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RasburicaseELITEK rasburicase
ELITEK (rasburicase) is a recombinant urate-oxidase enzyme produced by a genetically modified Saccharomyces cerevisiae strain. The cDNA coding for rasburicase was cloned from a strain of Aspergillus flavus. Rasburicase is a tetrameric protein with identical subunits of a molecular mass of about 34 kDa. The molecular formula of the monomer is C1523H2383N417O462S7. The monomer, made up of a single 301 amino acid polypeptide chain, has no intra- or inter-disulfide bridges and is N-terminal acetylated. The drug product is a sterile, white to off-white, lyophilized powder intended for intravenous administration following reconstitution. ELITEK is supplied in 3-mL colorless, glass vials containing 1.5 mg rasburicase, 10.6 mg mannitol, 15.9 mg L-alanine, and between 12.6 and 14.3 mg of dibasic sodium phosphate. The diluent solution for reconstitution, supplied in a 2 mL clear, glass ampule,
is composed of 1.0 mL sterile Water for Injection, USP, and 1.0 mg Poloxamer
188. The product reconstituted with diluent is a clear, colorless solution.
In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of uric acid into an inactive and soluble metabolite (allantoin). Rasburicase is only active at the end of the purine catabolic pathway. Pharmacokinetics of rasburicase were evaluated in two studies that enrolled
patients with lymphoid leukemia (B and T cell), non-Hodgkin’s lymphoma (including
Burkitt’s lymphoma) or acute myelogenous leukemia. ELITEK exposure, as measured
by CLINICAL STUDIES ELITEK was administered in three studies to 265 patients with acute leukemia or non-Hodgkin’s lymphoma. The clinical studies were largely limited to pediatric patients (246 of 265). ELITEK was administered as a 30-minute infusion once (n=251) or twice (n=14) daily at a dose of 0.15 or 0.20 mg/kg/dose (total daily dose 0.20-0.40 mg/kg/day). ELITEK was administered prior to and concurrent with anti-tumor therapy, which consisted of either systemic chemotherapy (n=196) or steroids (n=69). Study 1 The demographics of the two study arms (ELITEK vs. allopurinol) were as follows: age <13 years (82% vs. 76%), males (59% vs. 72%), Caucasian (59% vs. 72%), ECOG performance status 0 (89% vs. 84%), and leukemia (74% vs. 76%). The median interval, in hours, between initiation of ELITEK and of anti-tumor treatment was 20 hours, with a range of 70 hours before to 10 hours after the initiation of anti-tumor treatment (n=24, data not reported for 3 patients). The uric acid AUC0-96 hr was significantly lower in the ELITEK group (128 ± s.e. 14 mg·hr/dL) as compared to the allopurinol group (328 ± s.e. 26 mg·hr/dL). All but one patient in the ELITEK arm had reduction and maintenance of uric acid levels to within or below the normal range during the treatment. The incidence of renal dysfunction was similar in the two study arms; one patient in the allopurinol arm developed acute renal failure. Study 2 The study population demographics were: age <13 years (76%), males (61%), Caucasian (91%), ECOG performance status = 0 (92%), and leukemia (89%). The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 2 was 99% (106/107). Study 3 The study population demographics were: age <13 years (76%), Caucasian (83%), males (67%), ECOG = 0 (67%), and leukemia (88%). The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 3 was 92% in the 0.15 mg/kg group (n=12) and 95% in the 0.20 mg/kg group (n = 119). Pooled Analyses Reduction of Uric Acid Levels ELITEK is indicated for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid. DOSAGE AND ADMINISTRATION The recommended dose and schedule of ELITEK is 0.15 or 0.20 mg/kg as a single daily dose for 5 days. Because the safety and effectiveness of other schedules have not been established, dosing beyond 5 days or administration of more than one course of ELITEK is not recommended. Chemotherapy should be initiated 4 to 24 hours after the first dose of ELITEK. DO NOT ADMINISTER AS A BOLUS INFUSION. ELITEK should be administered as an intravenous infusion over 30 minutes. Reconstitution Procedure Further Dilution and Administration The reconstituted ELITEK contains no preservatives and must be administered within 24 hours of reconstitution. The reconstituted or diluted solution can be stored up to 24 hours at 2-8°C. Discard any unused product. ELITEK should be infused through a different line than that used for the infusion
of other concomitant medications. If use of a separate line is not possible,
the line should be flushed with at least 15 mL of saline solution prior to and
after infusion with ELITEK. HOW SUPPLIED NDC 0024-5150-10: One carton containing 3 single-use vials each containing 1.5 mg of rasburicase and 3 ampules each containing 1.0 mL diluent. Storage and Handling References Manufactured and distributed by Sanofi-Synthelabo Inc. ESS-4A Revised July 2002
SIDE EFFECTS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. The data described below reflect exposure to ELITEK in 703 patients [63% male, 37% female; median age 10 years (range 10 days to 88 years); 73% Caucasian, 9% African, 4% Asian, 14% other/unknown]. ELITEK was studied for adverse reactions, regardless of severity, in 347 patients (265 pediatric and 82 adults) enrolled in one active-controlled trial (Study 1), two uncontrolled trials (Studies 2 and 3), and one uncontrolled safety trial (n=82). Additionally, an expanded access experience enrolled 356 patients, for whom reliably collected data were limited to serious adverse reactions. Among the 703 patients for whom serious adverse reactions were assessed, the most serious adverse reactions caused by ELITEK were allergic reactions including anaphylaxis (<1%), rash (1%), hemolysis (<1%), and methemoglobinemia (<1%) (see BOXED WARNINGS and WARNINGS). The commonly observed serious adverse reactions were fever (5%), neutropenia with fever (4%), respiratory distress (3%), sepsis (3%), neutropenia (2%), and mucositis (2%). The following additional serious adverse reactions were observed in <1% of patients regardless of causality: acute renal failure, arrhythmia, cardiac failure, cardiac arrest, cellulitis, cerebrovascular disorder, chest pain, convulsions, cyanosis, diarrhea, dehydration, hot flushes, ileus, infection, intestinal obstruction, hemorrhage, myocardial infarction, paresthesia, pancytopenia, pneumonia, pulmonary edema, pulmonary hypertension, retinal hemorrhage, rigors, thrombosis, and thrombophlebitis. Among the 347 patients for whom all adverse reactions regardless of severity were assessed, the most frequently observed adverse reactions (incidence >10%) were vomiting (50%), fever (46%), nausea (27%), headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%). In Study 1, an active control study, the following adverse events occurred more frequently in ELITEK-treated subjects than allopurinol-treated subjects: vomiting, fever, nausea, diarrhea, and headache. Although the incidence of rash was similar in the two arms, severe rash (NCI CTC3, Grade 3 or 4) was reported only in one ELITEK-treated patient. Immunogenicity In a study of 28 healthy volunteers, the incidence of antibody responses to either a single dose or to 5 daily doses was assessed. Binding antibodies to rasburicase were detected by ELISA in 17/28 (61%) volunteers and neutralizing antibodies were detected in 18/28 (64%) volunteers. Time to detection of antibodies ranged from 1 to 6 weeks after ELITEK exposure. In two subjects with extended follow-up, antibodies persisted for 333 and 494 days. The incidence of antibody responses in patients with hematologic malignancy has not been adequately assessed. In clinical trials of patients with hematologic malignancies, 24 of the 218 patients tested (11%) developed antibodies by day 28 following ELITEK administration. However, this is not a reliable estimate of the true incidence of antibody responses in patients with hematologic malignancies, because the data from the healthy volunteer study indicate that antibody may not be detectable until some time point beyond day 28. The incidence of antibody responses detected is highly dependent on the sensitivity
and specificity of the assay, which have not been fully evaluated. Additionally,
the observed incidence of antibody positivity in an assay may be influenced
by several factors, including serum sampling, timing and methodology, concomitant
medications, and underlying disease. For these reasons, comparison of the incidence
of antibodies to ELITEK with the incidence of antibodies to other products may
be misleading. DRUG INTERACTIONS 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 Uric acid must be analyzed in plasma. Blood must be collected into pre-chilled
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 BOXED WARNINGS, Interference with Uric Acid
Measurement).
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 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 BOXED 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 BOXED 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,
methylene-blue administration) implemented (see BOXED
WARNINGS, Methemoglobinemia). PRECAUTIONS General Carcinogenesis, Mutagenesis, Impairment of Fertility 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 Nursing Mothers Pediatric Use Geriatric Use |
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