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Elspar (Asparaginase) - Indications and Dosage

 
 



INDICATIONS AND USAGE

ELSPAR is indicated in the therapy of patients with acute lymphocytic leukemia. This agent is useful primarily in combination with other chemotherapeutic agents in the induction of remissions of the disease in pediatric patients. ELSPAR should not be used as the sole induction agent unless combination therapy is deemed inappropriate. ELSPAR is not recommended for maintenance therapy.

DOSAGE AND ADMINISTRATION

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. (See DOSAGE AND ADMINISTRATION, Special Handling.)

As a component of selected multiple agent induction regimens, ELSPAR 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% (D5 W). ELSPAR has little tendency to cause phlebitis when given intravenously. Anaphylactic reactions require the immediate use of epinephrine, oxygen, and intravenous steroids.

When administering ELSPAR intramuscularly, 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.

Unfavorable interactions of ELSPAR with some antitumor agents have been demonstrated. It is recommended therefore, that ELSPAR 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 ELSPAR may interfere with the action of drugs such as methotrexate which require cell replication for their lethal effect. ELSPAR may interfere with the enzymatic detoxification of other drugs, particularly in the liver.

Recommended Induction Regimens:

When using chemotherapeutic agents in combination for the induction of remissions in patients with acute lymphocytic leukemia, regimens are sought which provide maximum chance of success while avoiding excessive cumulative toxicity or negative drug interactions.

One of the following combination regimens incorporating ELSPAR is recommended for acute lymphocytic leukemia in pediatric patients:

In the regimens below, Day 1 is considered to be the first day of therapy.

Regimen I

Prednisone 40 mg/square meter of body surface area per day orally in three divided doses for 15 days, followed by tapering of the dosage as follows:

20 mg/square meter for 2 days, 10 mg/square meter for 2 days, 5 mg/square meter for 2 days, 2.5 mg/square meter for 2 days and then discontinue.

Vincristine sulfate 2 mg/square meter of body surface area intravenously once weekly on Days 1, 8, and 15 of the treatment period. The maximum single dose should not exceed 2.0 mg.

Asparaginase 1,000 I.U./kg/day intravenously for ten successive days beginning on Day 22 of the treatment period.

Regimen II

Prednisone 40 mg/square meter of body surface area per day orally in three divided doses for 28 days (the total daily dose should be to the nearest 2.5 mg), following which the dosage of prednisone should be discontinued gradually over a 14 day period.

Vincristine sulfate 1.5 mg/square meter of body surface area intravenously weekly for four doses, on Days 1, 8, 15, and 22 of the treatment period. The maximum single dose should not exceed 2.0 mg.

Asparaginase 6,000 I.U./square meter of body surface area intramuscularly on Days 4, 7, 10, 13, 16, 19, 22, 25, and 28 of the treatment period. When a remission is obtained with either of the above regimens, appropriate maintenance therapy must be instituted. ELSPAR should not be used as part of a maintenance regimen. The above regimens do not preclude a need for special therapy directed toward the prevention of central nervous system leukemia.

It should be noted that ELSPAR has been used in combination regimens other than those recommended above. It is important to keep in mind that ELSPAR administered intravenously concurrently with or immediately before a course of vincristine and prednisone may be associated with increased toxicity. Physicians using a given regimen should be thoroughly familiar with its benefits and risks. Clinical data are insufficient for a recommendation concerning the use of combination regimens in adults. Asparaginase toxicity is reported to be greater in adults than in pediatric patients.

Use of ELSPAR as the sole induction agent should be undertaken only in an unusual situation when a combined regimen is inappropriate because of toxicity or other specific patient-related factors, or in cases refractory to other therapy. When ELSPAR is to be used as the sole induction agent for pediatric patients or adults the recommended dosage regimen is 200 I.U./kg/ day intravenously for 28 days. When complete remissions were obtained with this regimen, they were of short duration, 1 to 3 months. ELSPAR has been used as the sole induction agent in other regimens. Physicians using a given regimen should be thoroughly familiar with its benefits and risks.

Patients undergoing induction therapy must be carefully monitored and the therapeutic regimen adjusted according to response and toxicity.

Such adjustments should always involve decreasing dosages of one or more agents or discontinuation depending on the degree of toxicity. Patients who have received a course of ELSPAR, if retreated, have an increased risk of hypersensitivity reactions. Therefore, retreatment should be undertaken only when the benefit of such therapy is weighed against the increased risk.

Intradermal Skin Test:

Because of the occurrence of allergic reactions, an intradermal skin test should be performed prior to the initial administration of ELSPAR and when ELSPAR 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 5.0 ml of diluent. From this solution (2,000 I.U./ml) withdraw 0.1 ml and inject it into another vial containing 9.9 ml 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 reaction does not preclude the possibility of the development of an allergic reaction.

Desensitization:

Desensitization should be performed before administering the first dose of ELSPAR 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 ELSPAR 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.

For convenience the following table is included to calculate the number of doses necessary to reach the patient's total dose for that day:

   Injection
   Number
ELSPAR
Dose in I.U.
Accumulated
Total Dose
    1 1 1
    2 2 3
    3 4 7
    4 8 15
    5 16 31
    6 32 63
    7 64 127
    8 128 255
    9 256 511
   10 512 1023
   11 1024 2047
   12 2048 4095
   13 4096 8191
   14 8192 16383
   15 16384 32767
   16 32768 65535
   17 65536 131071
   18 131072 262143
For example: a patient weighing 20 kg who is to receive 200 I.U./kg (total dose 4000 I.U.) would recieve injections 1 through 12 during desensitization.

 

Directions for Reconstitution

This drug may have toxic properties and must be handled and administered with care. Inhalation of dust or aerosols and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling ELSPAR. (See Special Handling.)

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. When reconstituted, ELSPAR should be a clear, colorless solution. If the solution becomes cloudy, discard.

For Intravenous Use

Reconstitute with Sterile Water for Injection or with Sodium Chloride Injection. The volume recommended for reconstitution is 5 ml for the 10,000 unit vials. Ordinary shaking during reconstitution does not inactivate the enzyme. This solution may be used for direct intravenous administration within an eight hour period following restoration. For administration by infusion, solutions should be diluted with the isotonic solutions, Sodium Chloride Injection or Dextrose Injection 5%. These solutions should be infused within eight hours and only if clear.

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. Some loss of potency has been observed with the use of a 0.2 micron filter.

For Intramuscular Use

When ELSPAR is administered intramuscularly according to the schedule cited in the induction regimen, reconstitution is carried out by adding 2 ml Sodium Chloride Injection to the 10,000 unit vial. The resulting solution should be used within eight hours and only if clear.

Special Handling

L-asparaginase may be irritating to eyes, skin and the upper respiratory tract. It has also been shown to be embryo-toxic and teratogenic by the intravenous route in animal studies. Due to the drug's potential toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of ELSPAR for administration. Inhalation of dust or aerosols and contact with skin or mucous membranes, especially those of the eyes, must be avoided. The National Institutes of Health presently recommends that the preparation of injectable anti-neoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers. Additional body garments should be used based upon the task being performed (e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing.

Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered.

Accidental Contact Measures

Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part should be washed immediately with soap and water. Medical attention should be sought. If inhaled, remove from exposure and seek medical attention. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION.)

HOW SUPPLIED

No. 4612 -- ELSPAR is a white lyophilized plug or powder supplied as follows:

NDC 0006-4612-00 in a sterile 10 ml vial containing 10,000 I.U. of asparaginase and 80 mg mannitol, an inactive ingredient

(6505-01-153-9650 10 mL vial).

STORAGE

Store at 2-8°C (36-46°F). ELSPAR does not contain a preservative. Unused, reconstituted solution should be stored at 2-8°C (36-46°F) and discarded after eight hours, or sooner if it becomes cloudy.

9463116    Issued August 2002.

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