Drug/Small Molecule:
rasburicase

last updated 05/09/2014

CPIC Dosing Guideline for rasburicase and G6PD

Summary

Rasburicase is contraindicated in G6PD deficient patients with or without chronic non-spherocytic hemolytic anemia (CNSHA). In patients with a negative or inconclusive genetic test result an enzyme activity test is recommended prior to rasburicase treatment to determine whether a patient is G6PD deficient. The G6PD gene is X-linked and therefore males only have one copy, whereas females have two copies. See full guideline for disclaimers, further details and supporting evidence.

Annotation

Aug 2014

Accepted article preview online May 2014, advance online publication 11 June 2014

  • Guidelines regarding the use of pharmacogenomic tests in determining whether rasburicase treatment should be undertaken have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
  • Excerpt from the 2014 rasburicase guideline:
    • "As stated above, rasburicase is contraindicated by the FDA, the EMA, and PMDA in those with G6PD deficiency (32-34) (see Table 2). If, on the basis of genotyping, a deficient status can be unambiguously assigned to a patient, that would be a sufficient contraindication to the use of rasburicase. However, due to the limitations of genetic testing (discussed above), in most cases it is necessary to perform G6PD enzyme testing to assign G6PD status."
  • These guidelines are applicable to
    • neonates
    • pediatrics
    • adults
  • Download and read:

Table 1: Recommended dosing of rasburicase by G6PD phenotype

Adapted from Table 1 and Table 2 of the 2014 guideline manuscript.

Phenotype (Genotype) a Examples of diplotypes b Implications for phenotypic measures Dosing recommendations for rasburicase Classification of recommendations c
Normal d. A male carrying a non-deficient (class IV) allele or a female carrying two non-deficient (class IV) alleles. Male: B, Sao Boria. Female: B/B, B/ Sao Boria. Low or reduced risk of hemolytic anemia. No reason to withhold rasburicase based on G6PD status d. Strong
Deficient or Deficient with CNSHA. A male carrying a class I, II or III allele, a female carrying two deficient class I-III alleles. Male: A-, Orissa, Kalyan-Kerala, Mediterranean, Canton, Chatham, Bangkok, Villeurbanne. Female: A-/A-, A-/ Orissa, Orissa/ Kalyan-Kerala, Mediterranean/ Mediterranean, Chatham/Mediterranean, Canton/ Viangchan, Bangkok/ Bangkok, Bangkok/ Villeurbanne. At risk of acute hemolytic anemia. Rasburicase is contraindicated; alternatives include allopurinol e. Strong
Variable d,f. A female carrying one non-deficient (class IV) and one deficient (class I-III variants) allele. B/A-, B/Mediterranean, B/Bangkok. Unknown risk of hemolytic anemia. To ascertain that G6PD status is normal, enzyme activity must be measured; alternatives include allopurinol e. Moderate

a "Class" refers to the WHO classifications from [Article:22293322], other details from [Article:4963040]. Class I variants are extremely rare; the distinction between class II and III variants is not clear; and the "class V" very high activity variant has only been reported in a single case [Article:4963040](*). Therefore, almost all patients will carry class II, III, or IV alleles. It should be noted that the class of a variant may have been assigned only by the clinical manifestations of a patient in which the variant was subsequently identified.
(*) Luzzatto, L. & Poggi, V. Glucose-6-Phosphate Dehydrogenase Deficiency In: Nathan and Oski's Hematology of Infancy and Childhood, 7th Edition (ed. Meloni, D., Anderson, A. Authors of the book: Orkin, S.H., Fisher, D.E., Look, A.T., Lux IV, S.E., Ginsburg, D., Nathan, D.G. ) (Saunders, Elsevier., 2009).
b Due to the large number of G6PD variants, many other diplotypes may be possible besides those given as examples here; see Supplemental Table S1 for a more comprehensive list of variant alleles with their assigned WHO class.
c Rating scheme described in Supplement (See Strength of Recommendations material).
d A negative or inconclusive genetic test cannot be assumed to indicate normal G6PD phenotype; an enzyme activity test is needed to assign G6PD phenotype in such cases.
e Allopurinol is associated with severe cutaneous reactions in the rare carriers of the HLA-B*58:01 allele [Article:23232549].
f Due to X-linked mosaicism, females heterozygous for one non-deficient (class IV) and one deficient (class I-III variants) allele may display a normal or a deficient phenotype. It is therefore difficult to predict the phenotype of these individuals (Supplement, G6PD heterozygotes).

Figure 1: Workflow for interpreting G6PD genotype and for assessing need for an enzyme activity test.

Figure 1 from the guideline manuscript.

*It should be noted that the class of a variant may have been assigned only by the clinical manifestations of a patient in which the variant was subsequently identified [Article:22293322].


PharmGKB annotates drug labels containing pharmacogenetic information approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency, Japan (PMDA). PharmGKB annotations provide a brief summary of the PGx in the label, an excerpt from the label and a downloadable highlighted label PDF file. A list of genes and phenotypes found within the label is mapped to label section headers and listed at the end of each annotation. PharmGKB also attempts to interpret the level of action implied in each label with the "PGx Level" tag.

Sources:

  • FDA Information is gathered from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" and from FDA-approved labels brought to our attention. Please note that drugs may be removed from or added to the FDA's Table without our knowledge. We periodically check the Table for changes and update PharmGKB accordingly. Drugs listed on the Table to our knowledge are tagged with the Biomarker icon. A drug label that has been removed from the Table will not have the Biomarker icon but will continue to have an annotation on PharmGKB stating the label has been removed from the FDA's Table. We acquire label PDF files from DailyMed.
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We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA, PMDA or other Medicine Agencies around the world - please contact feedback.



last updated 10/25/2013

FDA Label for rasburicase and G6PD

Genetic testing required

Summary

The drug label recommends screening patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek(rasburicase) therapy. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency who are treated with rasburicase are at risk of severe hemolysis. Rasburicase is contraindicated for such patients.

There's more of this label. Read more.


last updated 10/27/2013

European Medicines Agency (EMA) Label for rasburicase and G6PD

Actionable PGx

Summary

The EMA European Public Assessment Report (EPAR) contraindicates the use of rasburicase (Fasturtec) in patients with G6PD deficiency due to a risk of hemolytic anemia or methemoglobinemia. Testing or screening for G6PD deficiency is not mentioned.

There's more of this label. Read more.


Pharmaceuticals and Medical Devices Agency, Japan (PMDA) Label for rasburicase and G6PD

Genetic testing required

Summary

The PMDA package insert for rasburicase notes that foreign clinical studies have shown that patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency can have severe hemolytic reactions when administered rasburicase, and that screening of patients at risk for G6PD deficiency or other disorders known to cause erythroenzmopathy must be conducted.

There's more of this label. Read more.


Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?
Labor für Humangenetik Synlab MVZ Humane Genetik München. Test for Glucose-6-Phosphate Dehydrogenase Deficiency Variant in G6PD
Emory Molecular Genetics Laboratory Emory University School of Medicine. Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PD Sequence analysis of the entire coding region, deletion/duplication analysis
The Rare Disease Company, Centogene GmbH. Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PD Sequence analysis of the entire coding region
Medical Genetics Laboratory Diagenom GmbH. Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PD Sequence analysis of the entire coding region
Hehr Laboratory, Center for Human Genetics Regensburg University of Regensburg. Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PD Sequence analysis of the entire coding region
MVZ Dortmund, Dr. Eberhard and Partner, Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PD Sequence analysis of exons: 2-13
Molecular Genetics Center for Human Genetics and Laboratory Medicine Martinsried, Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PD Sequence analysis of the entire coding region
Molecular Biology Center, GENETAQ, Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PD Sequence analysis of the entire coding region
Molecular Genetics Laboratory ARUP Laboratories, Glucose-6-Phosphate Dehydrogenase (G6PD) 2 Mutations G6PDA- 202A_376G , rs1050829 , rs1050828
Molecular Diagnostics Division, Genome Research Group Centre for Cellular and Molecular Biology. Test for Glucose-6-Phosphate Dehydrogenase Deficiency rs137852339 , rs5030868 , rs78478128
PerkinElmer Genetics, Inc. Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PDA- 202A_376G , rs72554665 , rs5030868 , rs1050829 , rs1050828 , G6PD Sequence analysis of the entire coding region
Bioscientia GmbH Center for Human Genetics. Glucose-6-Phosphate Dehydrogenase Deficiency G6PDA- 202A_376G , rs72554665 , rs5030869 , rs5030868 , rs1050829 , rs1050828
bio.logis Center for Human Genetics. Test for Glucose-6-Phosphate Dehydrogenase Deficiency G6PDA- 202A_376G , rs72554665 , rs5030869 , rs5030868 , rs1050829 , rs1050828

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all rasburicase variant annotations

Gene ? Variant?
(142)
Alternate Names ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA G6PD A- 202A_376G N/A N/A N/A
No VIP available CA No VIP available G6PD B (wildtype) N/A N/A N/A
No VIP available CA VA G6PD Mediterranean, Dallas, Panama' Sassari, Cagliari, Birmingham N/A N/A N/A
No VIP available No Clinical Annotations available VA
G6PD deficiency N/A N/A N/A
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 142

Overview

Generic Names
  • Urate oxidase
  • Uricase
  • rasburicase
Trade Names
  • Elitek
  • Elitek (Sanofi-Synthelabo Inc)
  • Fasturtec
Brand Mixture Names

PharmGKB Accession Id:
PA10176

Description

Rasburicase is a recombinant urate-oxidase enzyme produced by a genetically modified Saccharomyces cerevisiae strain. The cDNA coding for rasburicase was cloned from a strain of Aspergillus flavus.

Source: Drug Bank

Indication

For treatment of hyperuricemia, reduces elevated plasma uric acid levels (from chemotherapy)

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Rasburicase catalyzes enzymatic oxidation of uric acid into an inactive and soluble metabolite (allantoin).

Source: Drug Bank

Pharmacology

Drugs used to treat lympohoid leukemia, non-Hodgkin's lymphoma and acute myelogenous leukemia often lead to the accumulation of toxic plasma levels of purine metabolites (i.e. uric acid). The injection of rasburicase reduces levels of uric acid and mitigates the toxic effects of chemotherapy induced tumor lysis.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Half-Life

18 hours

Source: Drug Bank

Volume of Distribution

Source: Drug Bank

Chemical Properties

Chemical Formula

C1521H2381N417O461S7

Source: Drug Bank

Canonical SMILES

Not Available

Source: Drug Bank

Average Molecular Weight

34109.5000

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. Oxidative Stress Regulatory Pathway (Erythrocyte)
    A simplified diagram to show several of the regulatory mechanisms that prevent oxidative stress in red blood cells, many of which require NADPH from the Pentose Phosphate Pathway.
  1. Uric Acid-Lowering Drugs Pathway, Pharmacodynamics
    A stylized diagram showing the drugs that act to prevent uric acid formation or enhance its excretion, and adverse reactions associated with these drugs.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this drug. To report a pathway, click here.

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
G6PD
No related drugs are available.

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to rasburicase: 28

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
PharmGKB summary: uric acid-lowering drugs pathway, pharmacodynamics. Pharmacogenetics and genomics. 2014. McDonagh Ellen M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Rasburicase Therapy in the context of G6PD Deficiency Genotype. Clinical pharmacology and therapeutics. 2014. Relling Mary V, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Rasburicase-induced methemoglobinemia in two African-American female patients: An under-recognized and continued problem. European journal of haematology. 2014. Roberts Daniel A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Methaemoglobinaemia in a G6PD-deficient child treated with rasburicase. BMJ case reports. 2014. Bontant Thomas, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
PharmGKB summary: methylene blue pathway. Pharmacogenetics and genomics. 2013. McDonagh Ellen M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Rasburicase Causing Severe Oxidative Hemolysis and Methemoglobinemia in a Patient with Previously Unrecognized Glucose-6-Phosphate Dehydrogenase Deficiency. Acta haematologica. 2013. Cheah Chan Y, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Lethal effect of a single dose of rasburicase in a preterm newborn infant. Pediatrics. 2013. Zaramella Patrizia, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Methemoglobinemia and hemolysis in a patient with G6PD deficiency treated with rasburicase. American journal of hematology. 2012. Sonbol Mohamad Bassam, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
PharmGKB summary: very important pharmacogene information for G6PD. Pharmacogenetics and genomics. 2012. McDonagh Ellen M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Methemoglobinemia induced by rasburicase in a pediatric patient: A case report and literature review. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2011. Ng John S, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2011. Vadhan-Raj S, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Prospective-retrospective biomarker analysis for regulatory consideration: white paper from the industry pharmacogenomics working group. Pharmacogenomics. 2011. Patterson Scott D, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug safety : an international journal of medical toxicology and drug experience. 2010. Youngster Ilan, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A ghostly presence-G6PD deficiency. American journal of hematology. 2010. Bain Barbara J. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Effect of allopurinol versus urate oxidase on methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia. Cancer. 2010. Crews Kristine R, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
[A severe G6PD deficiency revealed during a chemotherapy protocol including rasburicase]. Annales de biologie clinique. 2009. Joly P, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Exchange transfusion as treatment for rasburicase induced methemoglobinemia in a glucose-6-phosphate dehydrogenase deficient patient. Pediatric blood & cancer. 2008. Bhat Priya, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Methemoglobinemia and hemolytic anemia caused by rasburicase administration in a newly diagnosed child with Burkitt lymphoma/leukemia. Pediatric blood & cancer. 2008. Borinstein Scott C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
G6PD deficiency: the genotype-phenotype association. Blood reviews. 2007. Mason Philip J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Catalase deficiency may complicate urate oxidase (rasburicase) therapy. Free radical research. 2007. Góth László, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Report of two cases of rasburicase-induced methemoglobinemia. Leukemia & lymphoma. 2006. Kizer Nora, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Hemolysis and methemoglobinemia secondary to rasburicase administration. The Annals of pharmacotherapy. 2005. Browning Linda A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study. Cancer. 2003. Bosly André, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Urate-oxidase in the prevention and treatment of metabolic complications in patients with B-cell lymphoma and leukemia, treated in the Société Française d'Oncologie Pédiatrique LMB89 protocol. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2002. Patte C, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1997. Pui C H, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
G6PD deficiency. Blood. 1994. Beutler E. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Hemolytic anemia due to G6PD deficiency and urate oxidase in a kidney-transplant patient. Clinical nephrology. 1991. Ducros J, et al. PubMed

LinkOuts

GenBank:
X61766
Web Resource:
Wikipedia
UniProtKB:
Q00511
National Drug Code Directory:
0024-5150-10
DrugBank:
DB00049
Drugs Product Database (DPD):
2248416
FDA Drug Label at DailyMed:
0ae10bc4-6b65-402f-9db5-2d7753054922

Clinical Trials

These are trials that mention rasburicase and are related to either pharmacogenetics or pharmacogenomics.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.