Tailoring of Recommendations to Reduce Serious Cutaneous Adverse Drug Reactions: A Pharmacogenomics Approach

Abstract

The Health Sciences Authority launched a pharmacogenetics initiative in 2008 to facilitate evaluation of pharmacogenetics associations pertinent for Chinese, Malays and Indians in Singapore. The aim was to reduce the incidence and unpredictability of serious adverse drug reactions, with a focus on serious skin adverse drug reactions. This paper describes the gathering of evidence and weighing of factors that led to different genotyping recommendations for HLA-B*15:02 with carbamazepine and HLA-B*58:01 with allopurinol, despite both having strong genetic associations. Translation of pharmacogenomics at a national level requires careful deliberation of the prevalence of at-risk allele, strength of genetic associations, positive predictive value, cost-effectiveness and availability of alternative therapies. Our experience provides a perspective on translating genomic discoveries in advancing drug safety.

SJS/TEN 2019: From science to translation

“…SCAR guides highlighted the importance of prompt withdrawal of drugs in suspected SCAR cases. Post-market reports of CBZ-induced SCAR cases subsequently decreased by >95% [26]. Usage of CBZ decreased modestly overall, though new CBZ users declined by 40%.…”

Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults

“…A comprehensive PGx panel (which need not be limited to one single technology) that includes all actionable PGx markers can also prevent cases of rare but serious and expensive ADRs such as SJS/TEN, which can cost from US $1740 to US$25,540 per episode [38]. Patients requiring carbamazepine can potentially derive more benefit for no [12]. The amount that patients are willing to pay may also be much more than US $114.…”

“…In Singapore, genotyping for HLA-B*15:02 allele is performed prior to initiation of carbamazepine therapy in patients of Asian ancestry as standard of care for the avoidance of Steven's Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) [12]. A cost-effectiveness analysis supported the decision by the Ministry of Health to subsidize the cost of the genotyping test.…”

“…A cost-effectiveness analysis supported the decision by the Ministry of Health to subsidize the cost of the genotyping test. As a result, the number of cases of carbamazepine-associated SJS/TEN has dropped sharply from an average of 18 cases per year to only one case over 4 years after the implementation of HLA-B*15:02 testing [12]. This precedent may herald more of such PGx tests that demonstrate both clinical efficacy and cost-effectiveness.…”

Precision medicine in Thailand

“…Clinical studies showed the effectiveness of HLA‐B*15:02 screening prior to carbamazepine prescription to prevent SJS/TEN (Chen et al, ). Later on, the HLA‐B*15:02 testing has become a reimbursable pharmacogenetic test in Taiwan since 2011 and in Singapore since 2013 (Dong, Sung, & Finkelstein, ; Tan‐Koi et al, ).…”