hylaxis and serious allergic reactions. Allergic reactions have occurred with the first dose and with subsequent doses of Elspar. The risk of serious allergic reactions appears to be higher in patients with prior exposure to Elspar or other Escherichia coli-derived L-asparaginases.
Serious thrombosis, including sagittal sinus thrombosis
Pancreatitis, in some cases fulminant or fatal
Glucose intolerance, in some cases irreversible
Coagulopathy, including increased prothrombin time, increased partial thromboplastin time, and decreased fibrinogen, protein C, protein S and antithrombin III. CNS hemorrhages have been reported.
Hepatotoxicity, liver disorder and hepatic failure have been reported.
Central Nervous System effects including coma, seizures, and hallucinations.
Common Adverse Reactions
Azotemia, liver function abnormalities, including hyperbilirubinemia, and elevated transaminases.
Other
Hyperlipidemia and hypertriglyceridemia including clinically significant levels of triglycerides have been reported.
Fatty changes in the liver have been documented on biopsy.
6.2 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity, defined as development of binding and/or neutralizing antibodies to the product.
Elspar is a bacterial protein and can elicit antibodies in patients treated with the drug. In 2 prospectively designed clinical trials (N=59 and 24), approximately one quarter of the patients developed antibodies that bound to Elspar as measured by enzyme-linked immunosorbent assays (ELISA). Clinical hypersensitivity reactions to Elspar in studies were common ranging from 32.5% to 75%. In these studies, concomitant medications and dosing schedules varied. Patients with hypersensitivity reactions were more likely to have antibodies than those without hypersensitivity reactions. Hypersensitivity reactions have been associated with increased clearance of Elspar. Incidence of antibody formation was lower upon first administration of Elspar than second administration. The frequency of antibody formation in adults relative to children is unknown. There is insufficient information to comment on neutralizing antibodies; however, higher levels of antibody correlated with a decrease in asparaginase activity.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications and underlying disease. Therefore, comparison of the incidence of antibodies to Elspar with the incidence of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
No formal drug interaction studies between Elspar and other drugs have been performed.
8 USE IN SPECIFIC POPULATIONS
8.1 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 International Units/kg (approximately equivalent to the recommended human dose, when adjusted for total body surface area). Resorptions, gross abnormalities and skeletal abnormalities were observed. The intravenous administration of 50 or 100 International Units/kg (approximately equivalent to 10 to 20% of the recommended human dose, when adjusted for total body surface area) to pregnant rabbi |
