Elspar Side Effects, and Drug Interactions - Asparaginase

Elspar Side Effects, and Drug Interactions - Asparaginase

SIDE EFFECTS

Allergic reactions, including skin rashes, urticaria, arthralgia, respiratory distress, and acute anaphylaxis have been reported. (See WARNINGS.) Acute reactions have occurred in the absence of a positive skin test and during continued maintenance of therapeutic serum levels of ELSPAR.

In pediatric patients with advanced leukemia, a lower incidence of anaphylaxis has been reported with intramuscular administration, although there was a higher incidence of milder hypersensitivity reactions than with intravenous administration.¹⁶

Fatal hyperthermia has been reported.

Pancreatitis, sometimes fulminant and fatal, has occurred during or following therapy with ELSPAR.^4-7,17

Hyperglycemia with glucosuria and polyuria has been reported in low incidence. Serum and urine acetone usually have been absent or negligible in these patients; this syndrome thus resembles hyperosmolar, nonketotic, hyperglycemia induced by a variety of other agents. This complication usually responds to discontinuance of ELSPAR, judicious use of intravenous fluid, and insulin, but may be fatal on occasion.

In addition to hypofibrinogenemia, depression of various other clotting factors has been reported. Most marked has been a decrease in plasma levels of factors V and VIII with a variable decrease in factors VII and IX. A decrease in circulating platelets has occurred in low incidence which, together with the increased levels of fibrin degradation products in the serum, may indicate development of a consumption coagulopathy.Bleeding has been a problem in only a minority of patients with demonstrable coagulopathy. However, intracranial hemorrhage and fatal bleeding associated with low fibrinogen levels have been reported.^6,7,18 Increased fibrinolytic activity, apparently compensatory in nature, also has occurred.

Some patients have shown central nervous system effects consisting of depression, somnolence, fatigue, coma, confusion, agitation,and hallucinations varying from mild to severe.^6,7,10,12,13 Rarely, a Parkinson-like syndrome has occurred, with tremor and a progressive increase in muscular tone. These side effects usually have reversed spontaneously after treatment was stopped. Therapy with ELSPAR is associated with an increase in blood ammonia during the conversion of asparagine to aspartic acid by the enzyme. No clear correlation exists between the degree of elevation, of blood ammonia levels and the appearance of CNS changes. Chills, fever, nausea, vomiting, anorexia,abdominal cramps, weight loss, headache, and irritability may occur and usually are mild.

Azotemia, usually pre-renal, occurs frequently. Acute renal shutdown and fetal renal insufficiency have been reported during treatment.⁵ Proteinuria has occurred infrequently.

A variety of liver function abnormalities have been reported, including elevations of AST(SGOT), ALT(SGPT), alkaline phosphatase, bilirubin (direct and indirect), and depression of serum albumin, cholesterol (total and esters), and plasma fibrinogen. Increases and decreases of total lipids have occurred.¹⁹ Marked hypoalbuminemia associated with peripheral edema has been reported.¹⁰ However, these abnormalities usually are reversible on discontinuance of therapy and some reversal may occur during the course of therapy. Fatty changes in the liver have been documented by biopsy. Malabsorption syndrome has been reported.¹²

Rarely, transient bone marrow depression has been observed, as evidenced by a delay in return of hemoglobin or hematocrit levels to normal in patients undergoing hematologic remission of leukemia.Marked leukopenia has been reported.²⁰

DRUG INTERACTIONS

Tissue culture and animal studies indicate that ELSPAR can diminish or abolish the effect of methotrexate on malignant cells.¹⁴ 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.