Phenytoin: risk of Stevens-Johnson syndrome associated with HLA-B*1502 allele in patients of Thai or Han Chinese ethnic origin

If patients are known to be HLA-B*1502-positive, phenytoinshould be avoided when alternative therapy can be given.

Article date: January 2010

Phenytoin (brand leader Epanutin) is a commonly used antiepileptic drug. Phenytoin is one of the most common causes of antiepileptic-related cutaneous adverse reactions, including life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).1 A recent study 2 has shown a significant association between the human leukocyte antigen (HLA) allele HLA-B*1502 and phenytoin-induced SJS in patients of Thai or Han Chinese ethnic origin.

Healthcare professionals should be aware of the risk of SJS in patients of Thai or Han Chinese ethnic origin and the association with HLA-B1502 genetic variant when prescribing phenytoin. In these individuals with increased susceptibility, phenytoin should be avoided when alternative therapy can be given. However, available data are too limited to recommend screening of patients of Thai or Chinese ethnic origin for presence of the HLA-B1502 allele before starting phenytoin treatment.

Further information on the recent study

Locharernkul and co-workers’2 study included ten patients of Thai ethnic origin who had epilepsy and SJS induced by antiepileptic treatment; all tested positive for HLA-B1502 and had only been taking a single medicine. Of these, six had taken carbamazepine and four phenytoin. 50 antiepileptic-tolerant patients with epilepsy were recruited as controls and defined by the absence of allergic reactions on therapy for more than 3 months. Eight of 45 controls in the phenytoin-tolerant group tested positive for HLA-B1502. Comparison of the frequency of HLA-B*1502 in patients with phenytoin-associated SJS with that of the phenytoin-tolerant group showed a significant association (p=0·005).

When the phenytoin-tolerant group was used as control, the presence of HLA-B1502 had a 33% (95% CI 14–61%) positive predictive value for phenytoin-associated SJS, and its absence had a negative predictive value of 100% (91–100%). In the test for phenytoin-associated SJS, the HLA-B1502 allele has 100% (51–100%) sensitivity and 82% (69–91%) specificity.

HLA-B*1502 prevalence

The prevalence of HLA-B1502 is estimated at between 8·2% and 9% of the Thai population.2,3 The prevalence is similar in Han Chinese (8.6%). 4 The prevalence of HLA-B1502 is extremely low in the Caucasian population (1–2%).4 However, no conclusions can be drawn at present on the risk association between phenytoin-induced SJS and the presence of this allele in this population. Adequate information about risk association for patients of other ethnic origin is currently not available.

Advice for healthcare professionals:

  • HLA-B1502 may be associated with an increased risk of developing SJS in individuals of Thai or Han Chinese ethnic origin when treated with phenytoin. If these patients are known to be HLA-B1502-positive, phenytoin should be avoided when alternative therapy can be given. Use of phenytoin should only be considered if the benefits are thought to outweigh the risks
  • In the Caucasian and Japanese population, the frequency of HLA-B*1502 is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about risk association in other patients of other ethnic origin is currently not available

Further information:

See Drug Safety Update April 2008 for information and advice on the risk of carbamazepine-induced SJS associated with presence of HLA-B*1502 in those of Han Chinese, Hong-Kong Chinese, or Thai origin.

 

Article citation: Drug Safety Update Jan 2010, vol 3 issue 6: 2.

  1. Arif H, et al. Neurology 2007; 68: 1701–09.

  2. Locharenkul C, et al. Epilepsia 2008; 48: 1015–18.

  3. Pimatnothai N, et al. Tissue Antigens 2002; 59: 223–25.

  4. Chung WH, et al. Nature 2004; 428: 486.

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