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Allopurinol response

MedGen UID:
472719
Concept ID:
CN160494
Sign or Symptom
Synonyms: Zyloprim response
Drug:
Allopurinol
MedGen UID:
207
Concept ID:
C0002144
Pharmacologic Substance
A XANTHINE OXIDASE inhibitor that decreases URIC ACID production. It also acts as an antimetabolite on some simpler organisms.
 
Gene (location): HLA-B (6p21.33)

Definition

Allopurinol is widely prescribed for the treatment of hyperuricemia and gout. An estimated 25-30% of gout patients in the UK and the US are treated with allopurinol. However, 0.1-0.4% of patients treated with allopurinol experience severe cutaneous adverse reactions (SCAR), including drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The genetic variant HLA-B*58:01, along with non-genetic factors, is known to be associated with this risk. Patients who are HLA-B*58:01-positive (having at least one copy of the HLA-B*58:01 allele) have a significantly increased risk of allopurinol-induced SCAR compared to those who are negative for this allele. It is still possible for a HLA-B*58:01 negative patient to develop SCAR on allopurinol. Guidelines regarding the use of pharmacogenomic tests in dosing for allopurinol have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website. [from PharmGKB]

Additional descriptions

From Medical Genetics Summaries
Allopurinol is a xanthine oxidase inhibitor that decreases the production of uric acid. It is most commonly used in the management of gout and hyperuricemia (high levels of uric acid). The human leukocyte antigen B (HLA-B) plays an important role in how the immune system recognizes and responds to pathogens. The variant HLA-B*58:01 allele is strongly associated with severe cutaneous adverse reactions (SCAR) during treatment with allopurinol. This allele is most commonly found in Asian subpopulations, notably in individuals of Korean, Han Chinese, or Thai descent. At this time, the FDA-approved drug label does not discuss HLA-B genotype. However, the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that allopurinol should not be prescribed to patients who have tested positive for HLA-B*58:01, and that an alternative medication should be considered to avoid the risk of developing SCAR.  https://www.ncbi.nlm.nih.gov/books/NBK127547
From NCBI curation
Allopurinol is widely prescribed for the treatment of hyperuricemia and gout. An estimated 25-30% of gout patients in the UK and the US are treated with allopurinol. However, 0.1-0.4% of patients treated with allopurinol experience severe cutaneous adverse reactions (SCAR), including drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The genetic variant HLA-B*58:01, along with non-genetic factors, is known to be associated with this risk. Patients who are HLA-B*58:01-positive (having at least one copy of the HLA-B*58:01 allele) have a significantly increased risk of allopurinol-induced SCAR compared to those who are negative for this allele. It is still possible for a HLA-B*58:01 negative patient to develop SCAR on allopurinol. Guidelines regarding the use of pharmacogenomic tests in dosing for allopurinol have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the PharmGKB website.

Professional guidelines

PubMed

Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT
Clin Pharmacol Ther 2013 Feb;93(2):153-8. Epub 2012 Oct 17 doi: 10.1038/clpt.2012.209. PMID: 23232549Free PMC Article
Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R; American College of Rheumatology.
Arthritis Care Res (Hoboken) 2012 Oct;64(10):1431-46. doi: 10.1002/acr.21772. PMID: 23024028Free PMC Article

External

DailyMed Drug Label, ALLOPURINOL, 2010

Recent clinical studies

Etiology

Wen CC, Yee SW, Liang X, Hoffmann TJ, Kvale MN, Banda Y, Jorgenson E, Schaefer C, Risch N, Giacomini KM
Clin Pharmacol Ther 2015 May;97(5):518-25. Epub 2015 Apr 6 doi: 10.1002/cpt.89. PMID: 25676789Free PMC Article

Diagnosis

Wright DF, Duffull SB, Merriman TR, Dalbeth N, Barclay ML, Stamp LK
Br J Clin Pharmacol 2016 Feb;81(2):277-89. Epub 2015 Dec 29 doi: 10.1111/bcp.12799. PMID: 26451524Free PMC Article

Therapy

Wright DF, Duffull SB, Merriman TR, Dalbeth N, Barclay ML, Stamp LK
Br J Clin Pharmacol 2016 Feb;81(2):277-89. Epub 2015 Dec 29 doi: 10.1111/bcp.12799. PMID: 26451524Free PMC Article
Wen CC, Yee SW, Liang X, Hoffmann TJ, Kvale MN, Banda Y, Jorgenson E, Schaefer C, Risch N, Giacomini KM
Clin Pharmacol Ther 2015 May;97(5):518-25. Epub 2015 Apr 6 doi: 10.1002/cpt.89. PMID: 25676789Free PMC Article

Prognosis

Wright DF, Duffull SB, Merriman TR, Dalbeth N, Barclay ML, Stamp LK
Br J Clin Pharmacol 2016 Feb;81(2):277-89. Epub 2015 Dec 29 doi: 10.1111/bcp.12799. PMID: 26451524Free PMC Article

Clinical prediction guides

Wright DF, Duffull SB, Merriman TR, Dalbeth N, Barclay ML, Stamp LK
Br J Clin Pharmacol 2016 Feb;81(2):277-89. Epub 2015 Dec 29 doi: 10.1111/bcp.12799. PMID: 26451524Free PMC Article

Recent systematic reviews

Wen CC, Yee SW, Liang X, Hoffmann TJ, Kvale MN, Banda Y, Jorgenson E, Schaefer C, Risch N, Giacomini KM
Clin Pharmacol Ther 2015 May;97(5):518-25. Epub 2015 Apr 6 doi: 10.1002/cpt.89. PMID: 25676789Free PMC Article

Therapeutic recommendations

This section contains excerpted1information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2015 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC): Given the high specificity for allopurinol-induced 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 Table 1). However, testing negative for HLA-B*58:01 does not totally eliminate the possibility of developing SCAR, especially in the European population.

Please review the complete therapeutic recommendations that are located here (1, 2).

2012 Statement from the American College of Rheumatology (ACR): Prior to initiation of allopurinol, rapid polymerase chain reaction-based HLA-B*5801 screening should be considered as a risk management component in subpopulations where both the HLA-B*5801 allele frequency is elevated and the HLA-B*5801-positive subjects have a very high hazard ratio ("high risk") for severe allopurinol hypersensitivity reaction (e.g., Koreans with stage 3 or worse chronic kidney disease and all those of Han Chinese and Thai descent).

Please review the complete therapeutic recommendations that are located here (3).

Table 1. HLA-B phenotypes and the therapeutic recommendations for allopurinol therapy, adapted from CPIC
The strength of therapeutic recommendations is “strong” (1). HLA-B, human leukocyte antigen BSCAR, severe cutaneous adverse reaction*X, any HLA-B genotype other than HLA-B*58:01*Xb, any HLA-B genotype other than HLA-B*58:01Table is adapted from Hershfield M.S., Callaghan J.T., Tassaneeyakul W., Mushiroda T., Thorn C.F., Klein T.E., Lee M.T.Clinical pharmacogenetics implementation consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clinical pharmacology and therapeutics. 2013;93(2):153–8 (1, 2).
GenotypeExamples of diplotypesPhenotypeTherapeutic recommendations
Noncarrier of HLA-B*58:01*X/*XbLow or reduced risk of allopurinol-induced SCARUse allopurinol per standard dosing guidelines
Carrier of HLA-B*58:01*5801/*Xb*5801/*5801Significantly increased risk of allopurinol-induced SCARAllopurinol is contraindicated

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug.

3. Khanna D., Fitzgerald J.D., Khanna P.P., Bae S., et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis care & research. 2012;64(10):1431–46.

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