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Rasburicase

Pronunciation

(ras BYOOR i kayse)

Index Terms

  • Recombinant Urate Oxidase
  • Urate Oxidase

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Elitek: 1.5 mg (1 ea); 7.5 mg (1 ea)

Brand Names: U.S.

  • Elitek

Pharmacologic Category

  • Enzyme
  • Enzyme, Urate-Oxidase (Recombinant)

Pharmacology

Rasburicase is a recombinant urate-oxidase enzyme, which converts uric acid to allantoin (an inactive and soluble metabolite of uric acid); it does not inhibit the formation of uric acid.

Distribution

Children: 110 to 127 mL/kg; Adults: 76 to 138 mL/kg

Onset of Action

Uric acid levels decrease within 4 hours of initial administration

Half-Life Elimination

~16 to 23 hours

Special Populations: Race

The geometric mean values of body weight–normalized clearance were approximately 40% lower in Japanese than in Caucasian patients.

Use: Labeled Indications

Hyperuricemia associated with malignancy: Initial management of uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies receiving chemotherapy expected to result in tumor lysis and elevation of plasma uric acid

Limitations of use: Indicated only for a single course of treatment

Contraindications

History of anaphylaxis or severe hypersensitivity to rasburicase or any component of the formulation; history of hemolytic reaction or methemoglobinemia associated with rasburicase; glucose-6-phosphatase dehydrogenase (G6PD) deficiency

Dosing: Adult

Hyperuricemia associated with malignancy: IV: 0.2 mg/kg once daily for up to 5 days (US labeling [use beyond 5 days or administration of more than 1 course is not recommended]) or up to 7 days (Canadian labeling) or

Alternate dosing (off-label; Coiffier 2008): 0.05 to 0.2 mg/kg once daily for 1 to 7 days (average of 2 to 3 days) with the duration of treatment dependent on plasma uric acid levels and clinical judgment (patients with significant tumor burden may require an increase to twice daily); the following dose levels are recommended based on risk of tumor lysis syndrome (TLS):

High risk: 0.2 mg/kg once daily (duration is based on plasma uric acid levels)

Intermediate risk: 0.15 mg/kg once daily (duration is based on plasma uric acid levels)

Low risk: 0.1 mg/kg once daily (duration is based on clinical judgment); a dose of 0.05 mg/kg was used effectively in one trial

Single-dose rasburicase (off-label dosing; based on limited data): 0.15 mg/kg (Campara 2009; Liu 2005) or 3 to 7.5 mg as a single dose (Hutcherson 2006; McBride 2013; McDonnell 2006; Reeves 2008; Trifilio 2006); repeat doses (1.5 to 6 mg) may be needed based on serum uric acid levels

Prevention in high-risk patients with hematologic malignancies (off-label dosing): 3 mg as a single dose (Jones 2015)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hyperuricemia associated with malignancy: IV: 0.2 mg/kg once daily for up to 5 days (US labeling [use beyond 5 days or administration of more than 1 course is not recommended]) or up to 7 days (Canadian labeling) or

Alternate dosing (off-label; Coiffier 2008): 0.05 to 0.2 mg/kg once daily for 1 to 7 days (average of 2 to 3 days) with the duration of treatment dependent on plasma uric acid levels and clinical judgment (patients with significant tumor burden may require an increase to twice daily); the following dose levels are recommended based on risk of tumor lysis syndrome (TLS):

High risk: 0.2 mg/kg once daily (duration is based on plasma uric acid levels)

Intermediate risk: 0.15 mg/kg once daily (duration is based on plasma uric acid levels); may consider managing initially with a single dose

Low risk: 0.1 mg/kg once daily (duration is based on clinical judgment); a dose of 0.05 mg/kg was used effectively in one trial

Single-dose rasburicase (off-label dosing; based on limited data): 0.15 mg/kg; additional doses may be needed based on serum uric acid levels (Liu 2005)

Prevention in high-risk patients with hematologic malignancies (off-label dosing): 0.2 mg/kg as a single dose (Jones 2015)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Reconstitute with provided diluent (use 1 mL diluent for the 1.5 mg vial and 5 mL diluent for the 7.5 mg vial). Mix by gently swirling; do not shake or vortex. Discard if discolored or containing particulate matter. Total dose should be further diluted in NS to a final volume of 50 mL. Do not use filters during reconstitution or administration.

Administration

IV infusion over 30 minutes; do not administer as a bolus infusion. Do not filter during infusion. If not possible to administer through a separate line, IV line should be flushed with at least 15 mL saline prior to and following rasburicase infusion.

The optimal timing of rasburicase administration (with respect to chemotherapy administration) is not specified in the US labeling. In some studies, chemotherapy was administered 4 to 24 hours after the first rasburicase dose (Cortes 2010; Kikuchi 2009; Vadhan-Raj 2012); however, rasburicase generally may be administered irrespective of chemotherapy timing. The Canadian labeling recommends initiating chemotherapy as soon as 4 hours after rasburicase administration.

Storage

The lyophilized drug product and the diluent for reconstitution should be stored at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Reconstituted solution and solution diluted for infusion may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F). Discard unused product.

Drug Interactions

There are no known significant interactions.

Test Interactions

Specific handling procedures must be followed to prevent the degradation of uric acid in plasma samples. Blood must be collected in prechilled tubes containing heparin anticoagulant. Samples must then be immediately immersed and maintained in an ice water bath. Prepare samples by centrifugation in a precooled centrifuge (4°C). Samples must be analyzed within 4 hours of collection.

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (50%)

Central nervous system: Headache (26%), anxiety (24%)

Dermatologic: Rash (13%; serious: <1%)

Endocrine & metabolic: Hypophosphatemia (17%), hypervolemia (12%)

Gastrointestinal: Nausea (27% to 58%), vomiting (38% to 50%), abdominal pain (20% to 22%), constipation (20%), diarrhea (20%), mucositis (15%)

Hepatic: Hyperbilirubinemia (16%), increased serum ALT (11%)

Immunologic: Antibody development (children: 11%; IgE: 6%), development of IgG antibodies (18%; neutralizing 8%)

Infection: Sepsis (12%; serious: 5%)

Respiratory: Pharyngolaryngeal pain (14%)

Miscellaneous: Fever (46%)

1% to 10%:

Cardiovascular: Ischemic heart disease (≥2%), supraventricular arrhythmia (≥2%)

Endocrine & metabolic: Hyperphosphatemia (10%)

Gastrointestinal: Gastrointestinal infection (≥2%)

Hematologic & oncologic: Pulmonary hemorrhage (≥2%)

Hypersensitivity: Hypersensitivity (4%)

Infection: Infection (abdominal, ≥2%)

Respiratory: Respiratory failure (≥2%)

<1% (Limited to important or life-threatening): Anaphylaxis, hemolysis, methemoglobinemia, seizure

ALERT: U.S. Boxed Warning

Hypersensitivity reactions:

Rasburicase may cause serious and fatal hypersensitivity reactions, including anaphylaxis. Immediately and permanently discontinue rasburicase in patients who experience a serious hypersensitivity reaction.

Hemolysis:

Do not administer rasburicase to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue rasburicase in patients developing hemolysis. Screen patients at higher risk for G6PD deficiency (eg, patients of African or Mediterranean ancestry) prior to starting rasburicase therapy.

Methemoglobinemia:

Rasburicase can result in methemoglobinemia in some patients. Immediately and permanently discontinue rasburicase in patients developing methemoglobinemia.

Interference with uric acid measurements:

Rasburicase enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in prechilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection.

Warnings/Precautions

Concerns related to adverse effects:

• Hemolysis: [US Boxed Warning]: Due to the risk for hemolysis (<1%), rasburicase is contraindicated in patients with G6PD deficiency. Discontinue immediately and permanently in any patient developing hemolysis. Patients at higher risk for G6PD deficiency (eg, African or Mediterranean descent) should be screened prior to therapy. Severe hemolytic reactions occurred within 2 to 4 days of rasburicase initiation.

• Hypersensitivity: [US Boxed Warning]: Serious and fatal hypersensitivity reactions (including anaphylaxis) have been reported; immediately and permanently discontinue in patients developing a serious hypersensitivity reaction. Reactions may occur at any time during treatment (including the initial dose); signs and symptoms may include bronchospasm, chest pain/tightness, dyspnea, hypotension, hypoxia, shock, or urticaria. The safety and efficacy of more than one course of administration has not been established.

• Methemoglobinemia: [US Boxed Warning]: Methemoglobinemia has been reported (<1%). Discontinue immediately and permanently in any patient developing methemoglobinemia. Initiate appropriate treatment (eg, transfusion, methylene blue) if methemoglobinemia occurs.

Other warnings/precautions:

• Hydration: Patients at risk for tumor lysis syndrome should receive appropriate IV hydration as part of uric acid management; however, alkalinization (with sodium bicarbonate) concurrently with rasburicase is not recommended (Coiffier 2008).

• Multiple courses: Rasburicase is immunogenic and can elicit an antibody response; efficacy may be reduced with subsequent courses of therapy.

• Uric acid degradation: [US Boxed Warning]: Enzymatic degradation of uric acid in blood samples will occur if left at room temperature, which may interfere with serum uric acid measurements; specific guidelines for the collection of plasma uric acid samples must be followed, including collection in prechilled tubes with heparin anticoagulant, immediate ice water bath immersion and assay within 4 hours (sample should remain on ice until analyzed).

Monitoring Parameters

Plasma uric acid levels (4 hours after rasburicase administration, then every 6 to 8 hours until TLS resolution), CBC, G6PD deficiency screening (in patients at high risk for deficiency); monitor for hypersensitivity reactions

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Use during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, anxiety, constipation, or mouth sores. Have patient report immediately to prescriber rash, fatigue, nausea, vomiting, diarrhea, abdominal pain, flu-like symptoms, pharyngitis, difficulty breathing, angina, shortness of breath, severe dizziness, passing out, loss of strength and energy, arrhythmia, swelling of arms or legs, or coughing up blood (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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