When is allopurinol (xanthine oxidase inhibitor) not indicated?

From the Guidelines

Allopurinol is not indicated in patients with a history of severe hypersensitivity reactions, during acute gout attacks, in those with severe renal impairment without dose adjustment, in pregnancy unless benefits outweigh risks, and in patients carrying the HLA-B*5801 allele, particularly those of certain ethnic descent. When considering the use of allopurinol, it's crucial to weigh the potential benefits against the risks, especially in specific patient populations. According to the 2020 American College of Rheumatology guideline for the management of gout 1, allopurinol is recommended as the first-line agent for all patients, including those with CKD stage ≥3, but with careful consideration of dose titration and potential interactions.

Key Considerations for Allopurinol Use

• Patients with severe hypersensitivity reactions to allopurinol, including Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with eosinophilia and systemic symptoms (DRESS), should avoid this medication due to the risk of life-threatening reactions.
• Allopurinol should not be initiated during acute gout attacks as it may worsen symptoms; instead, treatment should be started after the acute attack has resolved, as suggested by the guideline 1.
• Patients with severe renal impairment (CrCl <30 mL/min) require significant dose reduction rather than standard dosing, emphasizing the need for careful dose adjustment in renal impairment, as noted in the 2012 American College of Rheumatology guidelines for management of gout 1.
• Allopurinol should be avoided in pregnancy unless the benefits clearly outweigh the risks, given the limited safety data.
• Patients carrying the HLA-B5801 allele, particularly those of Han Chinese, Thai, or Korean descent, have a significantly higher risk of severe cutaneous adverse reactions and should avoid allopurinol if possible, as highlighted in the consideration for HLA-B5801 testing in selected patients 1.
• Concomitant use with certain medications like azathioprine or mercaptopurine requires careful dose adjustment due to drug interactions that can lead to dangerous levels of these medications. Given the most recent and highest quality evidence from the 2020 guideline 1, the approach to allopurinol use emphasizes careful patient selection, dose titration, and monitoring to minimize risks while maximizing benefits in the management of gout.

From the FDA Drug Label

Asymptomatic hyperuricemia is not an indication for treatment with allopurinol tablets (see INDICATIONS AND USAGE)

• Allopurinol is not indicated for use in the following cases:
  • Asymptomatic hyperuricemia
  • Children, with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism 2
  • Nursing women, as a precaution since the effect of allopurinol on the nursing infant is unknown 2
  • Pregnancy, unless clearly needed, as there are no adequate or well-controlled studies in pregnant women 2

From the Research

Allopurinol Contraindications

• Allopurinol is not indicated in patients with a history of hypersensitivity reactions to the drug, including allopurinol hypersensitivity syndrome (AHS) 3, 4, 5.
• Patients with chronic kidney disease are at increased risk of AHS, and alternative treatments may be considered 3.
• The presence of the HLA-B*5801 allele is a risk factor for AHS, and pretreatment testing may be recommended in certain ethnic groups 3, 4.
• Allopurinol may not be suitable for patients with fatty liver disease, as it may increase the risk of hepatotoxicity compared to alternative treatments like febuxostat 6.

Alternative Treatments

• Patients who are intolerant to allopurinol may be treated with alternative urate-lowering therapies, such as probenecid, sulfinpyrazone, or benzbromarone 7.
• Febuxostat may be a suitable alternative to allopurinol in patients with gout and fatty liver disease, as it has been shown to have a lower risk of hepatotoxicity 6.
• Recombinant urate oxidase may be used in the short-term prophylaxis and treatment of chemotherapy-associated hyperuricemia in patients with lymphoproliferative and myeloproliferative disorders 7.