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Black Box Warning
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
ANAPHYLAXIS, HEMOLYSIS, METHEMOGLOBINEMIA, AND INTERFERENCE WITH URIC ACID MEASUREMENTS
Anaphylaxis
Elitek® can cause severe hypersensitivity reactions including anaphylaxis. Immediately and permanently discontinue Elitek in patients who experience a serious hypersensitivity reaction [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1), ADVERSE REACTIONS (6.2)].
Hemolysis
Do not administer Elitek to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue Elitek in patients developing hemolysis. Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.2)].
Methemoglobinemia
Elitek can result in methemoglobinemia in some patients. Immediately and permanently discontinue Elitek in patients developing methemoglobinemia [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.3)].
Interference with Uric Acid Measurements
Elitek enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in pre-chilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection
Overview
Rasburicase is a recombinant urate-oxidase that is FDA approved for the treatment of plasma uric acid levels in pediatric and adult 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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include vomiting, nausea, pyrexia, peripheral edema, anxiety, headache, abdominal pain, constipation, and diarrhea.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
Elitek® is indicated for the initial management of plasma uric acid levels in pediatric and adult 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.
Limitation of use: Elitek is indicated only for a single course of treatment
Dosage
The recommended dose of Elitek is 0.2 mg/kg as a 30 minute intravenous infusion daily for up to 5 days. Dosing beyond 5 days or administration of more than one course is not recommended.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rasburicase in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasburicase in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Rasburicase in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rasburicase in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasburicase in pediatric patients.
Contraindications
Elitek is contraindicated in patients with a history of anaphylaxis or severe hypersensitivity to rasburicase or in patients with development of hemolytic reactions or methemoglobinemia with rasburicase.
Elitek is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD)
Warnings
ConditionName:
See full prescribing information for complete Boxed Warning.
ConditionName:
ANAPHYLAXIS, HEMOLYSIS, METHEMOGLOBINEMIA, AND INTERFERENCE WITH URIC ACID MEASUREMENTS
Anaphylaxis
Elitek® can cause severe hypersensitivity reactions including anaphylaxis. Immediately and permanently discontinue Elitek in patients who experience a serious hypersensitivity reaction [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1), ADVERSE REACTIONS (6.2)].
Hemolysis
Do not administer Elitek to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue Elitek in patients developing hemolysis. Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.2)].
Methemoglobinemia
Elitek can result in methemoglobinemia in some patients. Immediately and permanently discontinue Elitek in patients developing methemoglobinemia [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.3)].
Interference with Uric Acid Measurements
Elitek enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in pre-chilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection
Anaphylaxis
The safety and efficacy of Elitek have been established only for a single course of treatment once daily for 5 days.
Elitek can cause severe allergic reactions including anaphylaxis. In clinical studies, anaphylaxis was reported in <1% patients receiving Elitek. 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 urticaria. Immediately and permanently discontinue Elitek administration in any patient developing clinical evidence of a serious hypersensitivity reaction.
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, hemolysis occurs in <1% patients receiving Elitek; severe hemolytic reactions occurred within 2–4 days of the start of Elitek. Immediately and permanently discontinue Elitek administration in any patient developing hemolysis. Institute appropriate patient monitoring and support measures (e.g., transfusion support). Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek.
Methemoglobinemia
In clinical studies, methemoglobinemia occurred in <1% patients receiving Elitek. These included cases of serious hypoxemia requiring intervention with 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. Immediately and permanently discontinue Elitek administration in any patient identified as having developed methemoglobinemia. Institute appropriate monitoring and support measures (e.g., transfusion support, methylene-blue administration).
Laboratory Sample Handling Procedure
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. Immediately immerse plasma samples for uric acid measurement 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
Adverse Reactions
Clinical Trials Experience
Clinical Trials
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 data below reflect exposure to Elitek in 265 pediatric and 82 adult patients enrolled in one active-controlled trial (Study 1), two uncontrolled trials (Studies 2 and 3), and an uncontrolled safety trial (n=82). Additional data were obtained from an expanded access program of 356 patients, for whom data collection was limited to serious adverse reactions. Among these 703 patients 63% were male, the median age was 10 years (range 10 days to 88 years), 73% were Caucasian, 9% African, 4% Asian, and 14% other/unknown.
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 reactions 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 was reported only in one Elitek-treated patient.
Further studies, including one-active controlled study (Study 4) and four supportive studies, have been conducted in adult patients. In these studies, Elitek was administered to a total of 434 adult patients [58% male, 42% female; median age 56 years (range 18 years to 89 years); 52% Caucasian, 7% African, 14% Asian, 28% other/unknown].
Of these 434 patients, 275 adult patients with leukemia, lymphoma, or solid tumor malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomized in an open label trial receiving either Elitek alone, Elitek in combination with allopurinol, or allopurinol alone (Study 4).
A drug-related adverse reaction in Study 4 of any grade was experienced in 4.3% of Elitek-treated patients, 5.4% of Elitek/allopurinol-treated patients, and 1.1% of allopurinol-treated patients.
Table 1 presents the per patient incidence of adverse reactions by study arm in Study 4.
Hypersensitivity reactions occurred in 4.3% of Elitek-treated patients and 1.1% of Elitek/allopurinol-treated patients in Study 4. Clinical manifestations of hypersensitivity included arthralgia, injection site irritation, peripheral edema, and rash.
The following serious adverse reactions occurred at a difference in incidence of ≥2% in patients receiving rasburicase compared to patients receiving allopurinol in randomized studies (Study 1 and Study 4): pulmonary hemorrhage, respiratory failure, supraventricular arrhythmias, ischemic coronary artery disorders, and abdominal and gastrointestinal infections.
The incidence of anaphylaxis, hemolysis, and methemoglobinemia was less than 1% of the 887 rasburicase-treated patients entered on these clinical trials.
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Elitek can elicit anti-product antibodies that bind to rasburicase and in some instances inhibit the activity of rasburicase in vitro [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1)].
In clinical trials of pediatric patients with hematologic malignancies, 24/218 patients tested (11%) developed antibodies by day 28 following Elitek administration as assessed by qualitative ELISA.
Using quasi-quantitative immunoassays in rasburicase naïve adult patients with hematological malignancies, 47/260 (18%) patients were positive for anti-rasburicase immunoglobulin G (IgG), 21/260 (8%) patients were positive for anti-rasburicase neutralizing IgG, and 16/260 (6%) patients were positive for anti-rasburicase immunoglobulin E (IgE) from day 14 to 24 months after 5 daily doses of Elitek.
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.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rasburicase in the drug label.
Drug Interactions
No drug interaction studies 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 or inhibition potential. Clinically relevant P450-mediated drug-drug interactions are therefore not anticipated in patients treated with the recommended Elitek dose and dosing schedule.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rasburicase in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Rasburicase during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Rasburicase with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Rasburicase with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Rasburicase with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Rasburicase with respect to specific gender populations.
Race
There is no FDA guidance on the use of Rasburicase with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Rasburicase in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Rasburicase in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rasburicase in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Rasburicase in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous infusion
Reconstitution Procedure
Elitek must be reconstituted with the diluent provided in the carton.
Reconstitute the 1.5 mg vial of Elitek with 1 mL of diluent. Reconstitute the 7.5 mg vial of Elitek with 5 mL of diluent. Mix by swirling gently. Do not shake or vortex.
Inspect reconstituted Elitek visually for particulate matter and discoloration prior to administration. Discard solution if particulate matter is visible or product is discolored.
Further Dilution and Administration
Do not administer Elitek as a bolus injection.
Inject the calculated dose of reconstituted Elitek solution into an infusion bag containing the appropriate volume of 0.9% sterile sodium chloride, to achieve a final total volume of 50 mL.
Infuse over 30 minutes through a separate line or flush line with at least 15 mL of normal saline prior to and after Elitek infusion.
Do not use filters during reconstitution or infusion of Elitek.
Store reconstituted or diluted solution at 2–8°C.
Discard unused product solution 24 hours following reconstitution.
Monitoring
There is limited information regarding Monitoring of Rasburicase in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Rasburicase in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Rasburicase in the drug label.
Pharmacology
There is limited information regarding Rasburicase Pharmacology in the drug label.
