Abstract
In April 2013, the Ministry of Health and Health Sciences Authority of Singapore jointly issued recommendations for HLA-B*15:02 genotyping before starting carbamazepine (CBZ) in new patients of Asian ancestry as standard of care. The Ministry of Health also approved a 75% subsidy for HLA-B*15:02 genotyping to all patients on subsidy at public healthcare institutions. To understand the impact of these regulatory decisions, we researched the usage patterns for CBZ and levetiracetam, the trend of Stevens–Johnson syndrome/toxic epidermal necrolysis [Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)] reports associated with antiepileptic drugs and the take-up rates of HLA-B*15:02 tests in Singapore. In the 5-year post-policy period, we found that the annual number of reported SJS/TEN cases associated with all antiepileptic drugs was significantly decreased by 57% (p = 0.015); SJS/TEN cases associated with CBZ and phenytoin reduced by 92% and 42% respectively. New CBZ users decreased by 31% while new levetiracetam users approximately doubled. The annual number of HLA-B*15:02 tests conducted increased from 444 to approximately 1,200. Regulatory recommendations for HLA-B*15:02 genotyping as standard of care coupled with government subsidy for the test had contributed to a reduction in CBZ SJS/TEN in Singapore by >90%, in line with that observed in other Asian countries with similar policies. Additionally, the number of phenytoin-SJS/TEN cases also declined. Taken together, this represents a successful example of precision medicine through implementation of a genotyping program to reduce a rare but serious adverse drug reaction among at-risk individuals, while preserving the availability of an effective and low-cost medicine for the broader population.
Highlights
Carbamazepine (CBZ) is indicated in Singapore for the treatment of epilepsy and other conditions such as diabetic neuropathy, trigeminal neuralgia and bipolar disorders
The annual number of reported Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) cases associated with anti-epileptic drugs (AEDs) was significantly decreased by 57% from a 5-year prepolicy period (May 2008 to Apr 2013; median 16, range 11–24) as compared to that in the 5-year post-policy period (May 2013 to Apr 2018; median 7, range 5–11; p = 0.015; Figure 1A)
Genotyping status was reported in 2 cases, of which one was negative for HLA-B*15:02
Summary
Carbamazepine (CBZ) is indicated in Singapore for the treatment of epilepsy and other conditions such as diabetic neuropathy, trigeminal neuralgia and bipolar disorders. While CBZ is an effective drug and the drug of choice for several conditions, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with its use. These serious adverse reactions are associated with significant mortality and long-term morbidity. HLA-B*15:02 was observed to confer risk to phenytoin SJS–TEN in Han Chinese in Hong Kong and Taiwan, the association was not as strong as with CBZ (Man et al, 2007; Hung et al, 2010)
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