Asparaginase - Elspar®

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Usual Diluents

NS, D5W

Dilution Data

Summary (Dosage and administration)1:
Note: Preferred route: Intramuscular (IM). 6,000 International Units/m2 intramuscularly (IM) or intravenously (IV) three times a week Reconstitute in volume appropriate for the intended route of administration:
For IM administration, reconstitute in 2 mL
For IV administration, reconstitute in 5 mL For IM administration, limit the volume at a single injection site to 2 mL; if greater than 2 mL, use multiple injection sites. For IV administration, give over ≥ 30 min through side arm of an infusion of Sodium Chloride Injection or Dextrose Injection 5% (D5W). Use reconstituted Elspar within eight hours. Other 2: Avoid IV administration if possible - IV administration greatly increases the risk of allergic reactions. Dilution: Administer in 50-250 mL of D5W or NS over at least 30-60 minutes (never below 30 minutes). The manufacturer recommends a test dose (0.1 mL of a dilute 20 unit/mL solution) prior to initial administration and when given after an interval of 7 days or more. Intradermal skin test: observe the test site for at least 1 hour for a wheal or erythema. Important: a negative skin test does not preclude the possibility of an allergic reaction. During the procedure, a physician should be immediately available as well as epinephrine, diphenhydramine, and hydrocortisone at the bedside for potentially severe allergic reactions. The patient should also have a running I.V. in place.

DOSAGE AND ADMINISTRATION

Stability / Miscellaneous

WARNINGS	CLINICAL PHARMACOLOGY	INDICATIONS/USAGE
CONTRAINDICATIONS	DOSAGE AND ADMINISTRATION	HOW SUPPLIED
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INDICATIONS AND USAGE
Elspar is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).

CLINICAL PHARMACOLOGY

Mechanism of Action
The mechanism of action of Elspar is thought to be based on selective killing of leukemic cells due to 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. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.

Pharmacodynamics
The relationship between asparaginase activity and asparagine levels has been studied in clinical trials. In previously untreated, standard-risk ALL patients treated with native asparaginase in whom plasma enzyme activity was greater than 0.1 International Units/mL, plasma asparagine levels decreased from a pretreatment average level of 41 µM to less than 3 µM. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 µM (pretreatment) to 1.0 µM and 0.3 µM at day 7 and day 28 of induction, respectively.

Pharmacokinetics
In a study in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase resulted in a cumulative increase in plasma levels. Plasma half-life varied from 8 to 30 hours. Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels.

In a study in which patients with leukemia and metastatic cancer received intramuscular L-asparaginase, peak plasma levels of asparaginase were reached 14 to 24 hours after dosing. Plasma half-life was 34 to 49 hours.

CLINICAL STUDIES
Elspar was evaluated in an open-label, multi-center, single-arm study in which 823 patients less than 16 years of age with previously untreated acute lymphoblastic or acute undifferentiated leukemia received Elspar as a component of multi-agent chemotherapy for induction of first remission. Elspar was administered at a dose of 6,000 International Units/m2 intramuscularly 3 times a week for a total of 9 doses. Of 815 evaluable patients, 758 (93%) achieved a complete remission. In a previous study, in a similar patient population, which utilized an initial induction chemotherapy regimen containing the same agents without Elspar, 429 of 499 (86%) patients achieved a complete remission.

2. DOSAGE AND ADMINISTRATION

2.1 Recommended Dose
The recommended dose of Elspar is 6,000 International Units/m2 intramuscularly (IM) or intravenously (IV) three times a week.

2.2 Instructions for Administration
When Elspar is administered IM, the volume at a single injection site should be limited to 2 mL. If a volume greater than 2 mL is to be administered, two injection sites should be used. Discard unused portion.

When administered IV, give Elspar over a period of not less than thirty minutes through the side arm of an infusion of Sodium Chloride Injection or Dextrose Injection 5% (D5W). Discard unused portion.

2.3 Preparation and Handling Precautions
For IM administration, reconstitute Elspar by adding 2 mL Sodium Chloride Injection to the 10,000 unit vial. Withdraw volume of reconstituted Elspar containing calculated dose into sterile syringe. The reconstituted solution contains 5,000 international units (IU)/mL.

For IV administration, reconstitute Elspar by adding 5 mL Sterile Water for Injection or Sodium Chloride Injection to the 10,000 unit vial. Withdraw volume of reconstituted Elspar containing calculated dose into sterile syringe. The reconstituted solution contains 2,000 IU/mL.

Use reconstituted Elspar within eight hours.

Parenteral drug products should be inspected visually for particulate matter, cloudiness or discoloration prior to administration, whenever solution and container permit. If any of these are present, discard the solution. However, occasionally, a very small number of gelatinous fiber-like particles may develop on standing. Filtration through a 5.0 micron filter during administration will remove the particles with no resultant loss in potency.

3. DOSAGE FORMS AND STRENGTHS
10,000 International Units as lyophilized powder in single-use vial.

4. CONTRAINDICATIONS Serious allergic reactions to Elspar or other Escherichia coli-derived L-asparaginases Serious thrombosis with prior L-asparaginase therapy Pancreatitis with prior L-asparaginase therapy Serious hemorrhagic events with prior L-asparaginase therapy

5. WARNINGS AND PRECAUTIONS

5.1 Anaphylaxis and Serious Allergic Reactions
Serious allergic reactions can occur in patients receiving Elspar. The risk of serious allergic reactions is higher in patients with prior exposure to Elspar or other Escherichia coli-derived L-asparaginases. Observe patients for one hour after administration of Elspar in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (for example, epinephrine, oxygen, intravenous steroids, antihistamines). Discontinue Elspar in patients with serious allergic reactions.

5.2 Thrombosis
Serious thrombotic events, including sagittal sinus thrombosis can occur in patients receiving Elspar. Discontinue Elspar in patients with serious thrombotic events.

5.3 Pancreatitis
Pancreatitis, in some cases fulminant or fatal, can occur in patients receiving Elspar. Evaluate patients with abdominal pain for evidence of pancreatitis. Discontinue Elspar in patients with pancreatitis.

5.4 Glucose Intolerence
Glucose intolerance can occur in patients receiving Elspar. In some cases, glucose intolerance is irreversible. Monitor serum glucose.

5.5 Coagulopathy
Increased prothrombin time, increased partial thromboplastin time, and hypofibrinogenemia can occur in patients receiving Elspar. CNS hemorrhages have been observed. Monitor coagulation parameters at baseline and periodically during and after treatment. Initiate treatment with fresh-frozen plasma to replace coagulation factors in patients with severe or symptomatic coagulopathy.

5.6 Hepatotoxicity and Abnormal Liver Function
Fulminant hepatic failure occurs. Hepatotoxicity and abnormal liver function, including elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin (direct and indirect), and depression of serum albumin, and plasma fibrinogen can occur. Fatty changes in the liver have been documented on biopsy. Evaluate hepatic enzymes and bilirubin pretreatment and periodically during treatment

HOW SUPPLIED/STORAGE AND HANDLING
Dosage Form
NDC 67386-411-51

10,000 International Units as lyophilized powder in single dose vial individually packaged in a carton.

Storage and Handling
Keep vials refrigerated at 2-8°C (36-46°F).

Elspar does not contain a preservative. Store unused, reconstituted solution at 2-8°C (36-46°F) and discard after eight hours, or sooner if it becomes cloudy.

Reference(s)

1) [PACKAGE INSERT DATA] : Lundbeck Inc., Deerfield, IL 60015, U.S.A. ELSPAR (asparaginase) injection, powder, lyophilized, for solution Package insert. Revised: April 2010.
® Trademark of Lundbeck Inc.

2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.