 IU/mL; after IM injection, the
plasma level observed is 50% lower.
5.3 Preclinical safety data
The following effects have been observed in animals after intravenous injection,
leading to exposure rates similar to those observed in clinical practice: reversible
hepatotoxicity, resorption and significant foetal abnormalities in New Zealand
white rabbits, delayed growth and development, but also malformations of rat
embryos treated in vitro.
6. Pharmaceutical data
6.1 List of excepients
See section 4.5
Before reconstitution: The expiry date of the product is indicated on the
After reconstitution: The physical and chemical stability of the reconstituted
solution has been demonstrated for 24 hours at a temperature between 2°C and
8°C. However, from a microbiological perspective, the product should be used
immediately. If it is not used immediately, shelf life and storage conditions after
reconstitution and before use are the sole responsibility of the user and should
not exceed 24 hours at a temperature between 2°C and 8°C.
Reconstitution should be performed in strict aseptic conditions.
6.4. Special precautions for storage
Before reconstitution: Store in a refrigerator (between 2°C and 8°C).
After reconstitution: Do not freeze.
For storage conditions of the medicinal product after reconstitution, see section
6.5 Nature and contents of the container
7 ml colorless type II glass bottle closed with a bromobutyl stopper.
6.6 Special precautions for disposal and handling
This medicinal product must be handled and prepared with caution. The use of
gloves, safety goggles and a mask is recommended.
In case of skin contact with the concentrate or solution for infusion, the product
should be removed immediately and completely using soap and water.
In case of contact with a mucous membrane with the concentrate or solution for
infusion, it must be immediately rinsed thoroughly with water.
Do not mix with other medicinal products.
Any unused medicinal product or waste should be disposed of in accordance
with local requirements.
7. Manufacturer and Marketing authorization holder (MAH):
Manufacturer: Jazz pharmaceuticals France S.A.S, CITY ONE, 84 QUAI
CHARLES DE GAULLE 69006 LYON, France.
Importer: CTS Ltd., 4 Haharash Street, Hod Hasharon
The content of this leaflet was approved by the Ministry of Health in January
2018 and updated according to the guidelines of the Ministry of Health in January