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Asparaginase (Systemic)


VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Elspar; Kidrolase.

Another commonly used name is
colaspase .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leukemia, acute lymphocytic (treatment){01}{02}—Asparaginase is indicated, in combination with other agents, for induction of remissions in acute lymphocytic leukemia (primarily in pediatric patients {01} {02}). It is recommended that asparaginase not be used as part of a maintenance regimen {01} because of the rapid development of resistance (as cells develop the capability to synthesize asparagine) to the medication.

[Lymphomas, non-Hodgkin's (treatment)]—Asparaginase is used for treatment of lymphosarcoma and reticulum cell sarcoma (reticulosarcoma) {02}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Asparaginase is a high molecular weight enzyme obtained commercially from Escherichia coli {01} {02}.

Mechanism of action/Effect:

Asparaginase breaks down extracellular asparagine, which is required for cell survival, to aspartic acid and ammonia. Normal cells are capable of synthesizing their own asparagine but certain malignant cells are not. {01} {02} {06} Asparaginase interferes with protein synthesis and also with DNA and RNA synthesis, and appears to be cell cycle–specific for the G 1 phase of cell division {08}. Cell death then results from fragmentation of the cell into membrane-bound particles that are eliminated by phagocytosis {07}.


Other actions/effects:

Has immunosuppressant activity in animals {01} {02}.

Distribution:

Crosses the blood-brain barrier to only a limited extent; cerebrospinal fluid concentrations are less than 1% of concurrent plasma concentrations; slow sequestration by the reticuloendothelial system {01}.

Half-life:

Intramuscular—39 to 49 hours {01}.

Intravenous—8 to 30 hours {01}.

Onset of action:

Blood concentrations of asparagine fall to undetectable levels almost immediately after administration of asparaginase {06}. Normal or below-normal leukocyte counts are noted frequently within the first several days after treatment with asparaginase is started {01}.

Time to peak plasma concentration

After intramuscular administration—14 to 24 hours {01}.

Duration of action:

Concentrations of asparagine in the blood remain low for 7 to 10 days after discontinuation of therapy with asparaginase {07}.

Elimination:
    Unknown; only trace amounts appear in the urine following intravenous administration {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

In one study, cross-sensitivity between commercially available asparaginase and one product for investigational use derived from Erwinia carotovora was reported in 22.6% of patients. Allergic reactions included urticaria, tachypnea, wheezing, shortness of breath, pruritus, and tachycardia. {09}

Carcinogenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.

Intraperitoneal administration of 2500 Units of asparaginase per kg of body weight per day for 4 days reportedly caused a small increase in pulmonary adenomas in newborn Swiss mice {01}.

Mutagenicity

Asparaginase was not found to be mutagenic at concentrations of 152 to 909 international units (IU) per plate in the Ames microbial mutagen test with or without metabolic activation {01}.

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

First trimester: It usually is recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the teratogenic and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

Studies in mice and rats have shown that asparaginase, given in doses of greater than 1000 IU per kg of body weight (the recommended human dose), retards the weight gain of mothers and fetuses and causes resorptions, gross abnormalities, and skeletal abnormalities. Dose-dependent embryotoxicity and gross abnormalities also have been reported with intravenous administration of 50 or 100 IU of asparaginase per kg of body weight to pregnant rabbits on days 8 and 9 of gestation. {01}

FDA Pregnancy Category C. {01}

Breast-feeding

It is not known whether asparaginase is distributed into breast milk {01}. Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended while asparaginase is being administered because of the risks to the infant (adverse effects, carcinogenicity).

Pediatrics

Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of asparaginase in children. In fact, incidence of toxicity appears to be lower in pediatric patients than in adult patients {01}.


Geriatrics


No information is available on the relationship of age to the effects of asparaginase in geriatric patients.


Dental

Asparaginase may cause stomatitis associated with considerable discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone    (asparaginase may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse asparaginase-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents)


Antidiabetic agents, sulfonylurea or
Insulin    (asparaginase may alter blood glucose concentrations; for adult-onset diabetics, dosage adjustment of hypoglycemic medications may be necessary during and after asparaginase therapy)


Corticosteroids, glucocorticoid, especially prednisone or
» Vincristine    (concurrent use may enhance the hyperglycemic effect of asparaginase and may increase the risk of neuropathy and disturbances in erythropoiesis; toxicity appears to be less pronounced when asparaginase is administered after vincristine and prednisone rather than before or with these medications {01})


Immunosuppressant medications, other, such as:
Azathioprine
Chlorambucil
Cyclophosphamide
Cyclosporine
Mercaptopurine
Muromonab-CD3 or
Radiation therapy    (concurrent use with asparaginase may increase the total effects of these medications and radiation therapy; dosage reduction may be required)


» Methotrexate    (asparaginase may block the effects of methotrexate by inhibiting cell replication; this inhibition of methotrexate's action appears to correlate with suppression of asparagine concentrations {01}. Some studies indicate that administration of asparaginase 9 to 10 days before or within 24 hours after methotrexate administration does not produce this inhibition of antineoplastic effect and may reduce the gastrointestinal and hematological effects of methotrexate)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by asparaginase therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by asparaginase therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the asparaginase therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Thyroid function tests    (results may be altered because asparaginase decreases serum thyroxine-binding globulin concentrations within 2 days after the first dose; concentrations return to normal within 4 weeks of the last dose of asparaginase)

{01}With physiology/laboratory test values
Ammonia concentrations, blood{01} and
Blood urea nitrogen (BUN) concentrations{01}    (may be increased because of breakdown of asparagine)


Cholesterol    (serum concentrations may be reversibly decreased; increases and decreases of total lipids have occurred {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Pancreatitis, or history of    (potentially fatal acute hemorrhagic pancreatitis has been associated with asparaginase treatment {01})


» Previous allergic reaction to asparaginase{01}
Risk-benefit should be considered when the following medical problems exist
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


Diabetes mellitus    (asparaginase may increase blood glucose concentrations {01})


Gout, history of or
Urate renal stones, history of    (asparaginase may increase serum uric acid concentrations {01})


» Hepatic function impairment    (may be increased by asparaginase {01})


» Infection    (immunosuppressive effects)


» Caution should be used also in patients who have had previous cytotoxic drug therapy and radiation therapy.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Amylase concentrations, serum{01} and
Bone marrow aspiration studies{01} and
» Central nervous system (CNS) function, clinical and
» Coagulation tests, plasma{01}{03} and
Glucose concentrations, blood{01} and
Hepatic function{01} and
Peripheral blood count{01} and
Renal function and
Uric acid concentrations, serum{01}    (recommended at the initiation of therapy and at frequent intervals during therapy)




Side/Adverse Effects

Note: Incidence of toxicity appears to be greater in adult patients than in pediatric patients {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Allergic reaction{01} (trouble in breathing; joint pain; puffy face; skin rash or itching)
    
decrease in blood clotting factors{01}{03}{04} (unusual bleeding or bruising)—usually asymptomatic
    
hepatotoxicity, including fatty changes{01}{02} —asymptomatic
    
pancreatitis{01} (severe stomach pain with nausea and vomiting)

Note: Allergic reactions occur frequently and may be severe or even fatal. The risk is increased with repeated doses, but may occur on initial administration, including during desensitization. {01}
An allergic reaction to a therapeutic dose may occur even after a negative reaction to the intradermal skin test. Rarely, an anaphylactic reaction to the intradermal skin test itself may occur. {01}
Anaphylaxis may be less common after intramuscular than after intravenous administration in children with advanced leukemia (although incidence of mild allergic reactions may be increased) {01}, or when asparaginase is given in combination with immunosuppressive agents {06}.
The most common and most marked decreases in blood clotting factors occur in fibrinogen and factors V and VIII, with a variable decrease in factors VII and IX {01}. Bleeding is rare, but intracranial hemorrhage and fatal bleeding have been reported {01} {05}. A compensatory increase in fibrinolytic activity has also occurred {01}.
Hepatotoxicity usually occurs within 2 weeks of start of treatment.


Incidence less frequent
    
CNS effects, reversible{01} (confusion; drowsiness; hallucinations; mental depression; nervousness; unusual tiredness)
    
hyperglycemia{01} (frequent urination; unusual thirst)
    
hyperuricemia or uric acid nephropathy (lower back or side pain; swelling of feet or lower legs)
    
hypoalbuminemia{01} or renal failure{01} (swelling of feet or lower legs)
    
stomatitis (sores in mouth and on lips)

Note: CNS effects occur mostly in adults, in whom incidence may be as high as 30 to 60%; they usually occur within the first day of treatment and subside 1 to 3 days after asparaginase is withdrawn.
Hyperglycemia resembles hyperosmolar, nonketotic hyperglycemia {01}. It usually responds to withdrawal of asparaginase and appropriate treatment, but may occasionally be fatal {01}.
Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown leading to elevated serum uric acid concentrations {01}.
Azotemia, usually pre-renal, occurs frequently. Fatal renal insufficiency has been reported. {01}


Incidence rare
    
Hyperthermia {01}(fever or chills{01})
    
immunosuppression {01}(infection)
    
intracranial hemorrhage or thrombosis{01}{05} (severe headache; inability to move arm or leg)
    
leg vein thrombosis (pain in lower legs)
    
leukopenia {01}

Note: Leukopenia may be marked but bone marrow depression is transient {01}.
Hyperthermia may be fatal {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Hyperammonemia{01} (mild headache; loss of appetite; nausea or vomiting; stomach cramps; weight loss)



Those indicating the need for medical attention if they occur after medication is discontinued
    
Intracranial hemorrhage or thrombosis{05} (severe headache; inability to move arm or leg)
    
pancreatitis{01} (severe stomach pain with nausea and vomiting)




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Asparaginase (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to asparaginase

Pregnancy—Embryotoxicity and abnormalities reported in animals; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially probenecid, sulfinpyrazone, or previous cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, herpes zoster, pancreatitis, hepatic function impairment, or infection

Proper use of this medication
Caution with combination therapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

Possible nausea, vomiting, and loss of appetite; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if thyroid function test required; possible interference with test results


Side/adverse effects
Importance of discussing possible adverse effects, including cancer, with physician

Signs of potential side effects, especially allergic reaction, decrease in blood clotting factors, hepatotoxicity, pancreatitis, CNS effects, hyperglycemia, hyperuricemia or uric acid nephropathy, hypoalbuminemia or renal failure, stomatitis, hyperthermia, immunosuppression, intracranial hemorrhage or thrombosis, leg vein thrombosis, and leukopenia

Asymptomatic side effects, including hepatotoxicity

Physician or nurse can help in dealing with side effects


General Dosing Information
It is recommended that asparaginase be administered to patients only in a hospital setting under the supervision of a physician experienced in cancer chemotherapy. It is also recommended that equipment and medications (including epinephrine, diphenhydramine, oxygen, and intravenous steroids) necessary for treatment of a possible anaphylactic reaction be immediately available during each administration of asparaginase. {01}

A variety of dosage schedules and regimens of asparaginase, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response and appearance or severity of toxicity {01}.

Although the intradermal skin test has not been found entirely reliable in predicting allergic reactions to asparaginase, it is recommended that this test be performed prior to the initial administration of asparaginase and when a week or more has passed between doses. The test solution is prepared by adding 5 mL of sterile water for injection or 0.9% sodium chloride injection to the 10,000–International Unit (IU) vial of asparaginase, shaking to dissolve, and withdrawing 0.1 mL of the resulting solution (2000 IU per mL) and injecting it into another vial containing 9.9 mL of diluent to produce a test solution containing approximately 20 IU per mL. An intradermal injection of 0.1 mL (about 2 IU) is administered and the site observed for 1 hour for the appearance of a wheal or erythema, which indicates a positive reaction. {01}

It is recommended that a desensitization method of administration of the first dose be utilized in patients who have had a positive reaction to the intradermal skin test and on re-treatment of a patient with asparaginase. A recommended schedule begins with the intravenous administration of 1 IU and doubles the dosage every 10 minutes, provided no allergic reaction has occurred, until the accumulated total dosage equals the dosage for that day. {01}

It is recommended that when asparaginase is administered intravenously, it be given over a period of not less than 30 minutes through the side arm of an already running infusion of 0.9% sodium chloride injection or 5% dextrose injection. Asparaginase should not be infused through a filter. However, if gelatinous fiber-like particles develop on standing, reconstituted asparaginase may be filtered through a 5-micron filter during administration without loss in potency. Use of a 0.2-micron filter may result in a loss of potency. {01}

No more than 2 mL of asparaginase solution should be injected at a single intramuscular injection site {01}.

Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration and, in some cases, administration of allopurinol. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated. {01}

If pancreatitis occurs, it is recommended that asparaginase therapy be permanently discontinued {01}.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Combination chemotherapy
Asparaginase may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used.


Parenteral Dosage Forms

ASPARAGINASE FOR INJECTION

Usual adult dose
Acute lymphocytic leukemia
Induction: Intravenous, 200 IU per kg of body weight a day for twenty-eight days {01}.


Note: Because use of asparaginase in adults is primarily investigational at this time, the prescriber should consult the medical literature in choosing a specific dosage.


Usual pediatric dose
Acute lymphocytic leukemia
Intramuscular, 6000 IU per square meter of body surface on days 4, 7, 10, 13, 16, 19, 22, 25, and 28 of the treatment period, in combination with vincristine and prednisone {01} or

Intravenous, 1000 IU per kg of body weight per day for ten days beginning on day 22 of the treatment period, in combination with vincristine and prednisone {01}.


Note: Many dosage regimens of asparaginase are in use at this time. A review of all of them is impossible in this space. Consultation of current medical literature is recommended. Use of asparaginase as the sole induction agent generally is not recommended unless combination therapy is considered inappropriate.


Strength(s) usually available
U.S.—


10,000 IU (Rx) [Elspar (mannitol 80 mg)]

Canada—


10,000 IU (Rx) [Kidrolase]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) {01}.

Preparation of dosage form:
Caution: Asparaginase is a contact irritant, and both the powder and solution should be handled with care to prevent inhalation of dust or vapors or contact with skin or mucous membranes (especially eyes). If accidental contact occurs, the affected area should be flushed with water for at least 15 minutes. {01}

Elspar is reconstituted for intravenous use by adding 5 mL of sterile water for injection or 0.9% sodium chloride injection to a vial containing 10,000 IU of asparaginase and shaking to dissolve the medication {01}. (Caution: Overly vigorous shaking may cause foaming and difficulty in withdrawing the contents of the vial {10}.) Only a clear solution should be used. The resulting colorless solution, containing 2000 IU of asparaginase per mL, may be used for direct intravenous administration within 8 hours of reconstitution, provided the solution remains clear, or may be further diluted with 0.9% sodium chloride injection or 5% dextrose injection for administration by intravenous infusion. The infusion solution may also be used within 8 hours, provided it remains clear. {01}

Elspar is reconstituted for intramuscular use by adding 2 mL of 0.9% sodium chloride injection to the 10,000-IU vial. The resulting solution should be used within 8 hours provided it remains clear. {01}

If gelatinous fiber-like particles develop on standing, reconstituted Elspar may be filtered through a 5-micron filter during administration without loss in potency. Use of a 0.2-micron filter may result in a loss of potency. {01}

Kidrolase is reconstituted for intramuscular or intravenous use by adding 4 mL of sterile water for injection to a vial containing 10,000 IU of asparaginase and rotating gently to dissolve the medication. (Caution: Rotate gently; do not shake.) The resulting solution may be further diluted with 0.9% sodium chloride injection or isotonic glucose solution for administration by intravenous infusion. {02}

Stability:
Elspar—Contains no preservative. Unused, reconstituted solution should be stored at 2 to 8 °C (36 to 46 °F) and discarded after 8 hours or sooner if it becomes cloudy. {01}

Kidrolase—Unused, reconstituted solution may be stored at 2 to 8 °C (36 to 46 °F) for 14 days {02}.



Revised: 09/26/1997



References

Note: References used in the development and subsequent revisions of this monograph have not been incorporated into the database and therefore are not listed below.

  1. Elspar package insert (MSD—US), Rev 1/97.
  1. Kidrolase package insert (Rhone-Poulenc—Canada), Rev 5/91.
  1. Bezeaud A, Drouet L, Leverger G, et al. Effect of L-asparaginase therapy for acute lymphoblastic leukemia on plasma vitamin K–dependent coagulation factors and inhibitors. J Pediatr 1986 May; 108: 698-701.
  1. Legnani C, Palereti G, Pession A, et al. Intravascular coagulation phenomenon associated with prevalent fall in fibrinogen during L-asparaginase treatment in leukemic children. Haemostasis 1988; 18(3): 179-86.
  1. Feinberg WM, Swenson MR. Cerebrovascular complications of L-asparaginase therapy. Neurology 1988 Jan; 38: 127-33.
  1. Cheson BD. Miscellaneous chemotherapeutic agents. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997. p. 495-6.
  1. Calabresi P, Chabner BA. Chemotherapy of neoplastic diseases. In: Hardman JG, Limbird, Molinoff PB, et al, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 1268-9.
  1. Dorr RT, Fritz WL. Asparaginase. Cancer chemotherapy handbook. New York: Elsevier; 1980. p. 230-1.
  1. Billett AL, Carls A, Gelber RD, et al. Allergic reactions to Erwinia asparaginase in children with acute lymphoblastic leukemia who had previous allergic reactions to Escherichia coli asparaginase. Cancer 1992; 70: 201-6.
  1. Trissel LA. Handbook of injectable drugs. 9th ed. Bethesda, MD: American Society of Health-System Pharmacists; 1996.
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