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    Uricosuric Recombinant Enzyme

    BOXED WARNING

    Interference with uric acid measurements

    Rasburicase causes interference with uric acid measurements by enzymatically degrading uric acid in blood/plasma/serum samples left at room temperature; this results in low plasma uric acid assay readings. To ensure accurate measurements, collect blood into pre-chilled tubes containing heparin and immediately immerse and maintain the tube in an ice water bath. Prepare plasma samples by centrifugation in a pre-cooled centrifuge (4 degrees Celsius). Keep the plasma samples in an ice water bath and analyze within 4 hours of collection.

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant form of urate oxidase that catalyzes the breakdown of uric acid to allantoin
    Used in the initial treatment of hyperuricemia in patients with leukemia, lymphoma, or solid tumors who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid
    Hemolysis and methemoglobinemia have been reported; do not administer rasburicase in patients with glucose-6 phosphate dehydrogenase (G6PD) deficiency

    COMMON BRAND NAMES

    Elitek

    HOW SUPPLIED

    Elitek Intravenous Inj Pwd F/Sol: 1.5mg, 7.5mg

    DOSAGE & INDICATIONS

    For the initial management of plasma uric acid levels in adult and pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and elevation of plasma uric acid.
    NOTE: The FDA has designated rasburicase as an orphan drug for the treatment of malignancy-associated or chemotherapy-induced hyperuricemia.
    Weight-based dosing for the initial management of plasma uric acid levels.
    Intravenous dosage
    Adults

    0.2 mg/kg IV over 30 minutes once daily for up to 5 days.

    Adolescents, Children, and Infants 1 month and older

    0.2 mg/kg IV over 30 minutes once daily for up to 5 days. Patients receive IV hydration (3 L/m2 per day); some patients also receive urinary alkalinization as necessary.

    Fixed-dose therapy†.
    Intravenous dosage
    Adults

    3 mg and 6 mg (range, 1.5 to 7.5 mg) IV were the most frequently evaluated fixed doses of rasburicase in retrospective studies; most patients required only 1 fixed dose to achieve normalized uric acid levels. A single, 7.5-mg fixed dose of rasburicase was evaluated in a small, prospective, case-controlled study. Most patients in this study received additional supportive care measures to prevent tumor lysis syndrome such as allopurinol and/or alkalinization.

    MAXIMUM DOSAGE

    Adults

    0.2 mg/kg per day IV for up to 5 days.; fixed-dose†, 7.5 mg IV.

    Geriatric

    0.2 mg/kg per day IV for up to 5 days.; fixed-dose†, 7.5 mg IV.

    Adolescents

    0.2 mg/kg per day IV for up to 5 days.

    Children

    0.2 mg/kg per day IV for up to 5 days.

    Infants

    0.2 mg/kg per day IV for up to 5 days.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Dilution is required prior to administration as an infusion.
    Do not administer as an IV bolus.
     
    Reconstitution of rasburicase vial:
    Use the provided diluent. Add 1 mL of diluent to the 1.5-mg vial or 5 mL of diluent to the 7.5-mg vial for a final concentration of 1.5 mg/mL.
    Do not shake or vortex the vial; gently swirl to mix.
    Preparation of infusion:
    Inject the calculated dose of reconstituted rasburicase solution into an infusion bag containing the appropriate volume of 0.9% Sodium Chloride injection, to achieve a final total volume of 50 mL.
    Storage following infusion preparation: Store diluted infusion solution at 2 to 8 degrees C (36 to 46 degrees F); infuse within 24 hours of preparation.
     
    Intravenous infusion:
    Infuse the diluted solution IV over 30 minutes. Do not use filters during the infusion.
    Infuse through a separate line; if the use of a separate line is not possible, flush the line with at least 15 mL of 0.9% Sodium Chloride injection prior to and after each infusion.

    STORAGE

    Elitek:
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Interference with uric acid measurements

    Rasburicase causes interference with uric acid measurements by enzymatically degrading uric acid in blood/plasma/serum samples left at room temperature; this results in low plasma uric acid assay readings. To ensure accurate measurements, collect blood into pre-chilled tubes containing heparin and immediately immerse and maintain the tube in an ice water bath. Prepare plasma samples by centrifugation in a pre-cooled centrifuge (4 degrees Celsius). Keep the plasma samples in an ice water bath and analyze within 4 hours of collection.

    Acute bronchospasm, hypotension, mannitol hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis, shock, urticaria, yeast hypersensitivity

    There is a risk of serious hypersensitivity reactions or anaphylaxis with rasburicase use; fatal anaphylactic reactions have been reported. Rasburicase is contraindicated in patients with a known history of anaphylaxis or hypersensitivity reactions to rasburicase or any component of the product. Permanently discontinue rasburicase if a patient experiences signs or symptoms of a severe hypersensitivity reaction such as acute bronchospasm, chest pain/tightness, dyspnea, hypoxia, hypotension, shock, and urticaria. The rasburicase lyophilized vial contains mannitol; therefore, use caution in patients with a mannitol hypersensitivity. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae (yeast) strain and the DNA coding was cloned from a strain of Aspergillus flavus; use caution in patients with a yeast hypersensitivity.

    G6PD deficiency, hemolytic anemia, methemoglobin reductase deficiency, methemoglobinemia

    Rasburicase is contraindicated in patients with a known history of hemolysis or methemoglobinemia with rasburicase and in patients with glucose-6 phosphate dehydrogenase (G6PD) deficiency. Patients who have a high risk of G6PD deficiency, such as patients of African or Mediterranean ancestry, should be screened prior to starting rasburicase. Permanently discontinue rasburicase if a patient experiences hemolysis or methemoglobinemia; start appropriate monitoring and medical management (e.g., transfusion support, methylene blue). It is not known if the risk of methemoglobinemia or hemolytic anemia is increased in patients with deficiencies of cytochrome b5 reductase or of other enzymes with antioxidant activity; use rasburicase with caution in patients with methemoglobin reductase deficiency. Severe hemolytic reactions have occurred within 2 to 4 days of starting rasburicase.

    Pregnancy

    Rasburicase may cause fetal harm if used during pregnancy, based on data from animal studies. Rasburicase use has not been evaluated in pregnant women; weigh the benefits of therapy with the potential risk to the fetus in these patients. Multiple heart and great vessel malformations were observed in the offspring of pregnant rats who received IV rasburicase doses that resulted in 100 times the exposure seen with the recommended human dose. Additionally, decreased fetal body weights and heart and great vessel malformations occurred in the offspring of pregnant rabbits who received IV rasburicase doses that resulted in 5 to 54 times the exposure seen with the recommended human dose.

    Breast-feeding

    Advise patients that breast-feeding is not recommended during rasburicase treatment and for 2 weeks after the last dose due to the potential for serious adverse reactions in the breast-fed child. There are no data on the presence of rasburicase in human milk, the effects on the breast-fed child, or the effects on milk production.

    ADVERSE REACTIONS

    Severe

    infection / Delayed / 5.4-6.5
    hypophosphatemia / Delayed / 4.3-6.5
    abdominal pain / Early / 3.3-4.3
    elevated hepatic enzymes / Delayed / 3.3-4.3
    anxiety / Delayed / 0-3.3
    peripheral edema / Delayed / 2.2-3.3
    edema / Delayed / 0-3.3
    hyperbilirubinemia / Delayed / 2.2-3.3
    nausea / Early / 1.1-1.1
    vomiting / Early / 1.1-1.1
    methemoglobinemia / Early / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    bronchospasm / Rapid / 0-1.0
    seizures / Delayed / Incidence not known
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 20.0-20.0
    antibody formation / Delayed / 6.0-18.0
    hyperphosphatemia / Delayed / 9.8-15.2
    oral ulceration / Delayed / 15.0-15.0
    hemolysis / Early / 0-1.0
    hypoxia / Early / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    dyspnea / Early / 0-1.0
    supraventricular tachycardia (SVT) / Early / Incidence not known
    involuntary movements / Delayed / Incidence not known
    bleeding / Early / Incidence not known

    Mild

    fever / Early / 46.0-46.0
    headache / Early / 0-26.0
    diarrhea / Early / 20.0-20.0
    rash / Early / 0-13.0
    arthralgia / Delayed / 0-4.3
    injection site reaction / Rapid / 0-4.3
    urticaria / Rapid / 0-1.0

    DRUG INTERACTIONS

    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as rasburicase, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

    PREGNANCY AND LACTATION

    Pregnancy

    Rasburicase may cause fetal harm if used during pregnancy, based on data from animal studies. Rasburicase use has not been evaluated in pregnant women; weigh the benefits of therapy with the potential risk to the fetus in these patients. Multiple heart and great vessel malformations were observed in the offspring of pregnant rats who received IV rasburicase doses that resulted in 100 times the exposure seen with the recommended human dose. Additionally, decreased fetal body weights and heart and great vessel malformations occurred in the offspring of pregnant rabbits who received IV rasburicase doses that resulted in 5 to 54 times the exposure seen with the recommended human dose.

    Advise patients that breast-feeding is not recommended during rasburicase treatment and for 2 weeks after the last dose due to the potential for serious adverse reactions in the breast-fed child. There are no data on the presence of rasburicase in human milk, the effects on the breast-fed child, or the effects on milk production.

    MECHANISM OF ACTION

    Rasburicase catalyzes the enzymatic oxidation of uric acid to the inactive and more soluble metabolite, allantoin. Allantoin is metabolized by peptide hydrolysis and excreted. Rasburicase is a recombinant form of urate oxidase produced by cloning the gene for Aspergillus flavus urate oxidase for expression in Saccharomyces cerevisiae. Humans do not produce urate oxidase due to a nonsense mutation in the coding region of the gene. In some hematologic malignancies and solid tumors, effective anticancer therapy causes a rapid lysis of malignant cells and an abrupt release of cellular contents into the blood resulting in tumor lysis syndrome (TLS). TLS is characterized by hyperuricemia and electrolyte abnormalities (e.g., hyperkalemia, hyperphosphatemia, hypocalcemia) and may lead to acute renal failure, arrhythmias, and/or death. Allopurinol inhibits the xanthine oxidase enzyme and prevents the formation of uric acid. In addition to a unique mechanism of action, rasburicase differs from allopurinol in that it degrades preexisting uric acid, reduces uric acid levels quickly (usually within 4 hours), and does not lead to xanthine accumulation.

    PHARMACOKINETICS

    Rasburicase is administered as an intravenous infusion. In adult patients with leukemia, lymphoma, or other hematological malignancies, the mean volume of distribution was 75.8 to 138 mL/kg following rasburicase 0.15 to 0.2 mg/kg IV once daily for up to 5 days in a pharmacokinetic analysis. The mean terminal half-life range was 15.7 to 22.5 hours. Additionally, plasma uric acid levels decreased within 4 hours and were maintained below 7.5 mg/dL for at least 7 days in 98% of adult patients. There was no dose response effect on uric acid levels with the 0.2 mg/kg dosage. Rasburicase is metabolized by peptide hydrolysis.
     
    Affected cytochrome P450 isoenzymes: none
    Clinically relevant CYP450-mediated drug interactions are not expected in patients who receive the recommended rasburicase dose and dosing schedule. In vivo, rasburicase did not induce or inhibit the activity of CYP1A, CYP2A, CYP2B, CYP2C, CYP2E, or CYP3A.

    Intravenous Route

    The exposure at 24 hours (AUC0-24 hours) and Cmax increased when the rasburicase dose increased from 0.15 to 0.2 mg/kg IV; however, drug accumulation was minimal (less than 1.3 fold) between dosing days 1 and 5.