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Elspar (Asparaginase) - Warnings and Precautions

 
 



WARNINGS

It is recommended that asparaginase be administered to patients only in a hospital setting under the supervision of a physician who is qualified by training and experience to administer cancer chemotherapeutic agents, because of the possibility of severe reactions, including anaphylaxis and sudden death. The physician must be prepared to treat anaphylaxis at each administration of the drug. In the treatment of each patient the physician must weigh carefully the possibility of achieving therapeutic benefit versus the risk of toxicity.

Special handling procedures should be followed (see DOSAGE AND ADMINISTRATION, Special Handling).

 

WARNINGS

Allergic reactions to asparaginase are frequent and may occur during the primary course of therapy. They are not completely predictable on the basis of the intradermal skin test. Anaphylaxis and death have occurred even in a hospital setting with experienced observers.

Once a patient has received ELSPAR as part of a treatment regimen, retreatment with this agent at a later time is associated with increased risk of hypersensitivity reactions. In patients found by skin testing to be hypersensitive to asparaginase, and in any patient who has received a previous course of therapy with asparaginase, therapy with this agent should be instituted or reinstituted only after successful desensitization, and then only if in the judgement of the physician the possible benefit is greater than the increased risk. Desensitization itself may be hazardous. (See DOSAGE AND ADMINISTRATION, Intradermal Skin Test.)

In view of the unpredictability of the adverse reactions to asparaginase, it is recommended that this product be used in a hospital setting. Asparaginase has an adverse effect on liver function in the majority of patients. Therapy with asparaginase may increase pre-existing liver impairment caused by prior therapy or the underlying disease. Because of this there is a possibility that asparaginase may increase the toxicity of other medications.

The administration of ELSPAR intravenously concurrently with or immediately before a course of vincristine and prednisone may be associated with increased toxicity. (See DOSAGE AND ADMINISTRATION, Recommended Induction Regimens.)

PRECAUTIONS

General

This drug may have toxic properties and must be handled and administered with care. ELSPAR may be irritating to eyes, skin, and the upper respiratory tract. 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.)

Asparaginase has been reported to have immunosuppressive activity in animal experiments. Accordingly, the possibility that use of the drug in man may predispose to infection should be considered.

Asparaginase toxicity is reported to be greater in adults than in pediatric patients.

Laboratory Tests

The fall in circulating lymphoblasts often is quite marked; normal or below normal leukocyte counts are noted frequently within the first several days after initiating therapy. This may be accompanied by a marked rise in serum uric acid. The possible development of uric acid nephropathy should be borne in mind. Appropriate preventive measures should be taken, e.g., allopurinol, increased fluid intake, alkalization of urine. As a guide to the effects of therapy, the patient's peripheral blood count and bone marrow should be monitored frequently.

Frequent serum amylase determinations should be obtained to detect early evidence of pancreatitis. If pancreatitis occurs, therapy should be stopped and not reinstituted.

Blood sugar should be monitored during therapy with ELSPAR because hyperglycemia may occur.

Drug Interactions

Tissue culture and animal studies indicate that ELSPAR can diminish or abolish the effect of methotrexate on malignant cells. This effect on methotrexate activity persists as long as plasma asparagine levels are suppressed. These results would seem to dictate against the clinical use of methotrexate with ELSPAR, or during the period following ELSPAR therapy when plasma asparagine levels are below normal.

Drug/Laboratory Test Interactions

L-asparaginase 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-asparaginase.

Animal Toxicology

A one-month intravenous toxicity study of ELSPAR in dogs at doses of 250, 1000, and 2000 I.U./kg/day revealed reduced serum total protein and albumin with loss of body weight at the highest dose level and anorexia, emesis, and diarrhea at all dosage levels. A similar study in monkeys at doses of 100, 300, and 1000 I.U./kg/day also revealed reduction of serum total protein and albumin and body weight loss at all dosage levels. Bromsulfalein retention and fatty changes in the liver were noted in monkeys that were given 300 and 1000 I.U./kg/day. The rabbit was unusually sensitive to ELSPAR since a single intravenous dose of 1000 I.U./kg caused hypocalcemia associated with necrosis of the parathyroid cells, convulsions, and death in about one third of the animals. Some rabbits that died showed small thymic and lymph node hemorrhages and necrosis of the germinal centers in the lymph nodes and spleen. The intravenous administration of calcium gluconate alleviated or prevented the adverse effects.

Changes in the pancreatic islets (not pancreatitis) ranging from edema to necrosis were observed in the rabbits in the acute intravenous toxicity studies (doses of 12,500 to 50,000 I.U./kg) but not in rabbits that received 1000 I.U./kg. The anatomical changes and the hypocalcemia found in the rabbits were not observed in the subacute intravenous studies in the dogs and monkeys.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The intraperitoneal injection of 2500 I.U./kg/ day for 4 days in newborn Swiss mice resulted in a small increase in pulmonary adenomas; lymphatic leukemia was not increased.

L-asparaginase at concentrations of 152-909 I.U./plate was not mutagenic in the Ames microbial mutagen test with or without metabolic activation.

There are no adequate studies on the effects of asparaginase on fertility.

Pregnancy

Pregnancy Category C. In mice and rats ELSPAR has been shown to retard the weight gain of mothers and fetuses when given in doses of more than 1000 I.U./kg (the recommended human dose). Resorptions, gross abnormalities and skeletal abnormalities were observed. The intravenous administration of 50 or 100 I.U./kg (one-twentieth or one-tenth of the human dose) to pregnant rabbits on Day 8 and 9 of gestation resulted in dose dependent embryotoxicity and gross abnormalities. There are no adequate and well-controlled studies in pregnant women. ELSPAR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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

Pediatric Use

Asparaginase toxicity is reported to be greater in adults than in pediatric patients.

Geriatric Use

Clinical studies of ELSPAR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Page last updated: 2006-11-11

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