Leunase

Leunase

asparaginase

Manufacturer:

Kyowa Kirin

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
L-Asparaginase.
Description
Each vial contains L-aspaginase 10,000 K.U.
L-asparginase is a protein of tetramer which each subunit has 321 amino acid-residues.
L-asparaginase occurs as a white cylinder or needle crystals of monoclinic system.
Molecular weight: 141,000 (by Yhantis method).
Solubility: It is very soluble in water but practically insoluble in methanol, acetone or chloroform.
This product shows a pH value of 6.5-7.5 and osmotic pressure ratio of 0.02 (to be reconstituted with 1 mL of water for injection).
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: L-asparaginase exerts its antineoplastic activity by decomposing L-asparaginase in blood and thereby depriving asparagine requiring tumor cells of nutrients.
Actions/effects: L-asparaginase demonstrates antineoplastic activities against lymphoblastoma L5178Y of mice, lymphoma 6C3HED of mice and sarcoma Walker 256 of rats.
Clinical Studies: The results of clinical studies conducted at 36 institutions in Japan mainly in the patients with tumors in haematopoietic organs are summarized in Table 1. (See Table 1.)
Cases which were judged as "complete remission" or "partial remission" by multiple Japanese evaluation criteria concerning therapeutic effects in acute leukemia and malignant lymphoma were evaluated or responded.

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Pharmacokinetics: Blood concentrations: Blood concentrations of L-asparaginase changed as indicated in the following text when it was administered intravenously for 6 consecutive days in lymphosarcoma patients at a dose of 11,000 KU (200 KU/kg). (See figure.)

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Distribution (data from study in rats): The concentration of L-asparaginase detected 15 minutes after intravenous administration of 2,500 KU/kg of L-asparaginase in rats was highest in the liver followed by the spleen, lung, kidney, stomach and then by small intestine.
Excretion (data from study in rats): When L-asparaginase was intravenously administered in rats at a dose as large as 50,000 to 100,000 K.U./kg, only 0.014 to 0.032% of the dose was collected in urine within 24 hours after administration, indicating very little excretion of unchanged active substance. No activity was detected in urine after administration at a small dose.
Toxicology: Preclinical Safety Data: Carcinogenesis and mutagenesis: Carcinogenicity and mutagenicity studies for L-asparaginase have not been conducted.
Indications/Uses
Leunase is indicated for the treatment of acute lymphoid leukemia.
Dosage/Direction for Use
Intravenous route: The usual dosage is 50 to 200 K.U./kg bodyweight to be administered by intravenous drip infusion every day or every other day. The dosage may be adjusted depending on the age and condition of the patient.
Intramuscular route: The usual dosage is 10000 K.U./m2/day three times a week or 25000 K.U./m2/day once a week to be administered intramuscularly. The dosage may be adjusted depending on the condition of the patient.
Administration: For the intravenous route, LEUNASE should be reconstituted with 2 to 5 mL of water for injection, followed by dilution with replacement fluid to a total volume of 200 to 500 mL.
For the intramuscular route, LEUNASE should be reconstituted with 0.5 to 1.0 mL of water for injection or 5% glucose solution per 5000 K.U. of LEUNASE.
LEUNASE should not be directly reconstituted with isotonic sodium chloride solution, since it may cause the solution to become turbid due to salting out.
Contraindications
Patients with a history of serious hypersensitivity to any of the components of the product.
Warnings
Only those patients for whom LEUNASE therapy is considered appropriate should be treated in medical institutions well equipped for emergency care and under the supervision of physicians with adequate expertise and experience in the treatment of malignant hematopoietic tumors. Prior to the start of LEUNASE therapy, the patient or his/her family should be fully informed about its benefits and risks, and treatment should not be initiated without their consent.
Careful administration (LEUNASE should be administered with care in the following patients: Patients with pancreatitis or a history of pancreatitis [Exacerbation or recurrence of pancreatitis may occur].
Patients with hepatic dysfunction [Hyperammonemia is liable to occur].
Patients with renal dysfunction [Hypernatremia may occur].
Patients with bone marrow depression [The function of bone marrow may be depressed more strongly].
Patients complicated with infection [Infection by bone marrow depression may be deteriorated].
Patients with varicella [Fatal systemic disorders may occur].
Important precautions: Since serious coagulopathy such as cerebral haemorrhage, cerebral infarction and pulmonary haemorrhage may occur, patients should be monitored with frequent testing for fibrinogen, plasminogen, antithrombin, protein C, etc, during treatment, and if any abnormality is noted, appropriate measures such as suspension or discontinuance of administration should be taken.
Since serious acute pancreatitis may occur, patients should be carefully observed during treatment, and, if symptoms such as abdominal pain, vomiting and increase in pancreatic enzymes including amylase are noted, administration should be discontinued and appropriate measures should be taken.
Since serious diabetes mellitus may occur, patients should be carefully observed during treatment, and, if symptoms such as thirst, polydipsia and polyuria are noted, administration should be suspended or discontinued and appropriate measures should be taken.
Since serious adverse reactions such as bone marrow depression may occur, patient's condition should be carefully monitored with frequent laboratory testing (haematological test, liver function test and renal function test, etc). If any abnormality is observed, appropriate measures such as reduction of the dosage and suspension of administration should be taken. Additionally, LEUNASE should be administered with care because long-term use of the product may cause enhanced adverse reaction, which may be protracted.
Particular attention should be paid to the occurrence or aggravation of infectious disease and bleeding tendency.
LEUNASE should be administered with care in children while paying special attention to the manifestation of adverse reactions.
In case administration of LEUNASE is requires in children or patients with reproductive possibility, potential effects on gonad should be considered.
Muscle contracture associated with intramuscular administration of antibiotics and other medications has been reported. The precautions concerning use should be followed, and great caution should be exercised when administering LEUNASE intramuscularly (see Precautions).
Before LEUNASE is administered intramuscularly in patients with acute leukemia or malignant lymphoma, the physician should carefully read the related literature [e.g., Report on the applicability of public knowledge-based application by the committee reviewing unapproved drugs/off-label drugs with significant medical needs: L-Asparaginase (new dosage and administration for intramuscular injection in the treatment of acute leukemia and malignant lymphoma)].
Special Precautions
Precautions concerning use: Precautions during administration: Intradermal test is recommended in prior to the administration of LEUNASE, since the administration of LEUNASE may cause shock to occur.
Reconstitute 5000 K.U. of LEUNASE with 2 mL of water for injection, and then dilute the solution with isotonic sodium chloride solution to make a 5 mL solution. Take 0.1 mL of the solution and dilute with isotonic sodium chloride solution to make a one mL solution. Inject the solution intracutaneously (dosage: 10 K.U.) and observe the patient for 15 to 30 minutes for confirming that no abnormality occurs.
LEUNASE should be used immediately after reconstitution.
When administering LEUNASE intramuscularly, the following precautions should be followed in order to prevent any effects on the tissues, nerves, etc.
LEUNASE should not be injected more than once at the same site. Extra caution should be exercised in infants and children.
LEUNASE should not be administered at sites where the nerves run.
If after insertion of the needle, the patient complains of severe pain potentially associated with contact with a nerve, the needle should be withdrawn immediately, followed by injection at a different site.
Before injection, the inner cylinder should be pulled lightly to verify that there is no blood return.
LEUNASE should be administered at more than one site in divided doses if warranted by the dose volume and patient's condition.
The administrations of LEUNASE may cause skin disorders such as pain, redness and swelling in the injection site. Administration should be discontinued and appropriate measures should be taken if any such symptoms develops.
Other Precautions: It has been reported that LEUNASE has a higher potency than L-asparaginase preparations manufactured and used. Attention should, therefore, be paid to the dosage in case this product is used in consultation with therapies with other L-asparaginase preparations.
Effects on ability to drive and use machines: There is no evidence to indicate that treatment with this product alters the ability to drive and use machines.
Use in Children: LEUNASE should be administered with care in children while paying special attention to manifestation of adverse reactions.
In case administration of LEUNASE is required in children or patients with reproductive possibility, potential effects on gonad should be considered.
Use in Elderly: Since elderly patients often have reduced physiological function and, therefore, are particularly susceptible to hepatic disorder, LEUNASE should be administered with caution in elderly patients, paying special attention to the dose and patient's condition.
Use In Pregnancy & Lactation
US Pregnancy Category C (All Trimesters).
Administration of LEUNASE is not recommended in pregnant women or women who may possibly be pregnant. [Animal studies with mice and rats have shown teratogenicity of this drug manifested as exencephalia, anomaly of thoracic vertebra and ribs and delayed ossification.]
Nursing mothers should be discontinue breast feeding during treatment. [The safety of LEUNASE to breast-fed infants has not been established.]
Adverse Reactions
Clinical trial data and drug use-results survey data in Japan: Adverse reactions including abnormalities in laboratory data were reported in 128 of 188 (68.1%) patients treated with LEUNASE before approval for intravenous administration. A total of 302 patients treated were investigated before approval for intravenous administration and between approval and 1st May 1976. Main reported adverse reactions were nausea in 103 patients (34.1%), vomiting in 89 patients (29.5%), anorexia in 63 patients (20.9%), fever in 43 patients (14.2%), hyperammonemia in 12 of 96 patients (12.5%) and shock in 6 patients (2.0%).
Clinically significant adverse reaction(s): Shock or anaphylaxis may occur. Patients should be carefully observed during treatment, and, if symptoms such as urticaria, angioedema, chills, vomiting, dyspnoea, clouding of consciousness, convulsion and decreased blood pressure are observed, administration should be immediately stopped and appropriate measures should be taken.
Serious coagulopathy such as cerebral haemorrhage, cerebral infarction and pulmonary haemorrhage (decrease of fibrinogen, decrease of prothrombin, decrease of plasminogen, decrease of antithrombin, decrease of protein C, etc.) may develop. Patients should be carefully observed with frequent testing during treatment, and, if any abnormality is noted, appropriate measures such as suspension or discontinuance of administration should be taken.
Serious acute pancreatitis may occur. Patients should be carefully observed during treatment, and, if symptoms such as abdominal pain, vomiting and increases in pancreatic enzymes including amylase are noted, administration should be discontinues and appropriate measures should be taken.
Diabetes mellitus due to pancreatic endocrinopathy (inflammation of Langerhans' Islet) may also occur. Patients should be carefully observed during treatment, and, if symptoms such as thirst, polydipsia and polyuria are noted, administration should be suspended or discontinues and appropriate measures should be taken.
Hyperammonemia with consciousness disturbance may occur. Patients should be carefully observed with regular testing, and appropriate measures such as suspension or discontinuance of administration should be taken if any abnormality is observed.
Symptoms such as coma, consciousness disturbance and disorientation may occur. Patients should be carefully observed, and appropriate measures such as suspension or discontinuance of administration should be taken if any abnormality is noted.
Serious hepatic damage such as hepatic failure may occur. Patients should be carefully monitored by hepatic function test and, if any abnormality is noted, administration should be discontinued and appropriate measures should be taken.
Extensive organic disorder of brain, which resulted in death, has been reported.
Bone marrow depression may occur. Patients should be carefully monitored with frequent blood testing. In the event of an abnormality, appropriate measures such as dose reduction or suspension should be taken.
Severe infections such as pneumonia and sepsis may occur. Patients should be carefully monitored and, in the event of an abnormality, appropriate measures should be taken.
Other adverse reaction(s): Such adverse reactions as listed in Table 2 may occur. Patients should be carefully observed, and, if any abnormality occurs, appropriate measures such as reduction of the dose and suspension of administration should be taken. (See Table 2.)

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Drug Interactions
No drug-interaction has been reported.
Caution For Usage
Special precautions for disposal: Not applicable.
Incompatibilities: This product should not be mixed with other drugs.
Storage
Store in a cold place (store below 15°C).
Leunase must be used immediately after reconstitution.
Shelf-Life: 2 years.
ATC Classification
L01XX02 - asparaginase ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Infusion (vial) 10,000 KU x 5's.
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