Rasburicase

Dosage Forms

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

Solution Reconstituted, Intravenous [preservative free]:

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

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

Pediatric patients: 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

Use in Specific Populations

Special Populations: Race

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

Use: Labeled Indications

Hyperuricemia associated with malignancy: Initial management of plasma 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

Dosage and Administration

Dosing: Adult

Hyperuricemia associated with malignancy: IV: 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) (Coiffier 2008):

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): 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. A meta-analysis of 10 studies determined that the pooled response rate of single-dose rasburicase (doses ranging from 0.05 mg/kg to 0.2 mg/kg) was not inferior to daily rasburicase dosing while allowing for cost savings; monitor closely in case an additional dose may be needed (Feng 2013). Another meta-analysis of 15 studies determined that a single 6 mg dose was sufficient to lower and maintain uric acid and creatinine levels in adult patients with TLS; if the uric acid level is <12 mg/dL, single doses of 3 mg or 4.5 mg may be considered with close monitoring and if needed, repeat doses (Yu 2017).

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

Manufacturer’s labeling: IV: 0.2 mg/kg once daily for up to 5 days (use beyond 5 days or administration of more than 1 course is not recommended)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hyperuricemia associated with malignancy: Infants, Children, and Adolescents:

Multiple-dosing:

Manufacturer's labeling (Elitek): IV: 0.2 mg/kg/dose once daily for up to 5 days

Alternate dosing (Coiffier 2008): Limited data available: IV: 0.05 to 0.2 mg/kg/dose once daily for 1 to 7 days (average: 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 and baseline uric acid level >7.5 mg/dL: 0.2 mg/kg/dose once daily (duration is based on plasma uric acid levels)

Intermediate risk and baseline uric acid level <7.5 mg/dL: 0.15 mg/kg/dose once daily (duration is based on plasma uric acid levels); may consider managing initially with a single dose

Low risk and baseline uric acid level <7.5 mg/dL: 0.1 mg/kg/dose once daily (duration is based on clinical judgment); a dose of 0.05 mg/kg was used (with good results) in one trial

Single-dose: Limited data available: IV: 0.15 mg/kg/dose; additional doses may be needed based on serum uric acid levels (Liu 2005)

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

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. Because the provided diluent is in a glass ampule, the diluent should be filtered prior to adding to the rasburicase vial for reconstitution (ISMP [Smetzer 2017]).

Administration

IV: IV infusion over 30 minutes; do not administer as a bolus. 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 manufacturer's 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.

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%, postmarketing, and/or case reports: Anaphylaxis, hemolysis, methemoglobinemia, muscle spasm, seizure

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

Pregnancy Considerations

Based on data from animal reproduction studies, in utero exposure to rasburicase may cause fetal harm. Information related to the use of rasburicase in pregnancy is limited (Middeke 2014).

Patient Education

What is this drug used for?

• It is used to treat or prevent high uric acid levels during chemo.

Frequently reported side effects of this drug

• Headache
• Anxiety
• Constipation
• Mouth irritation
• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Methemoglobinemia like blue or gray color of the lips, nails, or skin; abnormal heartbeat; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath.
• Yellow skin
• Dark urine
• Pale skin
• Rash
• Fatigue
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Flu-like symptoms
• Sore throat
• Difficulty breathing
• Chest pain
• Shortness of breath
• Severe dizziness
• Passing out
• Severe loss of strength and energy
• Swelling of arms or legs
• Coughing up blood
• Signs of a significant reaction like 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.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.