L-Asparginase injection is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).

The mechanism of action of L-Asparginase is thought to be based on the selective killing of leukemic cells due to the depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme L­ asparaginase, kills the leukemic cells. Nomial cells, however, are less affected by the depletion due to their ability to synthesize asparagine.

L-Asparginase for Injection contains the enzyme L-Asparagine Amidohydrolase, type EC-2. Asparginase is not absorbed from the GI Tract and hence must be administered IM or IV. The IM route maintains efficacy and has not been shown to be less immunogenic. When given by the IM route, not more than 2 ml of the solution should be given at one injection site. L-Asparginase activity is expressed in terms of International Units according to the recommendation of the International Union of Biochemistry. One International Unit of Asparaginase is defined as the amount of enzyme required to generate 1 µmol of ammonia per minute at pH 7.3 and 37°C. The specific activity of Asparginase is at least 225 international Units per milligram of protein. L-Asparginase for Injection is provided as a sterile, white lyophilized plug or powder. Each vial contains 10,000 International Units or 5,000 International Units of Lyophilized L-Asparginase for Injection.

This drug may have toxic properties and must be handled and administered with care. Special handling procedures should be reviewed prior to handling and followed diligently during reconstitution and administration. Inhalation of dust or aerosols and contact with skin or mucous membranes, especially those of the eyes, must be avoided.

As a component of selected multiple-agent induction regimens, L-Asparginase may be administered by either the intravenous or the intramuscular route. When administered intravenously this enzyme should be given over a period of not less than thirty minutes through the side arm of an already running infusion of sodium chloride injection or dextrose injection 5%. L-Asparginase has little tendency to cause phlebitis when given intravenously. Anaphylactic reactions require the immediate use of epinephrine, oxygen and intravenous steroids. When administering L-Asparaginase intramuscularly, the volume at a single injection site should be limited to 2ml. If a volume greater than 2ml Is to be administered, two Injection sites should be used. Unfavorable interactions of L-Asparginase with some antitumor agents have been demonstrated. It is recommended, therefore, that L-Asparginase be used in combination regimens only by physicians familiar with the benefits and risks of a given regimen. During the period of its inhibition of protein synthesis and cell replication, L-Asparaginase may interfere with the enzymatic detoxification of other drugs, particularly in the liver.

Geriatric Use: Clinical studies of L-Asparginase did not include sufficient numbers of subjects aged 65 and older
to determine whether they respond differently from younger subjects.

L-Asparginase can diminish or abolish the effect of Methotrexate on malignant cells. Intravenous administration of L-Asparginase concurrently with or immediately before a course of Vincristine and Prednisolone may elicit increased toxicity.

Drug/laboratory Test Interaction: L-Asparginase has been reported to interfere with the interpretation of thyroid function tests by producing a rapid and marked reduction in serum concentrations of thyroxine-binding globulin within two days after the first dose. Serum concentrations of thyroxine-binding globulin returned to pretreatment values within four weeks of the last dose of L-Asparglnase.

The following serious adverse reactions occur with L-Asparginase treatment:

• Anaphylaxis and serious allergic reactions
• Serious thrombosis
• Pancreatitis
• Glucose intolerance
• Coagulopathy
• Hepatotoxicityandabnonnal liver function

The most common adverse reactions with L-Asparginase are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases.

Pregnancy Category C. In mice and rats L-Asparginase has been shown to retard the weight gain of mothers and fetuses when given in doses of more than 1000 International Units/kg (approximately equivalent to the recommended human dose, when adjusted for total body surface area). Resorptions, gross abnormalities and skeletal abnormalities were observed. The intravenous administration of 50 or 100 International Units/kg (approximately equivalent to 10 to 20% of the recommended human dose, when adjusted for total body surface area) to pregnant rabbits on days 8 and 9 of gestation resulted in dose-dependent embryotoxicity and gross abnormalities. There are no adequate and well-controlled studies in pregnant women. L-Asparginase should be given to a pregnant woman only if clearly needed.

Nursing Mothers: It is not known whether L-Asparginase is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from L-Asparginase, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

L-Asparginase for Injection is supplied in flint glass vials containing 5,000 I.U or 10,000 I.U of L­-Asparginase as a sterile, Lyophilized powder for Injection for reconstitution.

Keep vials refrigerated at 2-8°C. Protect from light. Do not freeze. L-Asparginase for Injection does not contain a preservative. Store unused, reconstituted solution at 2-8°C and discard after eight hours or sooner if it becomes cloudy.