Temporal trends and patterns in carbamazepine use, related severe cutaneous adverse reactions, and HLA‐B*15:02 screening: A nationwide study

Abstract

Objective: After discovering the association between the HLA-B*15:02 allele and carbamazepine-related severe cutaneous adverse reactions (SCARs), particularly in Southeastern Asian populations, clinical strategies to prevent carbamazepine-related SCARs have changed. We aimed to investigate 10-year trends in carbamazepine use and carbamazepine-related SCARs and to examine the patterns and determinants of HLA-B*15:02 screening in Taiwan. Methods: A nationwide study was performed using Taiwan's National Health Insurance Research Database. In the first part of the study, new users of carbamazepine were included, and those who experienced SCAR-related admissions were further identified. In the second part of the study, recipients of HLA-B*15:02 screening (reimbursed by Taiwan's National Health Insurance since June 2010) were included and multivariate logistic regression was used to explore factors associated with the use of screening. Results: The numbers of new users of carbamazepine and SCAR cases decreasedremarkably during the 10-year period (−82.6% and −87.1%, respectively), and the incidence rates of SCARs showed a downward trend after 2011. The screening rate of the HLA-B*15:02 allele increased to 24.9% in 2014. Neurologists (odds ratio 12.33, 95% confidence interval 9.30-16.35), psychiatrists (9.97, 7.31-13.61), and neurosurgeons (3.23, 2.42-4.32) were more likely to perform screening tests than other specialties were. Physicians practicing in medical centers (6.00, 5.51-6.54) were more likely to perform screening tests than those practicing in other hospitals, whereas the screening rates in clinics remained at 0.0% throughout the study period. Significance: In recent years, the number of carbamazepine-related SCAR cases has decreased substantially in Taiwan. However, only one-fourth of new users of carbamazepine received HLA-B*15:02 screening, and there were considerable disparities in the screening rates across different physician groups. Policymakers should consider solutions to barriers to implementing screening tests in clinical practice and should not neglect the value of other safety communications and regulations to complement the limitations of pharmacogenomic testing. K E Y W O R D S antiepileptic drugs, pharmacogenomic testing, Stevens-Johnson syndrome/toxic epidermal necrolysis

A Realistic Review of the Drug‐Injury Relief System in Taiwan: Challenges, Lessons, and Achievements

“…The implementation of these safety measures corresponds with a significant decline from 2011 in the number of CBZ‐associated drug‐injury relief applications ( Figure ). Another analysis of the National Health Insurance found that CBZ prescriptions fell steadily from 2005−2014, whereas HLA‐B*15:02 genetic testing rose significantly from 2010−2014; at the same time, cases of CBZ‐induced SCARs declined significantly from 2011 . From this real‐world evidence, it can be seen that in the case of CBZ, the introduction of several administrative measures and the active promotional initiatives of the TDRF combined to deliver tangible reductions in drug injury, and indicates that the drug‐injury relief system in Taiwan not only offers postinjury relief but is also playing a substantial role in pharmacovigilance and drug safety.…”

Genetic Predisposition to Anticonvulsant Hypersensitivity

“…The strength of the predisposition, together with identification in a cohort study that prospective genotyping reduced the incidence of SJS/TEN, has led to the recommendation in drug labels that HLA‐B*15:02 screening should be undertaken prior to the use of CBZ in South‐East Asian populations. In Taiwan, after screening was introduced, cases of CBZ‐induced SJS/TEN have declined by 87% over a 10‐year period, but this is not all due to the use of HLA‐B*15:02 testing because the use of CBZ also decreased by 83% over the same time period . Indeed only 25% of new users were screened before given CBZ, highlighting that implementation is far from perfect.…”

“…In Taiwan, after screening was introduced, cases of CBZ-induced SJS/TEN have declined by 87% over a 10-year period, but this is not all due to the use of HLA-B*15:02 testing because the use of CBZ also decreased by 83% over the same time period. 4 Indeed only 25% of new users were screened before given CBZ, highlighting that implementation is far from perfect. This is also reflected in a study from Hong Kong where the availability of a genetic test for HLA-B*15:02 drove clinicians away from the use of CBZ to other drugs, which were also associated with SJS/TEN, such that the total incidence of anticonvulsant-induced SJS/ TEN remained stable despite a decrease in CBZ-induced SJS/TEN.…”

High and variable population prevalence of HLA‐B*56:02 in indigenous Australians and relation to phenytoin‐associated drug reaction with eosinophilia and systemic symptoms

“…Phenytoin SJS/TEN has been strongly linked to the HLA‐B*15:02 allele and less commonly to other human leucocyte antigen (HLA)‐B alleles of the same B75 serotype ( HLA‐B*15:21 , B*15:11 , B*15:08 ) originally reported in Han Chinese from Taiwan but subsequently confirmed in other Asian countries including Malaysia, China, Thailand and India, where its frequency can be >10% . In Taiwan where screening for HLA‐B*15:02 is reimbursed, the use of carbamazepine and cases of carbamazepine‐related SCAR have declined . In Korean, Japanese and European populations, phenytoin‐associated DRESS due to HLA‐B*15:02 is rare due to very low allele frequency (< 0.5%).…”

“…1 In Taiwan where screening for HLA-B*15:02 is reimbursed, the use of carbamazepine and cases of carbamazepine-related SCAR have declined. 3 In Korean, Japanese and European populations, phenytoin-associated DRESS due to HLA-B*15:02 is rare due to very low allele frequency (< 0.5%). In a Malay population, 4 a different HLA-B allele in the B75 serotype, HLA-B*15:13 was associated with phenytoin SJS/TEN and DRESS.…”