Allopurinol-induced severe cutaneous adverse reactions and the role of HLA-B*5801 genotyping – a reminder

HSA would like to remind healthcare professionals about the risk of severe cutaneous adverse reactions (SCAR) with the use of allopurinol and the role of HLA-B*5801 genotyping prior to therapy initiation. In March 2016, the Ministry of Health (MOH) and HSA jointly issued a Dear Healthcare Professional Letter to inform that HLA-B*5801 genotyping prior to the initiation of allopurinol therapy is not required as standard of care.1 Nonetheless, healthcare professionals were also advised that they may consider genotyping patients who have pre-existing risk factors for allopurinol-induced SCAR such as renal impairment and older age, to identify those who are at a greater risk of allopurinol-induced SCAR.

Allopurinol is a uricosuric agent indicated for reducing urate/uric acid formation in gout and other conditions such as nephrolithiasis. It has been registered in Singapore since 1989 and there are currently seven registered allopurinol-containing products locally.

 

Local cases of allopurinol-induced SCAR

From March 2016 to 1 October 2021, HSA has received 80 cases of allopurinol-induced SCAR, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Six of these cases were fatal. Allopurinol was the sole suspected agent in majority (n=69, 86%) of the cases. Notably, most of the cases had risk factors for SCAR, such as older age and renal impairment. Of the 71 cases with age reported, close to two-thirds (65%) were aged 60 years and above. Renal function was reported in 42 cases, of which approximately two-thirds (64%) had renal impairment. Of the 41 cases where allopurinol dose was reported, nearly two-thirds (63%) received allopurinol 100mg or below daily while the remaining cases received daily doses ranging from more than 100mg to 300mg.

Information on when the HLA-B*5801 genotyping test was conducted, and the corresponding test results were available for 12 cases and 14 cases respectively. The majority of the cases were tested following the development of SCAR (71%) and were HLA-B*5801 positive (86%). Most of the HLA-B*5801-positive cases were aged 60 years and above (92%) and/or reported renal impairment of varying degrees (~67%). The remaining two HLA-B*5801-negative cases were aged 60 years and above and had chronic kidney disease.  

  

About HLA-B*5801 genotyping test

The HLA-B*5801 genotyping test has high sensitivity and selectivity of over 80% for allopurinol-induced SCAR.2 However, the rarity of allopurinol-induced SCAR (i.e. around 3 out of 1,000 patients on allopurinol may develop SCAR) leads to a low positive predictive value (PPV) of the HLA-B*5801 test (estimated PPV: 2%, i.e. approximately 2 out of 100 HLA-B*5801-positive people starting allopurinol may develop SCAR). The low PPV, together with a lack of alternative cost-effective urate-lowering therapy options, limit the overall value of routine genotyping from a health-systems perspective. Testing for the allele may be more useful in treatment decision-making if the patient is assessed to already be at a higher risk of allopurinol-induced SCAR with renal impairment or older age.3

Currently, the HLA-B*5801 genotyping test is available at the DNA Diagnostic & Research Laboratory at KK Women's and Children's Hospital, the Tan Tock Seng Hospital Molecular Diagnostic Laboratory, and the Tissue Typing Laboratory at HSA. The estimated turnaround time for the test result is one to seven working days.                          

HSA’s advisory     

Healthcare professionals are reminded of the following advisory, when considering the use of allopurinol in new patients:

  • Allopurinol should be used with caution especially in older patients with renal impairment. Consider starting at a low dose and titrate accordingly.
  • While HLA-B*5801 genotyping is not routinely recommended for new patients initiating allopurinol, healthcare professionals may consider genotyping patients who have pre-existing risk factors for allopurinol-induced SCAR such as renal impairment and older age, to identify those who are at a greater risk of allopurinol-induced SCAR. While patients who have tested negative for the HLA-B*5801 allele are at lower risk of developing allopurinol-induced SCAR, they can still develop SCAR as there are non-genetic factors that increase the risk. Hence, genetic testing, when ordered for at-risk patients, should not substitute for appropriate clinical vigilance and patient management.
  • Healthcare professionals are advised to consider and discuss with their patients the benefits of treatment with allopurinol and its risks, including SCAR, as well as the availability of pre-treatment HLA-B*5801 genotyping test before prescribing allopurinol.
  • Healthcare professionals are also advised to educate patients on the recognition of early signs and symptoms of SCAR and the importance of prompt drug withdrawal and medical consultation at the first sign of rash. Patient educational materials such as the Patient Education Aid in the Appropriate Care Guide3 and Consumer guide on Safe Use of Allopurinol4 may be used and distributed to patients during medication counselling.

Healthcare professionals are encouraged to report any suspected serious adverse reactions related to allopurinol to the Vigilance and Compliance Branch of HSA.

 

References

  1. https://www.hsa.gov.sg/announcements/safety-alert/allopurinol-induced-serious-cutaneous-adverse-reactions-and-the-role-of-genotyping
  2. Front Pharmacol 2020; 11: 567048
  3. ACE Appropriate Care Guide ‘Gout Achieving the Management Goal’ dated 20 December 2019
  4. https://www.hsa.gov.sg/consumer-safety/articles/safe-use-of-allupurinol
Healthcare professional, Industry member, Therapeutic Products
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