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Guideline Summary
Guideline Title
Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing.
Bibliographic Source(s)
Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther. 2013 Feb;93(2):153-8. [40 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Hyperuricemia and gout

Guideline Category
Prevention
Risk Assessment
Treatment
Clinical Specialty
Family Practice
Internal Medicine
Medical Genetics
Pharmacology
Preventive Medicine
Rheumatology
Intended Users
Advanced Practice Nurses
Pharmacists
Physician Assistants
Physicians
Guideline Objective(s)

To provide pharmacogenetic information relevant to the clinical use of human leukocyte antigen B (HLA-B)*58:01 genotyping results in patients with indications for allopurinol use

Target Population

Individuals with hyperuricemia or gout

Interventions and Practices Considered

Allopurinol therapy based on human leukocyte antigen B (HLA-B)*58:01 genotype

Major Outcomes Considered
  • Risk of allopurinol-induced severe cutaneous adverse reaction (SCAR)
  • Risk of allopurinol-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)
  • Risk of allopurinol-induced hypersensitivity
  • Other adverse effects of allopurinol
  • Positive and negative predictive value of human leukocyte antigen B (HLA-B)*58:01 testing

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Searches of Unpublished Data
Description of Methods Used to Collect/Select the Evidence

The guideline authors searched the PubMed database (1966 to October 2011) for keywords ((HLA OR HLA-B OR HLA-B58 OR HLA-B*58:01) AND (allopurinol)), and retrieved fifty articles. Of those fifty the majority were review articles. The guideline authors identified nine primary studies of the pharmacogenomics of allopurinol hypersensitivity and one meta-analysis. The recent meta-analysis of human leukocyte antigen B (HLA-B)*5801 and allopurinol-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) stated that in their literature review they found only six relevant primary studies in their database search that included MEDLINE, Pre-MEDLINE, Cochrane Library, EMBASE, International Pharmaceutical Abstracts (IPA), CINAHL, PsycINFO, the World Health Organization (WHO) International, Clinical Trial Registry, and ClinicalTrials.gov External Web Site Policy from their inceptions to June 2011. The additional three studies included in the corpus of literature include those that used a genome-wide association study (GWAS) design and were published after June 2011.

To construct an HLA-B*58:01 minor allele frequency table based on ethnicity, allele frequency information was obtained from Allele Frequency Net Database (www.allelefrequencies.net External Web Site Policy). It is an online repository for HLA allele frequencies from both previously published and unpublished sources. All previously published data were manually checked against the original publications to verify the HLA-B*58:01 allele frequencies. In some cases, sample sizes or allele frequencies were updated to reflect only subjects successfully genotyped for HLA-B*58:01 (rather than the total sample size of the study) or to correct errata in the original publication. The combined analysis included 38,979 Caucasians, 5,811 Black or Africans, 882 Middle Easterners, 3,318 Hispanic or Latino and 11,531 Asians.

Number of Source Documents

The guideline authors identified nine primary studies of the pharmacogenomics of allopurinol hypersensitivity and one meta-analysis.

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Level of Evidence

High: Evidence includes consistent results from well-designed, well-conducted studies.

Moderate: Evidence is sufficient to determine effects, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence.

Weak: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information.

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Evidence was summarized into tables (see the "Availability of Companion Documents" field) and graded (see the "Rating Scheme for the Strength of the Evidence" field).

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The Clinical Pharmacogenetics Implementation Consortium's dosing recommendations are based weighing the evidence from a combination of preclinical functional and clinical data, as well as on some existing disease-specific consensus guidelines. Three categories were chosen for recommendations: strong, moderate, optional (see the "Rating Scheme for the Strength of the Recommendations" field).

Overall, the dosing recommendations are simplified to allow rapid interpretation by clinicians.

Rating Scheme for the Strength of the Recommendations

Strength of Therapeutic Recommendations

Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.

Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.

Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation

Not stated

Recommendations

Major Recommendations

The strength of therapeutic recommendations (Strong, Moderate, Optional) is defined at the end of the "Major Recommendations" field.

Therapeutic Recommendations

The Taiwan Department of Health has updated the labeling for allopurinol to include information on human leukocyte antigen B (HLA-B)*58:01 (http://www.doh.gov.tw/EN2006/Newsroom/Press_list.aspx?year=2009&doc_no=72847 External Web Site Policy). The updated label describes the strong association between HLA-B*58:01 and allopurinol-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in the Han-Chinese population and recommends testing for the allele before the use of allopurinol. The updated label does not recommend such testing for patients who have had no adverse events after prolonged use of allopurinol. At the time of writing this article, the U.S. Food and Drug Administration (FDA) had not updated the labeling for allopurinol. However, given the high specificity for allopurinol-induced severe cutaneous adverse reactions (SCAR), allopurinol should not be prescribed to patients who have tested positive for HLA-B*58:01. Alternative medication should be considered for these patients to avoid the risk of developing SCAR. For patients who have tested negative, allopurinol may be prescribed as usual (see the table below). However, testing negative for HLA-B*58:01 does not totally eliminate the possibility of developing SCAR, especially in the European population.

Several clinical factors have been reported to be associated with an increased risk for allopurinol hypersensitivity. Renal dysfunction is the most significant nongenetic factor, and patients with renal insufficiency were four times more likely to develop adverse events than those with normal renal function. The risk of allopurinol-induced hypersensitivity is also reported to increase with the concomitant use of ampicillin or amoxicillin.

In addition to SCAR, allopurinol therapy is also associated with a 2%–3% incidence of less severe rashes unassociated with systemic symptoms or organ damage. FDA guidelines recommend discontinuing allopurinol if a rash develops. Until recently, only uricosuric drugs such as probenecid and benzbromarone were available for the patients who need to discontinue allopurinol due to skin rash. However, probenecid is often less effective than allopurinol, particularly in patients with renal insufficiency, and benzbromarone is not an approved drug in many countries. This has prompted attempts to induce tolerance to allopurinol by rechallenge with gradual escalation of low doses as tolerated. This unreliable approach has not been widely accepted, and its use may decline because alternative urate-lowering therapies are now available. Febuxostat, which received FDA approval in 2009, is available in 19 countries. It is a nonpurine xanthine oxidase inhibitor that is primarily metabolized in the liver to inactive glucuronide and excreted into the urine and bile. Therefore, mild to moderate renal impairment might have little impact on the pharmacokinetics of febuxostat. It was reported to be tolerated in 12 of 13 patients with a history of severe allopurinol hypersensitivity. In 2010, the FDA approved pegloticase, a PEGylated urate oxidase, as an orphan drug for treating patients with refractory chronic gout who had an inadequate response to, or were intolerant of, other urate-lowering drugs. Newer urate-lowering drugs are in clinical trials.

Table. Recommended Therapeutic Use of Allopurinol by Human Leukocyte Antigen (HLA)-B Genotype

Genotype Implications for Phenotypic Measures Recommendations for Allopurinol Classification of Recommendations
Noncarrier of HLA-B*58:01 (*X/*X)a Low or reduced risk of allopurinol-induced SCAR Use allopurinol per standard dosing guidelines Strong
Carrier of HLA-B*58:01 (HLA-B*58:01/*X,a HLA-B*58:01/HLA-B*58:01) Significantly increased risk of allopurinol-induced SCAR Allopurinol is contraindicated Strong

HLA-B, human leukocyte antigen-B; SCAR, severe cutaneous adverse reaction.

aHLA-B genotype other than HLA-B*58:01 is indicated by *X.

Definitions:

Strength of Therapeutic Recommendations

Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.

Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.

Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The evidence summarized in Supplemental Table S4 (see the "Availability of Companion Documents" field) has been graded using the slightly modified three-tiered system required by the Clinical Pharmacogenetics Implementation Consortium (see the "Rating Scheme for the Strength of the Evidence" field). Every effort was made to present evidence from high-quality studies, which provided the framework for the strength of therapeutic recommendations.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Given the high negative predictive value of the allele, especially in patients of Asian descent (>99%), human leukocyte antigen B (HLA-B)*58:01 testing could significantly reduce the incidence and risk for allopurinol-associated severe cutaneous adverse reaction (SCAR).

Potential Harms
  • As with any laboratory test, one potential risk could come from genotyping error. A false-negative genotyping result could lead to allopurinol-induced adverse events.
  • Genotypes are lifelong characteristics; such errors could have a broader health implication if other associations with human leukocyte antigen B (HLA-B)*58:01 are identified in the future.
  • Several clinical factors have been reported to be associated with an increased risk for allopurinol hypersensitivity. Renal dysfunction is the most significant nongenetic factor, and patients with renal insufficiency were four times more likely to develop adverse events than those with normal renal function. The risk of allopurinol-induced hypersensitivity is also reported to increase with the concomitant use of ampicillin or amoxicillin.
  • In addition to severe cutaneous adverse reaction (SCAR), allopurinol therapy is also associated with a 2%–3% incidence of less severe rashes unassociated with systemic symptoms or organ damage. Food and Drug Administration guidelines recommend discontinuing allopurinol if a rash develops.

Contraindications

Contraindications

Allopurinol is contraindicated in carriers of human leukocyte antigen B (HLA-B)*58:01.

Qualifying Statements

Qualifying Statements

Caveats: Appropriate Use and/or Potential Misuse of Genetic Tests

  • The positive predictive value for human leukocyte antigen B (HLA-B)*58:01 is ~1.5% and the negative predictive value is 100% (based on the data from the Han-Chinese and Thai populations). Therefore, a significant number of patients carrying the allele will not develop severe cutaneous adverse reactions (SCAR) when they receive allopurinol treatment. New genetic factors may be identified in the future to differentiate the HLA-B*58:01 carriers who are or are not likely to develop SCAR. The most severe SCAR (toxic epidermal necrolysis) carries a 30% mortality rate. However, further study is warranted on the development of SCAR in European populations.
  • HLA-B*58:01 predicts only allopurinol-induced SCAR, not other adverse events (such as mild skin rash) that a patient might experience during allopurinol treatment. The marker also does not predict the efficacy of treatment with allopurinol. Regardless of the genotyping results, physicians should monitor patients closely.

Disclaimer

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines 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, in addition to identifying questions for further research. New evidence may have emerged since a guideline was submitted for publication. Guidelines are limited in scope and are not applicable to interventions or diseases not specifically identified. Guidelines do not account for all individual variation 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 the patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be solely made by the clinician and the patient. CPIC assumes no responsibility for any injury to persons or damage to property related to any use of CPIC's guidelines, or for any errors or omissions.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Resources
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
Staying Healthy
IOM Domain
Effectiveness
Safety

Identifying Information and Availability

Bibliographic Source(s)
Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther. 2013 Feb;93(2):153-8. [40 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2013 Feb
Guideline Developer(s)
Clinical Pharmacogenetics Implementation Consortium - Independent Expert Panel
Source(s) of Funding

This work was funded by National Institutes of Health (NIH) grant GM61374.

Guideline Committee

Not stated

Composition of Group That Authored the Guideline

Authors: MS Hershfield, Departments of Medicine and Biochemistry, Duke University School of Medicine, Durham, North Carolina, USA; JT Callaghan, ACOS for Research, Department of Veterans Affairs Medical Center, Departments of Medicine Pharmacology/Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA; W Tassaneeyakul, Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; T Mushiroda, Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, Japan; CF Thorn, Department of Genetics, Stanford University Medical Center, Stanford, California, USA; TE Klein, Department of Genetics, Stanford University Medical Center, Stanford, California, USA; MTM Lee, National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, School of Chinese Medicine, China Medical University, Taichung, Taiwan, Laboratory for International Alliance, RIKEN Center for Genomic Medicine, Yokohama, Japan

Financial Disclosures/Conflicts of Interest

MS Hershfield is a co-inventor of pegloticase (Krystexxa) and is a consultant to, and receives royalties from, Savient Pharmaceuticals. MTM Lee is a paid consultant of YongLin Healthcare Foundation. The other authors declared no conflict of interest.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available from the Pharmacogenomics Knowledgebase Web site External Web Site Policy.

Availability of Companion Documents

Supplementary material, including tables and methodological information, is available from the Pharmacogenomics Knowledgebase Web site External Web Site Policy.

In addition, an interactive dosing table is available from the Pharmacogenomics Knowledgebase Web site External Web Site Policy.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on May 15, 2013. The information was verified by the guideline developer on June 25, 2013.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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