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 34kDa. 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 and 10-mL colorless, glass vials. Each 3-mL vial contains 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. Each 10-mL vial contains 7.5 mg rasburicase, 53 mg mannitol, 79.5 mg L-alanine, and between 63 and 71.5 mg dibasic sodium phosphate.

The diluent solution for reconstitution is supplied in a 2-mL or 5-mL clear, glass ampule. The 2-mL ampule contains 1 mL Water for Injection, USP, and 1 mg Poloxamer 188. The 5-mL ampule contains 5 mL Water for Injection, USP, and 5 mg Poloxamer 188. The product reconstituted with diluent is a clear, colorless solution.

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.

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.

TWO DIFFERENT STRENGTHS ARE AVAILABLE (1.5 mg vial and 7.5 mg vial)

Reconstitution Procedure

Determine the number of vials of ELITEK needed to achieve the proper dosage, based on the individual patient's weight and the dose per kilogram. ELITEK must be reconstituted in the diluent provided.

To each 1.5 mg vial of ELITEK, add 1 mL of the provided reconstitution solution (diluent) and mix by swirling very gently. Do not shake or vortex.

To each 7.5 mg vial of ELITEK, add 5 mL of the provided reconstitution solution (diluent) and mix by swirling very gently. Do not shake or vortex.

Reconstituted ELITEK should be inspected visually for particulate matter and discoloration prior to administration, and discarded if particulate matter is visible or if product is discolored.

Further Dilution and Administration

Using aseptic technique and syringes of appropriate volume, remove the predetermined dose of ELITEK from the reconstituted vials and inject into an infusion bag containing the appropriate volume of 0.9% sterile sodium chloride, to achieve a final total volume of 50 mL. This final solution for injection is to be infused over 30 minutes. No filters should be used for the infusion.

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.

NDC 0024-5150-10: One carton containing 3 single-use vials each containing 1.5 mg of rasburicase and 3 ampules each containing 1 mL Water for Injection, USP, and 1 mg Poloxamer 188.

NDC 0024-5151-75: One carton containing 1 single-use vial containing 7.5 mg of rasburicase and 1 ampule containing 5 mL Water for Injection, USP, and 5 mg Poloxamer 188.

Storage and Handling

The lyophilized drug product and the diluent for reconstitution should be stored at 2-8°C (36-46°F). Do not freeze. Protect from light.

Manufactured by sanofi-aventis U.S. LLC, Bridgewater, NJ 08807. Revised October 2007. FDA revision date: 9/10/2007

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 methemoglo-binemia ( < 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

ELITEK is immunogenic in healthy volunteers, and can elicit antibodies that inhibit the activity of rasburicase in vitro (see BOXED WARNINGS, Anaphylaxis and WARNINGS, Anaphylaxis).

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.

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 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).

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. This can occur at any time during treatment including the first dose. Signs and symptoms of these reactions include bronchospasm, chest pain and tightness, dyspnea, hypoxia, hypotension, shock, 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).

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.

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

Rasburicase is teratogenic in rabbits and rats. Pregnant rabbits were dosed with rasburicase at levels of 2, 10 or 20 mg/kg (equivalent to 10, 50 and 100 times the human equivalent dose). Mortality occurred at 2 and 20 mg/kg, abortions at 10 mg/kg and clinical signs of toxicity appeared at all dose levels. At doses equal to or greater than 10 mg/kg, decreases were observed in uterine weight and viable fetuses while increases were observed in the number of fetal resorptions and post-implantation loss. Additionally, fetal body weights were decreased while increases occurred in heart and great vessel malformation at all doses levels. In offspring of pregnant rats given 50 mg/kg (equivalent to 250 times the human dose), multiple heart and great vessel malformations were observed. There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, ELITEK should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

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 AUC_{0-96 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.

REFERENCES

3. National Cancer Institute Common Toxicity Criteria, Version 2.0 (http://ctep.cancer.gov/reporting/ctc.html).

Several cases of overdosage with ELITEK have been reported without any specific adverse events associated with the overdose. The maximum dose of ELITEK that has been administered as a single dose is 1.3 mg/kg; the maximum daily dose that has been administered is 1.3 mg/kg/day. According to the mechanism of action of ELITEK, an overdose will lead to low or undetectable plasma uric acid concentration, which has no known clinical consequences. Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specific antidote for ELITEK has been identified.

ELITEK is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD) (see BOXED WARNINGS, Hemolysis and WARNINGS, Hemolysis).

ELITEK is contraindicated in patients with a known history of anaphylaxis or hypersensitivity reactions, hemolytic reactions or methemoglobinemia reactions to ELITEK or any of the excipients (see BOXED WARNINGS and WARNINGS).

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 AUC_{0-24 hr} and Cmax, tended to increase linearly with doses over a limited dose range (0.15 to 0.20 mg/kg). The overall elimination half-life was 18 hours. No accumulation of rasburicase was observed between days 1 and 5 of dosing. ELITEK mean volume of distribution was 110 to 127 mL/kg in pediatric patients. There are insufficient data to characterize pharmacokinetics in adult patients.

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

Study 1 was a randomized, open-label, controlled study conducted at six institutions, in which 52 pediatric patients were randomized to receive either ELITEK (n=27) or allopurinol (n=25).¹ The dose of allopurinol varied according to local institutional practice. ELITEK was administered as an intravenous infusion over 30 minutes once (n=26) or twice (n=1) daily at a dose of 0.20 mg/kg/dose (total daily dose 0.20-0.40 mg/kg/day). Initiation of dosing was permitted at any time between 4 to 48 hours before the start of anti-tumor therapy and could be continued for 5 to 7 days after initiation of anti-tumor therapy. Patients were stratified at randomization on the basis of underlying malignant disease (leukemia or lymphoma) and baseline serum or plasma uric acid levels ( < 8.0 mg/dL and ≥ 8.0 mg/dL). The primary study objective was to demonstrate a greater reduction in uric acid concentration over 96 hours (AUC_{0-96 hr}) in the ELITEK group as compared to the allopurinol group. Uric acid AUC_{0-96 hr} was defined as the area under the curve for plasma uric acid lev- els (mg·hr/dL), measured from the last value prior to the first dose of ELITEK until 96 hours after that first dose. Plasma uric acid levels were used for all uric acid AUC_0-96 hr calculations (see PRECAUTIONS, Laboratory Test Interactions).

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 AUC_0-96 hr was significantly lower in the ELITEK group (128 ± s.e. 14 mg·hr/dL) as compared to the allop-urinol 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

Study 2 was a multi-institutional, single-arm study conducted in 89 pediatric and 18 adult patients with hematologic malignancies. Patients received ELITEK at a dose of 0.15 mg/kg/day. The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours where maintenance of uric acid concentration was defined as: 1) achievement of uric acid concentration ≤ 6.5 mg/dL (patients < 13 years) or ≤ 7.5 mg/dL (patients ≥ 13 years) within a designated time point (48 hours) from initiation of ELITEK and maintained until 24 hours after the last administration of study drug; and 2) control of uric acid level without the need for allopurinol or other agents.

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

Study 3 was a multi-institutional, single-arm study conducted in 130 pediatric patients and 1 adult patient with hemato-logic malignancies.² Patients received ELITEK at either a dose of 0.15 mg/kg/day (n=12) or 0.20 mg/kg/day (n=119). The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours as defined for Study 2 above.

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

Dosing

For the pooled data set of the 3 clinical studies (n=265), total daily dosing for ELITEK ranged from 0.15 to 0.40 mg/kg/day with the majority receiving 0.20 mg/kg/day. The maximum daily doses received were 0.15 mg/kg/day in 116 patients, 0.20 mg/kg/day in 135 patients, 0.30 mg/kg/day (divided doses) in 3 patients, and 0.40 mg/kg/day (divided doses) in 11 patients. The safety and effectiveness of twice-daily dosing with ELITEK have not been established due to insufficient data (see DOSAGE AND ADMINISTRATION).

Reduction of Uric Acid Levels

Data from the 3 studies (n=265) were pooled and analyzed according to the plasma uric acid levels over time. The pretreatment plasma uric acid concentration was ≥ 8 mg/dL in 61 patients and was < 8 mg/dL in 200 patients. The median uric acid concentration at baseline, at 4 hours following the first dose of ELITEK, and the per patient fall in plasma uric acid concentration from baseline to 4 hours were calculated in those patients with both pre-treatment and 4-hour post-treatment values. Among patients with pre-treatment uric acid ≥ 8.0 mg/dL [baseline median 10.6 mg/dL (range 8.1 – 36.4)], the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 9.1 mg/dL (0.3 – 19.3 mg/dL). Among the patients with a pre-treatment plasma uric acid level < 8 mg/dL [baseline median 4.6 mg/dL (range 0.2 – 7.9 mg/dL)], the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 4.1 mg/dL (0.1 – 7.6 mg/dL).

Figure 1. Box and Whisker Plot of Uric Acid Concentration at designated time blocks. ELITEK administration began immediately after baseline.

Figure 1 is a box and whisker plot of plasma uric acid levels inclusive of 261 of the 265 ELITEK treated patients from Studies 1, 2, and 3. Of the 261 evaluable patients, plasma uric acid concentration was maintained (see Clinical Studies, Study 2, for the definition of uric acid concentration maintenance) by 4 hours for 92% of patients (240/261), by 24 hours for 93% of patients (245/261), by 48 hours for 97% of patients (254/261), by 72 hours for 99% of patients (260/261), and by 96 hours for 100% of patients (261/261). Of the subset of 61 patients whose plasma uric acid level was elevated at baseline ( ≥ 8 mg/dL), plasma uric acid concentration was maintained by 4 hours for 72% of patients (44/61), by 24 hours for 80% of patients (49/61), by 48 hours for 92% of patients (56/61), by 72 hours for 98% of patients (60/61), and by 96 hours for 100% (61/61).

REFERENCES

1. Goldman SC, Holcenberg JS, Finklestein JZ. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood. 2001;97:2998-3003.

2. Pui C-H, Mahmoud HH, Wiley JM et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol. 2001;19:697-704.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

RASBURICASE - INJECTION

(ras-BYUR-ih-case)

COMMON BRAND NAME(S): Elitek

WARNING: This drug can cause a severe allergic reaction. If you develop new symptoms such as chest pain, trouble breathing, severe dizziness, or rash/hives, stop using this medication and seek immediate medical attention. Do not restart this medication if this severe allergic reaction has occurred. Consult the doctor or pharmacist for more details.

Do not take this medication if you have a metabolic condition called glucose-6-phosphate dehydrogenase (G6PD) deficiency because it can severely damage your red blood cells leading to anemia (hemolysis). If you are of African or Mediterranean descent, you may be at higher risk for G6PD deficiency and you should be tested to see if you have this condition before starting this medication.

This medication can cause a condition that affects the ability of your red blood cells to carry oxygen (methemoglobinemia). Do not restart this medication if this effect occurs; consult the doctor for details.

This medication can interfere with accurate measurement of uric acid in the blood, resulting in falsely low levels (see Drug Interactions section). Be sure to tell all laboratory personnel that you are using this drug.

USES: This medication is used to prevent high blood levels of uric acid from occurring in children with cancer (e.g., leukemia, lymphoma, solid malignant tumors) who are about to receive cancer chemotherapy treatment. When chemotherapy is given, cancer cells are destroyed, releasing large amounts of uric acid into the bloodstream. This medication allows uric acid to more easily be removed from the body by the kidneys.

HOW TO USE: Inject this medication directly into a vein (IV) slowly over 30 minutes, or as directed by your doctor. Do not give as a rapid (bolus) infusion. This medication should be started in a hospital/clinic. Rasburicase is given once a day for 5 days. Correct timing of cancer chemotherapy and rasburicase doses is important. Start chemotherapy 4 to 24 hours after the first dose of rasburicase.

Follow all instructions for proper mixing and dilution with correct IV fluids. When mixing the drug, swirl gently. Do not shake the vial. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Do not use a filter when injecting this medication. This drug should be given through a separate IV line from other medications if possible. If you have questions regarding the use of this medication, consult the pharmacist.

Intravenous (IV) fluids should be given with this medication to also help decrease your uric acid levels.

SIDE EFFECTS: Also see the Warnings section.

Vomiting, nausea, headache, stomach pain, constipation, diarrhea, mouth sores/ulcers or rash may occur. If any of these effects persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: persistent sore throat, fever, chills.

Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: chest pain, trouble breathing, severe dizziness, weakness, yellowing eyes and skin, dark urine, blue or gray skin color.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact the doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Also see the Warnings section.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult the doctor or pharmacist if you have: previous severe allergic reaction to this medication, certain metabolic conditions (e.g., G6PD deficiency), previous red blood cell damage (e.g., hemolysis, methemoglobinemia) with this medication.

Before using this medication, tell the doctor the medical history, especially of: kidney disease, dehydration, any allergies.

Caution is advised when using this drug in children less than 2 years old because they may be more sensitive to the side effects of the drug.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Breast-feeding is not recommended while using this drug.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

Tell the doctor of all prescription and nonprescription medication you may use, especially: allopurinol.

This medication can interfere with the uric acid in the blood sample tubes when the tubes remain at room temperature, therefore leading to falsely low uric acid results. Laboratory personnel must follow special procedures to process the blood sample.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Laboratory tests (e.g., uric acid levels) should be performed to monitor your progress.

MISSED DOSE: It is important that each dose be used as scheduled. If you miss a dose, contact your doctor immediately. He/she will establish a new dose schedule. Do not "double-up" the dose to catch up.

STORAGE: Store the medication in the refrigerator at 36 to 46 degrees F (2 to 8 degrees C). Do not freeze. Protect from light.

Once mixed, the medication may be stored for up to 24 hours in the refrigerator. Discard the medication if it is not given within 24 hours after mixing.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.