VA Class:GA500
ATC Class:V03AF07
Rasburicase, a biosynthetic (recombinant DNA origin) form of urate oxidase, is an enzyme that catalyzes oxidation of uric acid into an inactive and soluble metabolite, allantoin.1, 4, 5, 6
Chemotherapy-Induced Hyperuricemia
Rasburicase is used for the initial management of plasma uric acid concentrations in pediatric patients with leukemia, lymphoma, or solid tumors who are receiving chemotherapy expected to result in tumor lysis and subsequent elevation of plasma uric acid concentrations.1, 2, 3, 4, 5, 6 Results of 2 open-label, clinical studies in patients with acute leukemia or non-Hodgkin's lymphoma (76% of whom were younger than 13 years of age) indicate that rasburicase administered prior to and concurrently with chemotherapy for 5-7 consecutive days rapidly and effectively decreases plasma uric acid concentrations.1, 3 In these studies, 92-99% of patients who received rasburicase achieved age-adjusted target plasma uric acid concentrations (i.e., 6.5 mg/dL or less in children younger than 13 years of age or 7.5 mg/dL or less in those 13 years of age or older) within 48 hours following inititation of rasburicase therapy and maintained these concentrations for 24 hours after the last administered rasburicase dose without the need for allopurinol or uricosuric agents, despite receiving intensive chemotherapy.1, 3 In one of these 2 studies, the median reduction in plasma uric acid concentrations that occurred 4 hours following the first dose of rasburicase ranged from 8.7 mg/dL in patients with baseline hyperuricemia to 3.8 mg/dL in those without baseline hyperuricemia.3
Results of a third multicenter, randomized, open-label, comparative study in infants, children, and adolescents 4 months to 17 years of age with leukemia or lymphoma and a high risk for developing tumor lysis also indicate that IV rasburicase may be faster and more effective in decreasing plasma uric acid concentrations than oral allopurinol.1, 2, 4, 5, 6 In this study, patients who received IV rasburicase 4-48 hours (median interval: 20 hours) prior to initiation of chemotherapy had substantially greater reductions in plasma uric acid concentrations (86 versus 12%, respectively) 4 hours after administration of the drug than those who received oral dosages of allopurinol. 1, 2, 4, 5, 6 Patients who received IV rasburicase in the study experienced on average a 2.6-fold less exposure to uric acid during the first 96 hours of induction chemotherapy than those who received oral allopurinol.2 In addition, all patients with baseline hyperuricemia who received IV rasburicase achieved a plasma uric acid concentration of less than 8 mg/dL in less than 4 hours compared with none of those who received oral allopurinol.2, 5, 6 The different routes of administration for these 2 drugs (i.e., IV versus oral) are not believed to account for these differences.5 IV allopurinol, which was unavailable at the time of the study, has been shown to be equivalent to the oral formulation and does not appear to be more rapidly or substantially more effective than the oral formulation.5, 7, 8 However, comparative studies with IV rasburicase and IV allopurinol for the initial management of plasma uric acid concentrations in patients at high risk of developing tumor lysis are lacking.9
Although the ultimate goal of therapy in the treatment of hyperuricemia is to prevent adverse renal effects (e.g., renal insufficiency, acute renal failure) that can occur when excess uric acid crystallizes in the renal tubules and distal collecting system, this study was not designed to compare the possible renal effects of rasburicase and allopurinol.2, 4, 6 Further studies are needed to determine whether the more rapid control and reduction of plasma uric acid concentrations that is achieved with rasburicase therapy than is achieved with allopurinol therapy also will result in substantial decreases in metabolic complications and morbidity associated with tumor lysis syndrome, or the need for additional renal support (dialysis or hemofiltration).2 Because of cost considerations, some clinicians suggest reserving rasburicase for pediatric patients at high risk of developing tumor lysis syndrome either from rapid turnover of the cancer cells, such as leukemia or bulky lymphomas (e.g., Burkitt's or T-cell non-Hodgkin's lymphoma), or from chemotherapy.5, 6 Patients with a low risk of developing tumor lysis syndrome may respond just as well to standard therapies for hyperuricemia (e.g., allopurinol, urinary alkalinization, IV hydration).5
Reconstitution and Administration
Rasburicase is administered once daily by IV infusion over 30 minutes; the drug should not be administered as a rapid IV (“bolus”) injection.1 The safety and efficacy of twice daily dosing of rasburicase have not been established because of insufficient data.1
Rasburicase lyophilized powder for injection must be reconstituted and diluted prior to administration.1 Rasburicase lyophilized powder for injection is reconstituted by adding 1 mL of the diluent (sterile water for injection and poloxamer 188) provided by the manufacturer to a vial labeled as containing 1.5 mg of rasburicase to provide a solution containing 1.5 mg/mL; the number of vials needed to achieve the proper dosage is based on the patient's weight and the dose per kg.1 The solution should be mixed by swirling very gently (so as to not form a vortex) and should not be shaken.1 The appropriate dose should then be withdrawn from the vials and diluted with a sufficient volume of 0.9% sodium chloride injection to achieve a final volume of 50 mL.1
Reconstituted or diluted solutions of rasburicase can be stored up to 24 hours at 2-8°C.1 However, the manufacturer states that reconstituted solutions of the drug contain no preservatives and must be administered within 24 hours of reconstitution; any unused solution should be discarded.1
Rasburicase solutions should be inspected visually for particulate matter and/or discoloration prior to administration and should be discarded if either is present.1 The manufacturer recommends that filters not be used during IV administration of the drug.1 The manufacturer also states that rasburicase solutions should be infused through a different line than that used for the infusion of other concomitant drugs.1 If use of a separate line is not possible, the line should be flushed with at least 15 mL of 0.9% sodium chloride injection prior to and after infusion of rasburicase solutions.1
The recommended pediatric dosage of rasburicase is 0.15 or 0.2 mg/kg as a single daily dose for 5 days.1 Chemotherapy should be initiated 4-24 hours after the first dose of rasburicase.1 Because the safety and effectiveness of other dosing regimens have not been established, the manufacturer does not recommend administering the drug for more than 5 days or for more than one course of therapy.1 (See Sensitivity Reactions: Anaphylaxis under Cautions: Warnings/Precautions.)
No special population dosage recommendations at this time.1
Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.1 (See Warnings: Hemolysis under Cautions: Warnings/Precautions.)
Known hypersensitivity (e.g., anaphylaxis) or hematologic (e.g., hemolysis, methemoglobinemia) reactions to rasburicase or any ingredient (e.g., excipients) in the formulation.1
Grade 3 and 4 hemolytic reactions have been reported within 2-4 days of initiation of rasburicase therapy in 2 patients in clinical trials.1 Only one of these patients was found to have glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.1, 2 Rasburicase is contraindicated in patients with G-6-PD deficiency and the manufacturer recommends that patients who are at increased risk for G-6-PD deficiency (e.g., patients of African or Mediterranean descent) be screened prior to initiation of rasburicase therapy.1 Rasburicase should be immediately and permanently discontinued in patients who develop hemolysis, and appropriate patient monitoring and support measures initiated (e.g., transfusion support).1
Methemoglobinemia, resulting in serious hypoxemia that required medical intervention, has been reported in at least 2 patients in clinical trials.1 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.1 Rasburicase should be immediately and permanently discontinued in patients who develop methemoglobinemia, and appropriate monitoring and supportive measures (e.g., transfusion support, methylene blue administration) implemented.1
Interference with Uric Acid Measurements
Rasburicase causes enzymatic degradation of uric acid in blood/plasma/serum samples left at room temperature, resulting in spuriously low uric acid concentrations.1 To ensure accurate measurements, blood samples must be collected into prechilled test tubes containing heparin anticoagulant and immediately immersed and maintained in an ice water bath.1 The manufacturer of rasburicase states that uric acid concentrations must be analyzed in plasma.1 Plasma samples must be prepared from whole blood by centrifugation in a pre-cooled centrifuge (4°C) and be assayed within 4 hours of sample collection.1
Severe sensitivity reactions, including anaphylaxis, have been reported in clinical studies.1 If manifestations of a serious sensitivity reaction (e.g., chest pain, dyspnea, hypotension, urticaria) occur, rasburicase should be immediately and permanently discontinued,1 and appropriate therapy initiated.9 Because patients with atopic allergy or asthma were excluded from clinical studies, the safety of rasburicase in these patients remains to be established.2, 3, 6 The safety and efficacy of rasburicase have been established only for a single course of treatment.1
Development of antibodies to rasburicase has been reported in healthy individuals and in patients with hematologic malignanies who received the drug in clinical trials.1, 3, 4 About 11% of patients receiving rasburicase in clinical studies developed antibodies to the drug within 28 days.1 Because studies in healthy volunteers indicate that antibodies may not be detectable until after 28 days, the manufacturer states that the true incidence of antibody formation to rasburicase is unknown.1
Rasburicase should be used concomitantly with IV hydration according to standard medical practice for the management of plasma uric acid in patients at risk for tumor lysis syndrome.1 Because rasburicase metabolizes uric acid into allantoin, a water soluble metabolite that is easily excreted in the urine, alkalinization of the urine is not needed.6, 9
Category C.1 (See Users Guide.)
Not known whether rasburicase is distributed into milk.1 Discontinue nursing or the drug, taking into account the importance of the drug to the mother.1
Safety and efficacy not established in children younger than 2 years of age.9
Experience in those 65 years of age and older insufficient to determine whether they respond differently from younger adults.1
Rasburicase has been used in a limited number of adults†.1 Experience in adults is insufficient to determine whether they respond differently from pediatric patients.1
Adverse effects occurring in at least 10% of patients receiving rasburicase in clinical trials include vomiting,1 fever,1 nausea,1 headache,1 abdominal pain,1 constipation,1 diarrhea,1 mucositis,1 and rash.1 Some of these adverse effects (e.g., vomiting, diarrhea, fever, rash) were observed more frequently in children younger than 2 years of age than in those 2-17 years of age.1
In addition, vomiting, fever, nausea, diarrhea, and headache reportedly occurred more frequently in patients receiving IV rasburicase than in those receiving oral allopurinol.1 The incidence of rash was similar in the 2 treatment groups, but severe rash (grade 3 or 4) was reported only in a patient who received rasburicase.1
No formal drug interaction studies have been performed in humans.1
Rasburicase does not metabolize cyclophosphamide, cytarabine, daunorubicin, etoposide, mercaptopurine, methotrexate, thioguanine, or vincristine in vitro; pharmacokinetic interactions unlikely.1
Rasburicase does not metabolize allopurinol in vitro; pharmacokinetic interactions unlikely.1
Rasburicase does not metabolize methylprednisolone in vitro; pharmacokinetic interactions unlikely.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Rasburicase does not appear to substantially induce or inhibit any of the major cytochrome P-450 (CYP) isoenzymes, including 1A, 2A, 2B, 2C, 2E, or 3A in preclinical in vivo studies; clinically relevant pharmacokinetic interactions unlikely.1
Rasburicase, a biosynthetic (recombinant DNA origin) form of urate oxidase, is an enzyme that catalyzes oxidation of uric acid into an inactive and soluble metabolite, allantoin.1 The drug is prepared from a genetically modified strain of Saccharomyces cerevisiae using the complementary DNA (cDNA) from a strain of Aspergillus flavus .1, 4, 6 In humans, production of uric acid is the final step in purine catabolism.1 Rasburicase is active only at the end of this catabolic pathway.1
Risk of sensitivity reactions (e.g., anaphylaxis).1 Importance of immediately seeking medical attention if symptoms of severe sensitivity (e.g., chest pain, dysnea, hypotension, urticaria) occur.1
Risk of adverse hematologic effects (e.g., hemolysis, methemoglobinemia).1
Importance of women informing clinicians immediately if they are or plan to become pregnant or to breast-feed.1
Importance of informing clinicians of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, existing or contemplated concomitant therapy, including prescription and OTC drugs.
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For IV infusion | 1.5 mg |
1. Sanofi-Aventis Inc. Elitek® (rasburicase) injection for intravenous use prescribing information. New York, NY; 2002 Jul 22.
2. Goldman SC, Holcenberg JS, Finklestein JZ et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood . 2001; 97:2998-3003. [PubMed 11342423]
3. Pui CH, 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. [PubMed 11157020]
4. Easton J, Noble S, Jarvis B. Rasburicase. Pediatr Drugs. 2001; 3:433-9
5. Anon. Rasburicase (Elitek®) for hyperuricemia. Med Letter Drug Ther . 2002; 44:96-7.
6. Lohr LK. Rasburicase, a new, recombinate form of urate oxidase, treats hyperuricemia in tumor lysis syndrome. Hem/Onc Today. October 2002. From the Hem/Onc Today website. Accessed 2003 Jan 23. [Web]
7. Smalley RV, Guaspari A, Haase-Statz S et al. Allopurinol: intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol . 2000; 18:1758-63. [PubMed 10764437]
8. Nabi Biopharmaceuticals. Aloprim® (allopurinol sodium) for injection, for intravenous infusion prescribing information (dated 1999 Jun). In: Physicians' desk reference. From the PDR electronic library website. Accessed 2003 Jan 27. [Web]
9. Sanofi-Aventis Inc., New York, NY: Personal communication.