Kyowa Hakko Kirin Co., Ltd.

Revised: Oct 2009 (6th version, Revisions associated with the amendment of Standard Commodity Classification No. of Japan
the Pharmaceutical Affairs Law)
874291

- ANTINEOPLASTIC ENZYME PREPARATION -

LEUNASE Injection 5000

LEUNASE Injection 10000
<L-asparaginase for Injection>
Powerful drug and Prescription drug*

Storage
Store in a cold place.
5000K.U. Injection 10000K.U. Injection
Expiration date Approval No. 21700AMX00049 21700AMX00051
2 years (Do not use after the expiration Date of listing in the NHI reimbursement price December 2005 December 2005
date indicated on the package.) Date of initial marketing in Japan September 1971 September 1971
* Caution: Use only pursuant to the direction of a physician, etc.

CONTRAINDICATIONS (LEUNASE Injection is DOSAGE AND ADMINISTRATION

contraindicated in the following patients.) The usual dosage is 50 to 200 KU/kg to be administered by
Patients with a history of serious hypersensitivity to any of intravenous drip infusion every day or every other day. The
the components of the product dosage may be adjusted depending on the age and condition of
the patient.
DESCRIPTION (Preparation)
1. Composition See 7. Precautions concerning Use.
Each vial of LEUNASE Injection 5000 and 10000 contains
the following ingredient. It is an injectable solution to be PRECAUTIONS
reconstituted before use. 1. Careful Administration (LEUNASE should be
Brand name LEUNASE LEUNASE administered with care in the following patients.)
Injection 5000 Injection 10000 (1) Patients with pancreatitis or a history of pancreatitis
Active Lyophilized
[Exacerbation or recurrence of pancreatitis may occur.]
5000K.U. 10000K.U. (2) Patients with hepatic dysfunction [Hyperammonemia is
ingredient L-asparaginase
(One K.U. of L-asparaginase is equivalent to the amount of liable to occur.]
L-asparaginase that decomposes L-asparagine and produces (3) Patients with renal dysfunction [Hypernitremia may
1mole of ammonia per minute at 37C.) occur.]
(4) Patients with marrow depression [Administration of
LEUNASE may exacerbate marrow depression.]
2. Product description
Brand name Appearance pH range Osmotic pressure
(5) Patients complicated with infection [Administration of
ratio LAUNASE may aggravate infection due to marrow
LEUNASE White powder 0.02 (To be depression.]
Injection or porous light reconstituted with (6) Patients with varicella [Fatal systemic disorders may
5000 mass 0.5mL of water occur.]
(lyophilized for injection, JP)
6.5 to 7.5
LEUNASE preparation) 0.02 (To be 2. Important Precautions
Injection reconstituted with (1) Since serious coagulopathy such as cerebral hem-
10000 1mL of water for orrhage, cerebral infarction and pulmonary hem-
injection, JP) orrhage may occur, patients should be monitored with
Stability : Comparatively stable to heat, pH and light in the frequent testing for fibrinogen, plasminogen, AT-III,
crystal state. protein C, etc. during treatment, and, if any abnormal-
Stable pH range in aqueous solution is 6.0 to 8.5. ity is noted, appropriate measures such as suspension
or discontinuance of administration should be taken.
INDICATIONS (2) Since serious acute pancreatitis may occur, patients
Acute leukemia (including blastic crisis in chronic leukemia), should be carefully observed during treatment, and, if
malignant lymphoma symptoms such as abdominal pain, vomiting and in-
2 Kyowa Hakko Kirin Co. , Ltd.

creases in pancreatic enzymes including amylase are noted, administration should be discontinued and ap-
noted, administration should be discontinued and ap- propriate measures should be taken.
propriate measures should be taken. Diabetes due to pancreatic endocrinopathy (in-
Since serious diabetes may also occur, patients should flammation of Langerhans' islet) may also occur.
be carefully observed during treatment, and, if symp- Patients should be carefully observed during treat-
toms such as thirst, polydipsia and polyuria are noted, ment, and, if symptoms such as thirst, polydipsia and
administration should be suspended or discontinued polyuria are noted, administration should be sus-
and appropriate measures should be taken. pended or discontinued and appropriate measures
(3) Since serious adverse reactions such as marrow should be taken.
depression may occur, patient's condition should be 4) Hyperammonemia with consciousness disturbance
carefully monitored with frequent laboratory testing may occur. Patients should be carefully observed
(hematological test, liver function test and renal func- with regular testing, and appropriate measures such
tion test, etc.). If any abnormality is observed, appro- as suspension or discontinuance of administration
priate measures such as reduction of the dosage and should be taken if any abnormality is observed.
suspension of administration should be taken. Addi- 5) Symptoms such as coma, consciousness distur-
tionally, LEUNASE should be administered with care bance and disorientation may occur. Patients
because long-term use of the product may cause en- should be carefully observed, and appropriate meas-
hanced adverse reactions, which may be protracted. ures such as suspension or discontinuance of admini-
(4) Particular attention should be paid to the occurrence or stration should be taken if any abnormality is noted.
aggravation of infectious disease and bleeding ten- 6) Serious hepatic damage such as hepatic failure
dency. may occur. Patients should be carefully monitored
(5) LEUNASE should be administered with care in by hepatic function test. And, if any abnormality is
children while paying special attention to the manifes- noted, administration should be discontinued and ap-
tation of adverse reactions. propriate measures should be taken
(6) In case administration of LEUNASE is required in 7) Extensive organic disorder of brain, which resulted
children or patients with reproductive possibility, po- in death, has been reported.
tential effects on gonad should be considered. (2) Other adverse reactions
Such adverse reactions as listed in the below table may
3. Adverse Reactions occur. Patients should be carefully observed, and, if
Adverse reactions including abnormalities in laboratory any abnormality occurs, appropriate measures such as
data were reported in 128 of 188 (68.1%) patients treated reduction of the dose and suspension of administration
with LEUNASE before approval. A total of 302 patients should be taken.
were investigated before approval and between approval
and 1st May 1976. Main reported adverse reactions were ≧5% 5% > 0.1% Incidence unknown
nausea in 103 patients (34.1%), vomiting in 89 patients Hyper- Rash
(29.5%), anorexia in 63 patients (20.9%), fever in 43 sensitivity
patients (14.2%), hyperammonemia in 12 of 96 patients Hematologic Thrombo- Anemia
(12.5%) and shock in 6 patients (2.0%). cytopenia
(1) Clinically significant adverse reactions Hepatic Fatty liver Hepatic function
1) Shock and anaphylactoid symptoms may occur. disorder
If any of symptoms such as urticaria, angioedema, Renal Edema, Albuminuria, diuretic
hypernitremia failure
chills, vomiting, dyspnea, clouding of consciousness,
Gastro- Anorexia,
convulsions, and decreased blood pressure is ob-
intestinal nausea,
served, administration should be immediately
vomiting,
stopped and appropriate measures should be taken. diarrhea
2) Serious coagulopathy such as cerebral hemor- Psycho Malaise Somnolence,
rhage, cerebral infarction and pulmonary hem- -neurologic anxiety,
orrhage (decrease of fibrinogen, decrease of headache
prothrombin, decrease of plasminogen, decrease of Others Fever Vascular pain,
AT-III, decrease of protein C, etc.) may develop. abnormal glucose
Patients should be carefully observed with frequent tolerance,
testing during treatment, and, if any abnormality is hyperlipaemia,
noted, appropriate measures such as suspension or sialoadenitis, parotitis
discontinuance of administration should be taken.
3) Serious acute pancreatitis may occur. Patients
should be carefully observed during treatment, and, if
symptoms such as abdominal pain, vomiting and in-
creases in pancreatic enzymes including amylase are
 Kyowa Hakko Kirin Co., Ltd. 3

4. Use in the Elderly PHARMACOKINETICS

Since elderly patients often have reduced physiological 1. Blood concentrations5)
function and, therefore, are particularly susceptible to Blood concentration of L-asparaginase changed as
hepatic disorder, LEUNASE should be administered with indicated in the below when it was administered
caution in elderly patients, paying special attention to the intravenously for 6 consecutive days in lymphosarcoma
dose and patient's condition. patients at a dose of 11,000 KU (200 KU/kg):

5. Use during Pregnancy, Delivery or Lactation

Blood concentration
(1) Administration of LEUNASE is not recommended in
pregnant women or women who may possibly be preg-
nant. [Animal studies with mice and rats have shown
teratogenicity of this drug manifested as exencephalia,
anomaly of thoracic vertebra and ribs and delayed ossi-
fication.]
(2) Nursing mothers should discontinue breast feeding (day)
during treatment. [The safety of LEUNASE in nursing
mothers has not been established.] 2. Distribution (data from study in rats)6)
The concentration of L-asparaginase detected 15 minutes
6. Pediatric Use after intravenous administration of 2,500 KU/kg of
See 2. Important Precautions 5) and 6) L-asparaginase in rats was highest in the liver followed by
spleen, lung, kidney, stomach and then by small intestine.
7. Precautions concerning Use
(1) Preparation2) 3. Excretion (data from study in rats)6)
1) Reconstitute LEUNASE initially with 2 to 5mL of When L-asparaginase was intravenously administered in
water for injection, JP (The Japanese Pharmaco- rats at a dose as large as 50,000 to 100,000 KU/kg, only
poeia), and then dilute the solution with replenisher 0.014 to 0.032% of the dose was collected in urine within
solution to 200 to 500mL. 24 hours after administration, indicating very little
2) Direct reconstitution with isotonic sodium chloride excretion of unchanged active substance. No activity was
solution, JP should be avoided because it may cause detected in urine after administration at a small dose.
the solution to become turbid due to salting out.
(2) Precautions during administration CLINICAL STUDIES7)~9)
1) Intradermal test is recommended in prior to the ad- The results of clinical studies conducted at 36 institutions in
ministration of LEUNASE, since the administration Japan mainly in the patients with tumors in hematopoietic
of LEUNASE may cause shock to occur. organs are summarized in the below table.
Reconstitute 5000 K.U. of LEUNASE with 2mL of Cases which were judged as "complete remission" or "partial
water for injection, and then dilute the solution with remission" by multiple Japanese evaluation criteria concerning
isotonic sodium chloride solution to make a 5mL so- therapeutic effects in acute leukemia and malignant lymphoma
lution. Take 0.1mL of the solution and dilute with were evaluated as responded.
isotonic sodium chloride solution to make a 1mL so-
lution. Inject 0.1mL of the solution intracutaneously Response rate
Disease Type
(dosage: 10 K.U.),3) and observe the patient for 15 to (responded/treated)
30 minutes for confirming that no abnormality oc- Lymphocytic
75.0% (51/68)
leukemia
curs.
Acute leukemia Myelocytic
2) LEUNASE should be used immediately after recon- 40.8% (29/71)
leukemia
stitution.
Others 44.4% (4/9)
(3) Route of administration
Hodgkin's disease 36.4% (4/11)
LEUNASE should not be administered by other routes Malignant
Reticulosarcoma 53.8% (7/13)
than intravenous drip infusion. lymphoma
Lymphosarcoma 68.9% (13/19)
(4) Other precautions
Total 56.5% (108/191)
It has been reported that LEUNASE has a higher
potency than other L-asparaginase preparations
PHARMACOLOGY
manufactured and used in other countries4). Attention
1. Antineoplastic activity10)-12)
should, therefore, be paid to the dosage in case this
L-asparaginase demonstrates antineoplastic activities
product is used in consultation with therapies
against lymphoblastoma L5178Y of mice, lymphoma
prevailing in other countries.
6C3HED of mice and sarcoma Walker 256 of rats.
4 Kyowa Hakko Kirin Co. , Ltd.

2. Mechanism of action7)13) 1-6-1, Ohtemachi, Chiyoda-ku, Tokyo

L-asparaginase exerts its antineoplastic activity by de- 100-8185 Japan
composing L-asparagine in blood and thereby depriving Tel: 03-3282-0069 0120-850-150 (toll free)
asparagine requiring tumor cells of nutrients. Fax: 03-3282-0102
Time：9:00－17:30 （except Saturdays, Sundays and national
PHYSICOCHEMISTRY holidays）
L-asparaginase is a protein composed of four subunits
containing 321 amino acids each. MANUFACTURED AND DISTRIBUTED BY:
Nonproprietary name : L-asparaginase (JAN) Kyowa Hakko Kirin Co., Ltd.
Molecular weight : 141,000 (by Yhantis method) 1-6-1, Ohtemachi, Chiyoda-ku, Tokyo, Japan
Description : L-asparaginase occurs as a white
cylinder or needle crystal of mono-
clinic system.
Solubility : It is very soluble in water but
practically insoluble in methanol, ace-
tone or chloroform.

PACKAGING
LEUNASE Injection 5000: Boxes of one vial
LEUNASE Injection 10000: Boxes of one vial

REFERENCES
1) Ohguro, T., et al.: Yamaguchi Medical Journal, 18,
271, 1969
2) Company data: Tsuchiya, T., et al; The stability of the
solution after reconstitution of LEUNASE Injection
(10000 K.U.)
3) Tsuchiya, J., et al: Journal of Medical Technology,
32(2), 205, 1988
4) Nowak-Goettl, U., et al.: Haematologica, 81, 127, 1996
5) Fujita, H., et al.: Jpn. J. Cancer Chemother., 1(2), 215,
1974
6) Negishi, T., et al.: Pharmacometrics, 4 (4), 593, 1970
7) Yamada, K., et al.: The Medical Frontline , 25, 1064,
1970
8) Minoshima, A., et al.: Pediatrics of Japan, 11, 81, 1970
9) Nagamura, S., et al.: Jpn. J. Cancer Clin., 10, 1032,
1970
10) Kidd, J. G.: Recent Results in Cancer Research;
Experimental and Clinical Effects of L-Asparaginase:
Springer-Verlag, P.3, 1970
11) Burchenal, J. H., et al.: Recent Results in Cancer
Research; Experimental and Clinical Effects of
L-Asparaginase: Springer-Verlag, P.102, 1970
12) Patterson Jr, M. K.: Recent Results in Cancer Re-
search; Experimental and Clinical Effects of
L-Asparaginase: Springer-Verlag, P.22, 1970
13) Broome, J. D.: Recent Results in Cancer Research;
Experimental and Clinical Effects of L-Asparaginase:
Springer-Verlag, P.15, 1970

REQUEST FOR LITERATURE OR INQUIRY

ABOUT PRODUCT INFORMATION SHOULD BE
MADE TO:
Please request for the company data as well as literature cited
in the REFERENCE to the following.
Medical Information Office
Kyowa Hakko kirin Co., Ltd.