Rasburicase (DB00049): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Safety in the Management of Hyperuricemia

Executive Summary

Rasburicase is a potent, recombinant urate oxidase enzyme that represents a cornerstone in the modern management of hyperuricemia, particularly in the context of Tumor Lysis Syndrome (TLS) secondary to chemotherapy. As a biotech therapeutic, it addresses a critical unmet need created by the limitations of traditional uricostatic agents. Its unique uricolytic mechanism of action—the direct enzymatic degradation of existing uric acid into the highly soluble metabolite allantoin—confers a significant therapeutic advantage, characterized by a remarkably rapid onset of action and profound efficacy. This allows for the swift resolution of life-threatening hyperuricemia, mitigating the risk of acute kidney injury and enabling the timely administration of aggressive anticancer regimens.

The clinical utility of Rasburicase is, however, balanced by a distinct and serious safety profile, underscored by several U.S. Food and Drug Administration (FDA) Black Box Warnings. The most critical of these is the absolute contraindication in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, a pharmacogenomic consideration rooted directly in the drug's mechanism of action. The production of hydrogen peroxide as a byproduct of uric acid catalysis can precipitate severe hemolysis and methemoglobinemia in these susceptible individuals. Furthermore, its nature as a foreign protein carries an inherent risk of hypersensitivity and anaphylaxis.

In clinical practice, the high acquisition cost of Rasburicase has driven a significant evolution in its application, moving from the initially approved five-day, weight-based regimen towards more cost-effective, evidence-based single-dose or fixed-dose strategies. This report provides an exhaustive analysis of Rasburicase, synthesizing the available evidence on its biochemical properties, pharmacological profile, pivotal clinical trial data, comprehensive safety considerations, and evolving role in clinical oncology and beyond.

Biochemical and Pharmaceutical Profile

This section establishes the fundamental identity of Rasburicase, detailing its molecular structure, biotechnological origin, and pharmaceutical formulation. This biochemical foundation is essential for understanding its enzymatic function, clinical properties, and immunogenic potential.

Identification and Nomenclature

Rasburicase is identified and classified through a series of internationally recognized naming conventions and coding systems that define its place in pharmacology and regulatory frameworks.

• Generic Name: Rasburicase [1]
• Brand Names: The drug is marketed globally under distinct brand names, most notably Elitek® in the United States and Fasturtec® in the European Union.[1]
• DrugBank ID: DB00049 [1]
• CAS Number: 134774-45-1 [5]
• Synonyms and External IDs: The compound is also referred to as Rasburicasa, Recombinant urate oxidase, and by its developmental code name, SR 29142.[2]
• Regulatory and Classification Codes:
• Anatomical Therapeutic Chemical (ATC) Code: V03AF07, which classifies it as a detoxifying agent for antineoplastic treatment.[1]
• FDA Unique Ingredient Identifier (UNII): 08GY9K1EUO.[7]
• Drug Class: It is classified as an antihyperuricemic agent and, more broadly, as an enzyme therapeutic.[1]

The following table consolidates the primary identifiers for Rasburicase, providing a comprehensive reference.

Table 1: Key Drug Identifiers and Properties

Identifier Type	Value	Source(s)
Generic Name	Rasburicase	1
US Brand Name	Elitek®	1
EU Brand Name	Fasturtec®	1
DrugBank ID	DB00049	1
CAS Number	134774-45-1	5
ATC Code	V03AF07	1
FDA UNII	08GY9K1EUO	7
Drug Class	Antihyperuricemic Agent, Enzyme	1

Molecular Structure and Physicochemical Properties

Rasburicase is a complex biologic drug with a well-defined protein structure that dictates its enzymatic function.

• Biochemical Nature: It is a biotech drug, specifically a recombinant protein that functions as a tetramer, formed by the assembly of four identical subunits.[2]
• Monomer Composition: Each subunit is a single polypeptide chain composed of 301 amino acids.[3] The structure is notable for its lack of intra- or inter-chain disulfide bridges, and the N-terminus of the polypeptide is acetylated.[8] The primary amino acid sequence is publicly available.[2]
• Molecular Formula & Weight: The chemical formula of the monomer is reported as C1521​H2381​N417​O461​S7​ or, with slight variation, C1523​H2383​N417​O462​S7​.[2] The average molecular weight of a single subunit is approximately 34 kDa, with the total average weight of the protein being 34,109.5 Da.[2]
• 3D Structure: While no Protein Data Bank (PDB) entry is explicitly designated for the commercial drug Rasburicase, its structure is that of its source enzyme, urate oxidase from the fungus Aspergillus flavus. Several high-resolution crystal structures of this enzyme have been deposited in the PDB, including entries such as 1R4U, 3CKU, and 1WS3.[9] These structures reveal a tunnel-shaped, dimeric barrel protein architecture, providing a detailed structural blueprint for its active site and the basis of its catalytic mechanism.
• Physical Properties: The final drug product is formulated as a sterile, white to off-white, lyophilized powder for reconstitution.[3] It has a calculated isoelectric point of 7.16, indicating it is near neutral at physiological pH, and a hydrophobicity value of -0.465, consistent with a soluble protein.[7]

Recombinant Production and Formulation

The manufacturing process of Rasburicase is a key aspect of its pharmaceutical profile, ensuring a high-purity product and distinguishing it from earlier-generation urate oxidases.

• Biotechnological Origin: Urate oxidase is an enzyme found in most mammals but is absent in humans due to a nonsense mutation that occurred during hominoid evolution.[3] To overcome this, Rasburicase is produced using recombinant DNA technology.[2]
• Genetic Source and Expression System: The gene, in the form of complementary DNA (cDNA), that codes for the urate oxidase enzyme was isolated from a strain of the fungus Aspergillus flavus. This gene was then cloned into and expressed by a genetically modified strain of the yeast Saccharomyces cerevisiae, which serves as the production host.[2] This biotechnological process allows for the large-scale manufacturing of a highly purified and consistent enzyme product. This is a crucial advancement, as older, non-recombinant urate oxidase preparations derived from other sources were associated with a higher incidence of immunogenic and hypersensitivity reactions, largely attributed to the presence of impurities.[13] The recombinant production method is therefore not merely a technical detail but a direct determinant of the drug's improved safety profile relative to its predecessors.
• Commercial Formulation: Rasburicase is supplied in single-use glass vials containing either 1.5 mg or 7.5 mg of the active drug as a lyophilized powder.[3] The formulation includes several excipients to ensure stability and proper reconstitution, including mannitol, L-alanine, and dibasic sodium phosphate. It is packaged with a specific diluent for reconstitution, which consists of Water for Injection and Poloxamer 188, a non-ionic surfactant.[8] Upon reconstitution, the solution has a final concentration of 1.5 mg/mL.[3]

The very nature of Rasburicase as a foreign protein, originating from a fungus, is fundamental to its clinical profile. While its enzymatic activity is highly beneficial, its non-human structure presents foreign epitopes to the human immune system. This structural foreignness is the direct molecular basis for its inherent immunogenic potential, which manifests clinically as the risk of hypersensitivity reactions and, in severe cases, anaphylaxis. This risk is so significant that it is highlighted in an FDA Black Box Warning, directly linking the drug's fundamental biochemistry to its most critical safety liabilities.

Mechanism of Action and Pharmacodynamics

The therapeutic efficacy of Rasburicase is derived from its potent and specific enzymatic activity, which offers a distinct pharmacological approach to managing hyperuricemia compared to traditional therapies.

Enzymatic Catalysis of Uric Acid

Rasburicase functions by intervening at the final step of the purine degradation pathway in humans.

• Core Mechanism: In humans, the breakdown of purines from nucleic acids culminates in the formation of uric acid, a poorly soluble compound.[3] Rasburicase is a recombinant urate oxidase enzyme that directly targets and catalyzes the enzymatic oxidation of this uric acid.[2]
• Biochemical Reaction: The catalytic process involves the interaction of uric acid, molecular oxygen (O2​), and water at the enzyme's active site. This reaction yields three products: allantoin, carbon dioxide (CO2​), and hydrogen peroxide (H2​O2​).[3]
• Significance of Allantoin: The key to the drug's efficacy lies in the properties of its primary product, allantoin. Allantoin is an inactive metabolite that is approximately five to ten times more soluble in urine than its precursor, uric acid.[3] This dramatic increase in solubility is critical in the context of TLS, as it allows the purine breakdown products to be efficiently and safely excreted by the kidneys. This prevents the supersaturation of urine with uric acid, thereby avoiding the formation and precipitation of uric acid crystals within the renal tubules—the primary event that leads to obstructive nephropathy and acute kidney injury.[12]

The biochemical reaction catalyzed by Rasburicase is not without consequence. The production of hydrogen peroxide (H2​O2​), an oxidizing agent, is an unavoidable byproduct of the intended enzymatic activity.[3] This fact is of paramount clinical importance, as it forms the direct molecular basis for the drug's most significant contraindication: Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. In healthy individuals, red blood cells possess robust antioxidant systems, reliant on NADPH produced by the G6PD enzyme, to neutralize oxidative stressors like

H2​O2​. In G6PD-deficient individuals, this protective capacity is compromised. The introduction of an exogenous H2​O2​ load from Rasburicase administration can overwhelm the diminished antioxidant defenses of their red blood cells, leading to oxidative damage, severe hemolysis, and methemoglobinemia.[19] This creates an unbreakable causal chain from the drug's fundamental mechanism of action to its most severe, genetically-determined toxicity.

Comparative Pharmacology: Rasburicase vs. Xanthine Oxidase Inhibitors

A clear understanding of Rasburicase's mechanism requires a direct comparison with the other major class of drugs used for hyperuricemia, the xanthine oxidase inhibitors (e.g., allopurinol).

• Uricolytic vs. Uricostatic Action: This distinction is the central tenet of their comparative pharmacology. Rasburicase is a uricolytic agent, meaning it actively breaks down and eliminates pre-existing uric acid from the plasma.[12] Allopurinol, conversely, is a uricostatic agent. It acts further upstream in the purine pathway by inhibiting the enzyme xanthine oxidase. This action blocks the conversion of the precursors hypoxanthine and xanthine into uric acid, thereby preventing the formation of new uric acid.[12]
• Clinical Implications: This mechanistic difference has profound clinical implications. Because allopurinol does not affect the existing pool of uric acid, its effect on plasma levels is delayed, typically taking 24 to 48 hours to become apparent.[12] It is therefore primarily a prophylactic agent and is ill-suited for the rapid reversal of an acute hyperuricemic crisis. Rasburicase's ability to degrade existing uric acid allows it to act almost immediately, making it the superior choice for the acute management of established, severe hyperuricemia seen in TLS.[12] Furthermore, by blocking xanthine oxidase, allopurinol can cause the accumulation of its substrates, xanthine and hypoxanthine. These precursors are also poorly soluble and can precipitate in the renal tubules, potentially contributing to xanthine nephropathy.[12] Rasburicase avoids this issue by acting at the end of the pathway.

This mechanistic superiority of Rasburicase has fundamentally altered the therapeutic paradigm for patients at high risk of TLS. Prior to its availability, management was limited to prophylactic and supportive measures such as hydration, urinary alkalinization, and allopurinol. Rasburicase introduced a potent, preemptive, and rapidly corrective intervention. This allows oncologists to proceed with intensive chemotherapy regimens on schedule, even for patients with highly chemosensitive tumors and massive tumor burdens (e.g., Burkitt's lymphoma), with a much higher degree of confidence that the life-threatening metabolic consequences of rapid cell lysis can be effectively and immediately controlled.[18] In this context, Rasburicase functions not just as a treatment, but as an enabling technology that facilitates the safe delivery of optimal cancer therapy.

The following table provides a side-by-side comparison of the key pharmacological features of Rasburicase and allopurinol.

Table 2: Comparative Profile: Rasburicase vs. Allopurinol

Feature	Rasburicase	Allopurinol	Source(s)
Mechanism of Action	Uricolytic: Catalyzes oxidation of existing uric acid to allantoin.	Uricostatic: Inhibits xanthine oxidase, preventing new uric acid formation.	12
Effect on Existing Uric Acid	Yes, directly degrades and clears.	No, does not affect existing levels.	12
Onset of Action	Rapid (< 4 hours).	Slow (24-48 hours).	8
Effect on Precursors	None.	Increases plasma levels of xanthine and hypoxanthine.	12
Dosing in Renal Impairment	No dose adjustment required.	Dose adjustment required (active metabolite is renally cleared).	13

Uricolytic Effect Profile (Pharmacodynamics)

The pharmacodynamic effects of Rasburicase are characterized by a rapid onset, profound magnitude, and sustained duration of uric acid reduction.

• Onset of Action: The enzymatic action of Rasburicase is remarkably swift. Clinically significant reductions in plasma uric acid levels are consistently observed within 4 hours of administering the first intravenous dose.[3]
• Magnitude and Duration of Effect: Clinical trials have demonstrated the potent and durable effect of Rasburicase. Following daily administration of 0.15 or 0.20 mg/kg, plasma uric acid levels were successfully maintained below the target threshold of 7.5 mg/dL in 98% of adult and 90% of pediatric patients for at least seven days.[3] An analysis of pooled data from three studies involving 265 patients revealed the magnitude of this effect: in patients with a high baseline uric acid level (≥8.0 mg/dL), the median reduction from baseline was 9.1 mg/dL by the 4-hour time point.[8] Pharmacodynamic modeling has been used to further characterize this strong and rapid effect, confirming its clinical performance and aiding in the exploration of rational dosing regimens.[21]

Pharmacokinetic Profile (ADME)

The pharmacokinetic profile of Rasburicase—its absorption, distribution, metabolism, and excretion (ADME)—is characterized by properties that are exceptionally well-suited for its use in critically ill oncology patients, many of whom present with or are at risk for significant organ dysfunction.

Administration and Distribution

• Route of Administration: Rasburicase is administered exclusively via the intravenous (IV) route. The standard method is a 30-minute infusion.[6] Administration as a rapid IV bolus is contraindicated.[15]
• Volume of Distribution (Vd): Following IV administration, Rasburicase distributes primarily within the vascular compartment. Its mean volume of distribution is consistent with the physiological plasma volume, reported to range from 110 to 127 mL/kg in pediatric patients and from 75.8 to 138 mL/kg in adult patients.[2] This indicates limited distribution into extravascular tissues.

Metabolism and Elimination

The metabolic and elimination pathways of Rasburicase are a key feature of its clinical utility, conferring a predictable profile in a vulnerable patient population.

• Metabolic Pathway: As a therapeutic protein, Rasburicase does not undergo metabolism by the hepatic cytochrome P450 (CYP450) enzyme system. Instead, it is expected to be degraded via peptide hydrolysis into its constituent amino acids and small peptides, following the same general catabolic pathways as endogenous proteins.[13] Specific metabolism studies have not been formally conducted.[2]
• Organ Independence: A critical clinical feature of Rasburicase is that its clearance is independent of both hepatic and renal function.[13] This is a direct consequence of its metabolism via ubiquitous peptide hydrolysis. This organ independence means that no dose adjustments are necessary for patients with pre-existing or developing renal or hepatic impairment, a common scenario in the TLS setting.[13] This provides a significant advantage over drugs like allopurinol, whose active metabolite, oxypurinol, is cleared by the kidneys and requires dose reduction in patients with renal dysfunction to avoid accumulation and toxicity.[13] The pharmacokinetic profile of Rasburicase is therefore exceptionally well-matched to the pathophysiology of the disease it treats, where acute kidney injury is a primary concern.
• Elimination Half-Life: The mean terminal half-life of Rasburicase is consistent across pediatric and adult populations. It is reported to be approximately 18 hours [2], with studies showing a range of 15.7 to 22.5 hours [3] and 16 to 20 hours.[26]

Linearity and Accumulation

• Dose Linearity: Pharmacokinetic analyses have demonstrated that the exposure to Rasburicase, as measured by both the area under the concentration-time curve (AUC₀₋₂₄) and the maximum plasma concentration (Cmax), increases in a linear and dose-proportional manner over the clinically recommended dose range of 0.15 to 0.20 mg/kg.[3]
• Accumulation: Despite daily administration, no significant accumulation of the drug is observed over a five-day treatment course.[8] Steady-state plasma concentrations are typically achieved within two to three days of initiating therapy.[23]

The pharmacokinetic half-life of approximately 18 hours is a central determinant of the drug's clinical dosing strategy and the ongoing evolution of its use. This duration is sufficiently long to provide sustained suppression of uric acid levels with a convenient once-daily dosing schedule. At the same time, it is short enough that the drug's enzymatic effect will diminish within a few days after the final dose. This property is what underpins the clinical debate surrounding optimal dosing. While the initial five-day regimen ensures continuous and comprehensive coverage, the rapid and profound initial effect, combined with an 18-hour half-life, suggests that such prolonged treatment may be unnecessary for many patients. This pharmacokinetic profile makes an alternative "single dose, followed by as-needed" administration strategy pharmacologically plausible. A single dose can manage the initial, most critical phase of hyperuricemia, and the ~18-hour half-life allows for re-dosing after 24-48 hours if uric acid levels begin to rebound. This direct link between the drug's half-life and clinical practice has been instrumental in the development of more cost-effective protocols that aim to optimize therapeutic benefit while minimizing drug exposure and cost.

Clinical Applications and Efficacy

Rasburicase has a well-defined role in clinical oncology, supported by a robust evidence base from pivotal clinical trials. Its application is primarily focused on the management of a specific, life-threatening metabolic complication of cancer therapy.

Approved Indication: Management of Hyperuricemia in Tumor Lysis Syndrome (TLS)

• Core Indication: Rasburicase is officially indicated for the initial management of plasma uric acid levels in both pediatric and adult patients who have leukemia, lymphoma, or solid tumor malignancies and are undergoing anticancer therapy that is expected to cause tumor lysis and a subsequent elevation in plasma uric acid.[1]
• Therapeutic Goal: The drug is utilized for both the treatment of established hyperuricemia and for the prophylaxis (prevention) of hyperuricemia in patients who are identified as being at high risk for developing TLS.[7] Key risk factors for TLS include malignancies with a high proliferative rate and large tumor burden (e.g., Burkitt's lymphoma, B-cell acute lymphoblastic leukemia), pre-existing hyperuricemia (uric acid > 7.5 mg/dL), and compromised renal function.[7]
• Clinical Context: TLS is considered an oncologic emergency. The rapid and massive destruction of malignant cells releases large quantities of intracellular contents into the bloodstream. This leads to a cascade of metabolic disturbances, including hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia.[16] The precipitation of uric acid and calcium phosphate crystals in the renal tubules can lead to acute kidney injury, while severe electrolyte abnormalities can cause cardiac arrhythmias, seizures, and death. Due to its potent and rapid efficacy, Rasburicase is now widely considered a standard of care for the management of patients at high risk of TLS.[32]

Pivotal Clinical Trials and Evidence Base

The approval and widespread adoption of Rasburicase are founded on key clinical trials that demonstrated its clear superiority over the previous standard of care.

• Pediatric Approval (Goldman et al., 2001): The initial FDA approval for use in children was heavily influenced by a landmark randomized controlled trial that compared Rasburicase to allopurinol in 52 pediatric patients with leukemia or lymphoma at high risk for TLS.[17] The findings were not merely of non-inferiority but of overwhelming superiority.
• Key Finding: The trial revealed a dramatic difference in efficacy. Just four hours after the first dose, patients in the Rasburicase group experienced an 86% reduction in plasma uric acid (PUA), whereas the allopurinol group showed only a 12% reduction (p<0.0001). The primary efficacy endpoint, the area under the PUA concentration curve over the first 96 hours (AUC₀₋₉₆), was 2.6-fold lower in the Rasburicase group (128 mg/dL·h vs. 329 mg/dL·h), signifying a profoundly reduced exposure to toxic levels of uric acid.[17]
• Adult Approval (Cortes et al., 2010): The indication was expanded to include adults following a large, multicenter, Phase III randomized trial. This study enrolled 275 adult patients with hematologic malignancies at risk for TLS and assigned them to one of three treatment arms: Rasburicase alone, Rasburicase for three days followed by allopurinol, or allopurinol alone.[30]
• Key Finding: Rasburicase again proved superior. The primary endpoint was the PUA response rate, defined as achieving and maintaining a PUA level of ≤ 7.5 mg/dL during days 3 through 7 of treatment. The response rate was significantly higher in the Rasburicase-alone arm (87%) compared to the allopurinol-alone arm (66%) (p=0.001). For patients who presented with hyperuricemia at baseline, the median time to achieve PUA control was only 4 hours with Rasburicase, compared to 27 hours with allopurinol.[35]

This strong evidence base, demonstrating clear and statistically significant superiority over the prior standard of care, is the reason Rasburicase was rapidly adopted into clinical guidelines and became the standard of care for high-risk patients, despite its considerable cost.[32]

Table 3: Summary of Pivotal Clinical Trial Efficacy Data

Trial (Lead Author, Year)	Patient Population	Comparison Arms	Primary Efficacy Endpoint	Key Result	Source(s)
Goldman et al., 2001	52 Pediatric Patients with Leukemia/Lymphoma	Rasburicase vs. Allopurinol	Mean Uric Acid AUC₀₋₉₆	128 vs. 329 mg/dL·h (p<0.0001)	17
Cortes et al., 2010	275 Adult Patients with Hematologic Malignancies	Rasburicase vs. Rasburicase + Allopurinol vs. Allopurinol	PUA Response Rate (Days 3-7)	87% (Rasburicase) vs. 66% (Allopurinol) (p=0.001)	35

Investigational and Off-Label Uses

While its primary role is in TLS, the potent uricolytic activity of Rasburicase has led to its investigation and use in other clinical scenarios characterized by severe hyperuricemia.

• Refractory Gout: Rasburicase has been studied for the acute management of severe hyperuricemia in patients with refractory gout, particularly during gout flares.[5] A Phase 2 clinical trial (NCT00111657) has been completed for this indication.[37] However, its short half-life and potential for immunogenicity upon repeated exposure make it unsuitable for the chronic management of gout.[13]
• Non-Malignancy Acute Kidney Injury (AKI): There is emerging evidence for the use of Rasburicase in pediatric patients who develop severe hyperuricemia and AKI from causes other than malignancy. A study in children with underlying conditions such as congenital heart disease, post-kidney transplant complications, or metabolic diseases found that Rasburicase was highly effective in rapidly lowering uric acid levels and facilitating the recovery of renal function.[38]
• Other Conditions: Case reports and small series have described the off-label use of Rasburicase in other rheumatologic conditions and in cases of rhabdomyolysis associated with severe hyperuricemia and kidney failure.[3]

The successful application of Rasburicase in these non-malignant settings suggests a potential broadening of its therapeutic scope. The underlying pathophysiology in these conditions—acute kidney injury driven by crystal nephropathy—is mechanistically similar to that in TLS. This implies that the true clinical utility of Rasburicase may ultimately be defined not by the etiology of the hyperuricemia (e.g., cancer chemotherapy) but by the acuity and severity of the hyperuricemia itself. This could position Rasburicase as a critical care agent for any medical emergency characterized by dangerously high uric acid levels that threaten imminent renal failure, reframing it from a narrow "cancer support drug" to a broader "agent for hyperuricemic emergencies."

Dosing, Administration, and Monitoring

The practical application of Rasburicase in the clinical setting requires strict adherence to guidelines for dosing, preparation, and administration, as well as a critical awareness of its unique impact on laboratory monitoring.

Recommended Dosing Regimens

• FDA-Approved Dose: The U.S. FDA-approved dose of Rasburicase for both pediatric and adult populations is 0.2 mg/kg, administered as a once-daily intravenous infusion.[14] Some guidelines and studies also reference a dose of 0.15 mg/kg.[3]
• Treatment Course Limitation: The approved duration of therapy is for a maximum of five days. The safety and efficacy of Rasburicase have only been formally established for a single course of treatment. Therefore, dosing beyond five days or the administration of more than one course of therapy is not recommended.[14]

Alternative and Cost-Effective Dosing Strategies

A significant evolution in the clinical use of Rasburicase has been the development of alternative dosing strategies driven by pharmacoeconomic considerations. The standard five-day, weight-based regimen is associated with very high costs, prompting clinicians and institutions to explore more judicious use of the drug.[29]

• Clinical Rationale and Evidence: A substantial body of evidence from retrospective analyses, observational studies, and smaller prospective trials has demonstrated that lower, fixed-dose, and/or single-dose regimens are highly effective for the majority of patients.[29]
• Single fixed doses ranging from 1.5 mg to 7.5 mg have been shown to be effective in rapidly normalizing serum uric acid levels, often within the first 24 hours of administration.[29]
• A randomized controlled trial directly comparing a single dose of 0.15 mg/kg (followed by as-needed dosing) to the standard five-day regimen found that the single-dose approach was effective for most patients. Only a small subset of high-risk patients in the single-dose arm required a second dose for rebound hyperuricemia.[43]
• In response to this evidence, many cancer centers have developed institutional protocols that utilize these alternative strategies, such as a single fixed dose of 3 mg or 6 mg, with subsequent doses administered only if biochemical monitoring indicates a persistent or recurrent elevation in uric acid.[29]

This growing disconnect between the official FDA-approved labeling and the real-world clinical evidence supporting abbreviated, cost-effective regimens creates a notable clinical dilemma. While the approved regimen is supported by large Phase III trial data, the alternative strategies are backed by a wealth of practical evidence and offer dramatic cost savings. This trend represents a grassroots, evidence-driven evolution of clinical practice that has outpaced formal regulatory updates, reflecting an ongoing process of optimizing therapeutic value in the face of significant economic pressures.

Table 4: Dosing Regimens: FDA-Approved vs. Evidence-Based Alternative Dosing

Dosing Strategy	Regimen Details	Summary of Supporting Evidence / Key Findings	Source(s)
FDA-Approved	0.2 mg/kg IV daily for up to 5 days.	Supported by pivotal Phase III trials in pediatric and adult populations demonstrating superiority over allopurinol.	14
Single Fixed-Dose	1.5 mg, 3 mg, 6 mg, or 7.5 mg IV as a single dose.	Multiple retrospective and prospective studies show high rates of uric acid normalization within 24 hours. A 6 mg dose may be the most appropriate single dose for adults.	29
Single Weight-Based Dose	0.15 mg/kg IV as a single dose, with re-dosing as needed.	A randomized trial showed this was effective in most patients; only a subset of high-risk patients required a second dose.	40

Preparation, Administration, and Storage

Strict aseptic technique is required for the preparation and administration of Rasburicase, as the product contains no preservatives.[6]

• Reconstitution: The lyophilized powder must be reconstituted only with the specific diluent provided in the carton. The 1.5 mg vial is reconstituted with 1 mL of diluent, and the 7.5 mg vial with 5 mL. The vial should be mixed by gentle swirling and not by shaking or vortexing to avoid denaturing the protein.[14]
• Dilution and Administration: The calculated dose of the reconstituted solution is then withdrawn and further diluted in a 50 mL infusion bag of 0.9% sodium chloride injection. The final solution is administered as a 30-minute IV infusion.[6] It is critical that no filters are used during either the reconstitution or the infusion process.[14]
• IV Line Management: Rasburicase should be infused through a separate IV line. If a separate line is not available, the line must be flushed with at least 15 mL of normal saline both before and after the Rasburicase infusion to prevent interaction with other drugs.[14] The drug is potentially incompatible with glucose solutions and should not be diluted in them.[25]
• Storage: Prior to use, the lyophilized drug and diluent should be stored under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light. After reconstitution and dilution, the solution is stable for up to 24 hours under refrigeration.[14]

Critical Laboratory Monitoring Procedures

The enzymatic nature of Rasburicase necessitates a unique and mandatory protocol for handling blood samples for uric acid measurement. Failure to adhere to this protocol will lead to invalid results and potentially erroneous clinical decisions.

• Interference with Uric Acid Measurements: This issue is significant enough to be included as an FDA Black Box Warning. Rasburicase is an active enzyme that remains active ex vivo. If a blood sample from a patient receiving the drug is left at room temperature, the enzyme will continue to degrade uric acid within the collection tube. This enzymatic degradation leads to spuriously low and clinically misleading plasma uric acid readings.[8]
• Mandatory Sample Handling Protocol: To prevent ex vivo degradation and ensure an accurate measurement of the patient's true uric acid level, the following strict procedure must be followed:

1. Blood samples must be collected into pre-chilled tubes containing heparin anticoagulant.
2. Immediately after collection, the sample must be immersed and maintained in an ice water bath.
3. The plasma must be separated in a refrigerated centrifuge and the assay must be performed within 4 hours of collection.[15]

This sample handling protocol is more than a minor laboratory technicality; it represents a critical point of potential failure in the management of patients on Rasburicase. An inaccurate, falsely low uric acid level could lead a clinician to mistakenly believe the patient's hyperuricemia is controlled. This could result in the premature discontinuation of a necessary therapy or, in the context of an "as-needed" dosing strategy, a failure to administer a required subsequent dose. Such an error could allow for rebound hyperuricemia and the very renal complications the drug is intended to prevent, thus linking a seemingly routine laboratory procedure directly to major clinical outcomes and patient safety.

Safety, Tolerability, and Risk Management

The potent efficacy of Rasburicase is accompanied by a distinct and serious safety profile. A thorough understanding of its adverse effects, contraindications, and required risk mitigation strategies is essential for its safe use.

FDA Black Box Warnings: A Detailed Analysis

The FDA has mandated four Black Box Warnings for Rasburicase, highlighting its most severe and potentially life-threatening risks.[15]

• Anaphylaxis and Hypersensitivity Reactions: As a foreign protein, Rasburicase can trigger severe, IgE-mediated hypersensitivity reactions, including life-threatening anaphylaxis. These reactions can occur at any time during treatment, including upon the first exposure, and have been reported in <1% of patients in clinical studies.[15] Signs and symptoms include bronchospasm, chest pain and tightness, dyspnea, hypoxia, hypotension, shock, and urticaria.[15] The development of any serious hypersensitivity reaction necessitates the immediate and permanent discontinuation of the drug.[15] Fatal anaphylactic reactions, though extremely rare, have been reported.[12]
• Hemolysis: Severe hemolytic anemia can occur, typically within 2-4 days of starting therapy.[15] This adverse event is a direct result of the drug's mechanism of action. The enzymatic conversion of uric acid produces hydrogen peroxide, an oxidant that can cause severe damage to red blood cells in individuals with a G6PD deficiency. Administration of Rasburicase must be immediately and permanently stopped in any patient who develops hemolysis.[6]
• Methemoglobinemia: Rasburicase can also induce methemoglobinemia, a condition where the iron in hemoglobin is oxidized, rendering it unable to transport oxygen. This is also linked to the oxidative stress generated by hydrogen peroxide in susceptible individuals, such as those with G6PD deficiency or other hereditary enzyme deficiencies (e.g., cytochrome b5 reductase deficiency).[3] The drug must be immediately and permanently discontinued if methemoglobinemia develops.[20]
• Interference with Uric Acid Measurements: As detailed previously, the enzymatic activity of Rasburicase persists in vitro, leading to falsely low uric acid measurements if blood samples are not handled with a specific cold-chain protocol.[8]

Table 5: FDA Black Box Warnings and Associated Clinical Guidance

Boxed Warning	Description of Risk	Required Clinical Action / Precaution	Source(s)
Anaphylaxis	Can cause serious and fatal hypersensitivity reactions at any time during treatment.	Immediately and permanently discontinue if a serious reaction occurs. Monitor patients closely during and after infusion.	15
Hemolysis	Can cause severe hemolysis, particularly in patients with G6PD deficiency.	Do not administer to patients with G6PD deficiency. Screen at-risk populations prior to use. Immediately and permanently discontinue if hemolysis develops.	15
Methemoglobinemia	Can result in methemoglobinemia in susceptible individuals.	Immediately and permanently discontinue in patients who develop methemoglobinemia.	15
Interference with Uric Acid Measurements	Enzymatically degrades uric acid in blood samples at room temperature, leading to falsely low results.	Collect samples in pre-chilled tubes with heparin, immediately place on ice, and assay plasma within 4 hours.	15

The safety profile of Rasburicase is notable in that its most severe toxicities are not idiosyncratic but are direct, predictable consequences of its fundamental biochemical properties. The production of hydrogen peroxide is the mechanistic cause of hemolysis and methemoglobinemia in a genetically defined subpopulation (G6PD deficient), while its foreign protein structure is the cause of hypersensitivity. This predictability allows for a highly targeted and effective risk mitigation strategy centered on genetic screening (for G6PD) and vigilant clinical monitoring (for allergic reactions).

Contraindications and Pharmacogenomics

The use of Rasburicase is absolutely contraindicated in specific patient populations due to the high risk of severe adverse reactions.

• G6PD Deficiency: This is the most critical contraindication.[6] The scientific rationale is unequivocal: individuals with G6PD deficiency lack the ability to adequately protect their red blood cells from the oxidative stress induced by the hydrogen peroxide byproduct of the Rasburicase reaction, leading to acute hemolytic anemia.[19]
• Screening Recommendations: The FDA label and the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines strongly recommend screening patients at higher risk for G6PD deficiency prior to initiating therapy.[19] At-risk populations include individuals of African, Mediterranean, or South Asian ancestry.[6] Despite this clear guidance, real-world adherence to pre-treatment screening is often suboptimal. One study found that only a minority of at-risk patients were tested, and on average, test results became available more than 35 hours after the drug had already been administered.[50] This gap between established knowledge and clinical practice represents a significant patient safety vulnerability, often driven by the clinical urgency of treating TLS, which can lead to the bypassing of this crucial safety check.
• History of Reactions: Rasburicase is also contraindicated in any patient with a known history of anaphylaxis, severe hypersensitivity, hemolytic reactions, or methemoglobinemia associated with a previous exposure to the drug.[6]

Adverse Drug Reactions: Incidence and Management

Beyond the risks highlighted in the boxed warnings, Rasburicase is associated with a range of other adverse effects, many of which are common when used concomitantly with chemotherapy.

Table 6: Adverse Reactions with Incidence Rates (≥10%)

Adverse Reaction	Incidence (%)	Source(s)
Vomiting	50%	17
Fever	46%	17
Nausea	27%	17
Headache	26%	17
Abdominal Pain	20%	17
Constipation	20%	17
Diarrhea	20%	17
Mucositis	15%	17
Rash	13%	17

Other clinically significant adverse reactions reported at lower frequencies include peripheral edema, anxiety, and pharyngolaryngeal pain.[15] Rare but serious events such as convulsions and respiratory failure have also been reported.[51] Hypersensitivity reactions not amounting to anaphylaxis occurred in approximately 4% of patients in a large trial.[30] Liver enzyme elevations have also been observed, sometimes in the context of a hypersensitivity reaction.[7]

Immunogenicity

As a recombinant protein of fungal origin, Rasburicase can be recognized as foreign by the immune system and can elicit the formation of anti-drug antibodies.[48] In clinical trials involving pediatric patients, 11% of those tested developed antibodies to Rasburicase.[53] The development of these antibodies can have clinical consequences, potentially neutralizing the enzyme's activity and reducing its efficacy. This immunogenic potential is a primary reason why the administration of more than one course of treatment is not recommended.[13]

Regulatory and Developmental History

The path of Rasburicase from development to a global standard of care reflects a strategic, phased regulatory process that established its value first in a high-need niche population before expanding to broader use.

Timeline of Key Regulatory Approvals

• Orphan Drug Designation (US): Recognizing the need for better treatments for hyperuricemia in cancer patients, the U.S. FDA granted Rasburicase Orphan Drug Designation on October 11, 2000. The designation was for the "Treatment of malignancy-associated or chemotherapy-induced hyperuricemia".[54]
• European Union Approval: The European Commission granted a marketing authorisation for Fasturtec® (the brand name for Rasburicase in the EU) that was valid throughout the European Union on February 23, 2001.[55]
• Initial FDA Approval (Pediatric): Following successful clinical trials, the U.S. FDA granted its initial approval for Elitek® on July 12, 2002. This approval was specifically for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who were at risk for TLS.[17]
• Expanded FDA Approval (Adult): After a substantial period of further clinical investigation, the FDA expanded the approval to include adult patients on October 16, 2009. This decision was based on the positive results of the pivotal Phase III trial led by Cortes et al., which confirmed the drug's superiority over allopurinol in the adult population.[4]

The regulatory timeline reveals a deliberate and cautious global rollout strategy. The initial approval in the European Union in 2001 was followed by a targeted approval for the pediatric population in the U.S. in 2002. The subsequent expansion to the U.S. adult market did not occur for another seven years, pending the completion of a large, robust randomized trial. This phased approach reflects a common and prudent pathway for novel therapeutics, especially biologics with significant safety considerations. It allowed the manufacturer to first establish a strong foundation of efficacy and safety in a well-defined and critically ill population (children with hematologic cancers) before undertaking the larger studies required to secure an indication in the more heterogeneous adult population. The seven-year gap between the pediatric and adult approvals in the U.S. underscores the high evidentiary bar required by regulatory agencies for this expansion.

Synthesis and Expert Recommendations

Rasburicase has fundamentally transformed the management of hyperuricemia in patients at risk for Tumor Lysis Syndrome. Its clinical profile is defined by a powerful and rapid uricolytic efficacy that is mechanistically superior to older agents, but this benefit must be carefully weighed against a significant cost and a distinct, serious, but largely predictable and manageable safety profile.

Integrated Clinical Perspective

The available evidence firmly establishes Rasburicase as the standard of care for the prevention and treatment of hyperuricemia in patients at high risk for TLS.[32] Its ability to rapidly degrade pre-existing uric acid provides a level of control and a safety net that was previously unattainable with uricostatic agents like allopurinol. This efficacy allows for the safer administration of highly effective, and often highly cytotoxic, chemotherapy regimens. The primary risks associated with its use—hemolysis/methemoglobinemia in G6PD-deficient individuals and hypersensitivity reactions—are direct consequences of its biochemical nature. This predictability is a key feature of its profile, as it allows for targeted and effective risk mitigation strategies. The principal challenges to its widespread use are its high acquisition cost, which has spurred the development of alternative dosing strategies, and the logistical challenges of ensuring adherence to critical safety and laboratory protocols in the acute care setting.

Recommendations for Optimal Use and Future Research

Based on a comprehensive synthesis of the available data, the following recommendations are made to optimize the clinical use of Rasburicase and guide future research:

• Patient Selection and Risk Stratification: The use of Rasburicase should be guided by careful patient risk stratification. Its use is most appropriate for patients deemed to be at high risk for TLS (e.g., those with Burkitt's lymphoma, ALL with high white blood cell counts, or bulky disease with elevated LDH).[31] In patients at intermediate or low risk, traditional management with hydration and allopurinol may be sufficient. This risk-based approach ensures that this high-cost therapy is reserved for the patients who will derive the greatest clinical benefit.
• Adoption of Evidence-Based Dosing Strategies: While the FDA-approved regimen of 0.2 mg/kg for five days remains the official standard, clinical institutions should strongly consider the development and implementation of evidence-based protocols that utilize single, fixed-dose, or abbreviated-course strategies. The robust and growing body of evidence supporting the efficacy of these more cost-effective approaches (e.g., a single fixed dose of 3-6 mg) is compelling.[29] Such protocols should include clear, objective criteria for re-dosing based on serial monitoring of plasma uric acid levels.
• Mandatory Adherence to Safety and Laboratory Protocols:
• G6PD Screening: It is imperative that institutional policies mandate G6PD screening for all patients from at-risk populations (e.g., African, Mediterranean, South Asian ancestry) before the first dose of Rasburicase is administered. The urgency of TLS treatment cannot be an acceptable reason to bypass this critical safety check.
• Laboratory Sample Handling: Rigorous education and protocol enforcement for nursing and laboratory staff regarding the mandatory cold-chain handling of blood samples for uric acid measurement are essential. This is a critical patient safety issue, as inaccurate results can lead to erroneous and harmful clinical decisions.
• Directions for Future Research:
• There is a clear need for large, prospective, randomized controlled trials designed to formally establish the non-inferiority of single, fixed-dose Rasburicase regimens compared to the standard five-day, weight-based regimen. Such a trial would provide the Level 1 evidence needed to formally change regulatory labels and global standards of practice.
• Further investigation into the role of Rasburicase in non-malignant hyperuricemic emergencies is warranted. Prospective studies in patient populations with severe hyperuricemia from rhabdomyolysis, certain metabolic disorders, or post-transplant complications could clarify its utility and potentially expand its indications as a critical care agent.

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