KIDROLASE

אירבה דרשמ י"ע עבקנ הז ןולע טמרופ ךיראתב תואירבה דרשמ י"ע רשואו קדבנ ונכותו תו

01/2018

ןכדועו , ךיראתב תואירבה דרשמ תוארוהל םאתהב

01/2018

SUMMARY OF PRODUCT CHARACTERISTICS

1.

Name of the medicinal product:

KIDROLASE 10,000 I.U.

powder for solution for injection

2.

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.

3.

Pharmaceutical form

Powder for solution for injection.

4.

Clinical data

4.1.Therapeutic indications

- Acute lymphoblastic leukemia

- Acute myeloblastic leukemia

4.2. Posology and method of administration:

Posology

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

/day in

adults:

- 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

reaction.

Desensitization

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.

4.3. Contraindications

- 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

treatment.

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

administration.

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

be sought.

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.

Interaction

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

interaction

L-asparginase must not be mixed with other medicinal products before

administration.

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):

are not

Combinations that

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

fosphenytoin.

Methotrexate

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

frequently.

to take into consideration:

Combinations

Immunosuppressants (cyclosporine, everolimus, tacrolimus, temsirolimus,

sirolimus)

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.

Breastfeeding

It is uncertain whether KIDROLASE is exerted in breast milk. Therefore,

breastfeeding is not recommended during treatment with KIDROLASE.

Fertility

No fertility data are available.

4.7. Effects on the ability to drive a vehicle and operate machinery

Not applicable.

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

Not known

Infections, Sepsis that may be fatal

Blood system and lymphatic disorders

Very common

Clotting disorders – prolonged PT and

aPTT, abnormal clotting factors (VII, IX,

X and VIII), decreased antithrombin III,

plasminogen, protein C, protein S and

fibrinogen

; these disorders may be

the cause of haemorrhagic and

thrombotic complications.

Not known

Leukopaenia, Neutropaenia, Febrile

neutropaenia, Anaemia,

Thrombocytopaenia, Bone

marrowfailure

Immune system disorders

Very common

Anaphylactic reactions

Not known

Anaphylactic shock

Metabolism and nutrition disorders

Common

Hypertriglyceridaemia, High blood

amylase levels, High blood lipase

levels, Hyperglycaemia, Decrease in

insulin levels

Not known

Diabetic ketoacidosis,

Hyperammonaemia

Hypercholesterolaemia,

Hypoalbuminaemia

Psychiatric disorders

Not known

confusion

Nervous system disorders

Not known

Clinical signs of metabolic

encephalopathy such as

consciousness disorders with

confusion, Stupor, Episodes of

seizures

,epileptic Seizures

Coma.

Rare

Posterior Reversible Encephalopathy

Syndrome

Cardiac disorders

Not known

Myocardial infarction

Vascular disorders

Very common

Hypotension

common

Embolic, venous or more rarely arterial

thrombotic events

Not known

Haemorrhage, Hypertension,

Flushing

Respiratory, thoracic and mediastinal disorders

Very common

Laryngeal oedema

, Bronchospasm

Dyspnoea

Gastrointestinal disorders

Very common

Nausea, vomiting

Common

Acute pancreatitis, Diarrhoea,

Abdominal pain

Very rare

Haemorrhagic or necrotising

pancreatitis*

Not known

Fatal pancreatitis*

Hepatobiliary disorders

Common

Increase in bilirubin ALAT , ASAT,

GGT, alkaline phosphatases

Rare

Hepatic failure

Not known

Hepatomegaly, Cholestatic hepatitis,

hepatic steatosis, cytolytic hepatitis

Skin and subcutaneous tissue conditions

Very common

Urticaria, Pruritis, Erythema, Facial

oedema, Lip Swelling

Renal and urinary disorders

Not known

Renal failure

Reproductive system and hormonal disorders

Not known

Amenorrhoea, Azoospermia

General disorders and administration site conditions

Common

Fever, Chills, Peripheral oedema, Pain

Not known

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

encephalopathy.

- 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.

(For information

on precautions for use, see section 4.4).

Paediatric population

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

above.

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:

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=Advers

EffectMedic@moh.gov.il ).

4.9. Overdose

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.

Pharmaceutical properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: OTHER ANTINEOPLASTIC AGENT

ATC Code: L01XX02

L-asparaginase is a protein enzyme extracted from

Escherichia coli

cultures. It

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

synthesise aspargine.

Given this particular mechanism of action, there is no cross-resistance with other

cytostatic agents.

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

Glycine

Sodium hydroxide

6.2 Incompatibilities

See section 4.5

6.3. Shelf-life

Before reconstitution: The expiry date of the product is indicated on the

packaging materials.

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

6.3.

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

2018.