BOX WARNINGS
ANAPHYLAXIS
ELITEK may cause severe hypersensitivity reactions including anaphylaxis. ELITEK should be immediately and permanently discontinued in any patient developing clinical evidence of a serious hypersensitivity reaction (see WARNINGS, Anaphylaxis and ADVERSE REACTIONS, Immunogenicity).
HEMOLYSIS
ELITEK administered to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency can cause severe hemolysis. ELITEK administration should be immediately and permanently discontinued in any patient developing hemolysis. It is recommended that patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) be screened prior to starting ELITEK therapy (see CONTRAINDICATIONS and WARNINGS, Hemolysis).
METHEMOGLOBINEMIA
ELITEK use has been associated with methemoglobinemia. ELITEK administration should be immediately and permanently discontinued in any patient identified as having developed methemoglobinemia (see WARNINGS, Methemoglobinemia).
INTERFERENCE WITH URIC ACID MEASUREMENTS
ELITEK will cause enzymatic degradation of the uric acid within blood samples left at room temperature, resulting in spuriously low uric acid levels. To ensure accurate measurements, blood must be collected into pre-chilled tubes containing heparin anticoagulant and immediately immersed and maintained in an ice water bath; plasma samples must be assayed within 4 hours of sample collection (see PRECAUTIONS, Laboratory Test Interactions).
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WARNINGS
ANAPHYLAXIS
The safety and efficacy of ELITEK have been established only for a single course of treatment [once daily for 5 days (see DOSAGE AND ADMINISTRATION) ].
ELITEK may cause severe allergic reactions including anaphylaxis. Signs and symptoms of these reactions include anaphylactic shock, bronchospasm, chest pain, dyspnea, hypotension and/or urticaria. ELITEK administration should be immediately and permanently discontinued in any patient developing clinical evidence of a serious hypersensitivity reaction (see BOX WARNINGS, Anaphylaxis and ADVERSE REACTIONS, Immunogenicity).
HEMOLYSIS
ELITEK is contraindicated in patients with G6PD deficiency because hydrogen peroxide is one of the major by-products of the conversion of uric acid to allantoin. In clinical studies, two patients developed severe hemolytic reactions [National Cancer Institute Common Toxicity Criteria3(NCI CTC) grade 3 and 4] within 2-4 days of the start of ELITEK. G6PD deficiency was subsequently identified in one of these patients. ELITEK administration should be immediately and permanently discontinued in any patient developing hemolysis, and appropriate patient monitoring and support measures initiated (e.g., transfusion support). It is recommended that patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) be screened prior to starting ELITEK therapy (see BOX WARNINGS, Hemolysis and CONTRAINDICATIONS).
METHEMOGLOBINEMIA
In clinical studies, methemoglobinemia has been reported in 2 patients receiving ELITEK. Both patients developed serious hypoxemia requiring intervention with the appropriate medical support measures. It is not known whether patients with deficiency of cytochrome b5 reductase (formerly known as methemoglobin reductase) or of other enzymes with antioxidant activity are at increased risk for methemoglobinemia or hemolytic anemia. ELITEK administration should be immediately and permanently discontinued in any patient identified as having developed methemoglobinemia, and appropriate monitoring and support measures (e.g., transfusion support, methyleneblue administration) implemented (see BOX WARNINGS, Methemoglobinemia).
PRECAUTIONS
GENERAL
Patients on ELITEK should receive intravenous hydration according to standard medical practice for the management of plasma uric acid in patients at risk for tumor lysis syndrome.
DRUG INTERACTIONS
No studies of interactions with other drugs have been conducted in humans.
Rasburicase does not metabolize allopurinol, cytarabine, methylprednisolone, methotrexate, 6-mercaptopurine, thioguanine, etoposide, daunorubicin, cyclophosphamide or vincristine in vitro. No metabolic-based drug interactions are therefore anticipated with these agents in patients.
In preclinical in vivo studies, rasburicase did not affect the activity of isoenzymes CYP1A, CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A, suggesting no induction nor inhibition potential. Clinically relevant P450-mediated drug-drug interactions are therefore not anticipated in patients treated with the recommended ELITEK dose and dosing schedule.
LABORATORY TEST INTERACTIONS
At room temperature, ELITEK causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. The following special sample handling procedure must be followed to avoid ex vivo uric acid degradation.
Uric acid must be analyzed in plasma. Blood must be collected into prechilled tubes containing heparin anticoagulant. Samples must be immediately immersed in an ice water bath. Plasma samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection (see BOX WARNINGS, Interference with Uric Acid Measurement).
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term studies in animals to evaluate carcinogenic potential have not been performed.
ELITEK was non-genotoxic in the Ames, unscheduled DNA synthesis, chromosome analysis, mouse lymphoma, and micronucleus tests.
ELITEK did not affect reproductive performance or fertility in male or female rats at doses 8-fold higher than the human dose when corrected for differences in body surface area.
PREGNANCY CATEGORY C
Animal reproduction studies have not been conducted with ELITEK. It is also not known whether ELITEK can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ELITEK should be given to a pregnant woman only if clearly needed.
NURSING MOTHERS
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue ELITEK, taking into account the importance of the drug to the mother.
PEDIATRIC USE
The efficacy and safety of ELITEK was studied in 246 pediatric patients ranging in age from 1 month to 17 years. There were an insufficient number of patients in the 0-6 months age group (n=7) to determine whether they respond differently from older children. These patients were pooled into the <2 years of age group (n=24). Children <2 years of age had a higher mean uric acid AUC0-96 hr than those age 2-17 years (150 ± s.e. 16 mg·hr/dL vs. 108 ± s.e. 4 mg·hr/dL, respectively). In addition, the data suggest that children <2 years of age had a lower rate of success at achieving maintenance uric acid concentration by 48 hours [83% (95% CI of 62 to 95) vs. 93% (95% CI of 89 to 95), respectively]. Children <2 years old also experienced more toxicity. The following adverse events were observed more frequently in children less than 2 years of age compared to those age 2-17 years respectively: vomiting (75% vs. 55%), diarrhea (63% vs. 20%), fever (50% vs. 38%), and rash (38% vs. 10%).
GERIATRIC USE
Five of the 19 adults among the 265 patients enrolled in clinical studies of ELITEK, were age 65 or greater. Therefore, there are insufficient data to determine whether geriatric subjects, or adults in general, respond differently from pediatric subjects.
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