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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. ELITEK is indicated only for a single course of treatment.

A Pivotal Clinical Trial in Adults at Risk for TLS¹

Study Design¹

Study description¹

ELITEK was studied in a randomized, multicenter, open-label, parallel-group study conducted in patients with leukemai, lymphoma, and/or solid tumor malignancies at risk for hyperuricemia and TLS. A total of 275 adult patients were treated.

Patient Population^1,2

The median age of patients in the study was 56 years; 62% were males, 80% were Caucasian. At study entry:

• 66% of patients had leukemia
• 29% of patients had lymphoma
• 18% of patients were hyperuricemic (uric acid ≥7.5 mg/dL)
• 92% were at high risk for TLS—high risk for TLS was defined as hyperuricemia of malignancy, or a diagnosis of a very aggressive lymphoid malignancy (based on the Revised European-American Lymphoma [REAL] Classification), acute myeloid leukemia, chronic myeloid leukemia in blast crisis, or high-grade myelodysplastic syndrome (MDS)

Primary end point^1,2

The primary end point was the response rate in the mITT* population. Response rate was defined as number of patients with plasma uric acid levels maintained at ≤7.5 mg/dL between Day 3 an Day 7, after initiation of antihyperuricemic treatment.

Summary of Baseline TLS and Hyperuricemia Status^1,2†

^†None of these parameters were significantly different from one another in paired comparisons.
^‡High risk for tumor lysis syndrome (TLS) defined as hyperuricemia of malignancy or a diagnosis of a very aggressive lymphoma/leukemia. Hyperuricemia was defined as uric acid ≥7.5 mg/dL.

Reliable and Rapid Response with ELITEK (rasburicase)

Reliable response in adult patients^1,2

• 87% response rate for ELITEK vs 66% for allopurinol (p = 0.0009)*
• In the two arms containing ELITEK, uric acid levels were ≤2 mg/dL in 96% of patients at 4 hours of the day 1 dose

*Response rate in the ELITEK-alone arm was statistically greater than response rate in the allopurinol arm. However, the response rate for ELITEK/allopurinol was not statistically significant vs ELITEK.²

Summary of response rates¹

The plasma uric acid (PUA) response rate for the ELITEK arm was 87%, 78% in the ELITEK/allopurinol arm, and 66% in the allopurinol arm. The PUA response rates in the ELITEK group were significantly greater than in the allopurinol arm.

Important Safety Information for ELITEK (rasburicase)

Among the 275 adult patients in Study 4, hypersensitivity reactions occurred in 4.3% of patients treated with the ELITEK alone and 1.1% of patients treated with the ELITEK/oral allopurinol combination. Hypersensitivity reactions included arthralgia, injection site irritation, peripheral edema, and rash.

*Events were reported and graded according to NCI-CTC Version 3.0 and presented as preferred terms MedDRA version 10.1. Overall incidence ≥10% in any ELITEK arm and the difference between any ELITEK arm versus the allopurinol arm ≥5%.

Rapid Response in Adult Patients²*

Results:

• 4.1 hours/ ELITEK
• 27.0 hours/allopurinol

The difference in time to reach plasma uric acid control did not reach statistical significance.

*The comparison among the different groups was pre-specified in the study protocol.
^†Time to uric acid control was defined as time in hours from the first dose of study drug to the sampling time at which a plasma uric acid concentration of less than or equal to 7.5 mg/dL was achieved.

ELITEK was studied in a randomized, multicenter, open-label, parallel-group study conducted in patients with leukemia, lymphoma, and/or solid tumor malignancies at risk for hyperuricemia and TLS. The primary end point was response rate defined as percentage of patients with plasma uric acid levels maintained at ≤7.5 mg/dL between Day 3 and Day 7, after initiation of antihyperuricemic treatment.

Arm A: Patients received ELITEK 0.20 mg/kg/day as a 30-minute Infusion once daily for 5 days (n = 92).

Arm B: Patients received ELITEK 0.20 mg/kg/day as a 30-minute Infusion once daily from Day 1 through Day 3 followed by oral allopurinol 300 mg once daily from Day 3 through Day 5 (overlap on Day 3: ELITEK and allopurinol administered ~12 hours apart) (n = 92).

Arm C: Patients received oral allopurinol 300 mg once daily for 5 days (n = 91).¹

ELITEK (rasburicase) was approved in pediatric patients based on the outcomes of 3 clinical studies in pediatric patients, as well as a single clinical study in adults.^1,23,36-38

Reference: 1

Reference: 36

Reference: 23

Reference: 1

In addition to the above trials, another important clinical study was a Phase II clinical trial by Pui et al.

Reference: 37

Pooled Studies Overview (Studies 1, 2, and 3)

In patients at risk of elevated uric acid (n = 200, uric acid concentration <8 mg/dL), ELITEK produced an 89% reduction in uric acid levels by 4 hours. In 261 patients from the pooled studies, ELITEK maintained uric acid levels below 4 mg/dL in 92% of patients by 4 hours.

• Among the 265 pediatric patients in this pooled analysis, 61 were hyperuricemic at baseline. In those patients, ELITEK induced an 86% reduction in plasma uric acid concentration by 4 hours following the 1^st dose.¹
• Uric acid concentration was maintained in 72% and 100% of ELITEK-treated hyperuricemic pediatric patients by 4 hours and 96 hours, respectively.¹

The pooled analysis of the ELITEK clinical trials data in pediatric patients clearly shows that uric acid levels were rapidly reduced and remained low during the treatment period.

Among the 347 (265 pediatric; 82 adult) patients for whom all adverse reactions regardless of severity were assessed in Studies 1, 2 and 3, as well as an uncontrolled safety trial, 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%).

Adult Pivotal Study (Phase III); Study 4; Safety data

Study 4 was an active, controlled study including 275 adult patients with leukemia, lymphoma, or solid tumor malignancies. Among these 275 adult patients, hypersensitivity reactions occurred in 4.3% of patients treated with ELITEK alone and 1.1% of patients treated with the ELITEK /oral allopurinol combination. Hypersensitivity reactions included arthralgia, injection site irritation, peripheral edema, and rash. The most common Grade 3 or 4 adverse reactions regardless of relationship to study drug in the 3 arms of Study 4 (ELITEK alone; ELITEK combined with oral allopurinol; oral allopurinol alone) were sepsis (5.4%; 6.5%; 4.4%), hypophosphatemia (4.3%; 6.5%; 6.6%), anxiety (3.3%; 0%; 0%), abdominal pain (3.3%; 4.3%; 2.2%), hyperbilirubinemia (3.3%; 2.2%; 4.4%), and increased alanine aminotransferase (3.3%; 4.3%; 2.2%), respectively.

*mITT: modified intent-to-treat.

Anaphylaxis: ELITEK can cause severe hypersensitivity reactions including anaphylaxis. Immediately and permanently discontinue ELITEK in patients who experience a serious hypersensitivity reaction.

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.

Methemoglobinemia: ELITEK can result in methemoglobinemia in some patients. Immediately and permanently discontinue ELITEK in patients developing methemoglobinemia.

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.