Introduction
Carbamazepine (CBZ) is an anticonvulsant indicated for the treatment of epilepsy and other conditions such as bipolar disorders, alcohol-withdrawal syndrome, trigeminal neuralgia, diabetic neuropathy and diabetes insipidus centralis. It has been registered in Singapore since 1988 and there are currently nine registered CBZ-containing products, including Tegretol® (Novartis Singapore Pte Ltd) and four other generic brands.
A strong association has been established between HLA-B*1502 allele and CBZ-induced SJS/TEN in Asian populations. Alternative antiepileptics are available, and genotyping for the allele was determined to be cost effective in Singapore.1, 2 Consequently, MOH, in a joint Dear Healthcare Professional Letter with HSA in April 2013, stated that genotyping for HLA-B*1502 is the standard of care prior to the initiation of CBZ therapy in new patients of Asian ancestry.3
CBZ-induced SCAR Outcomes
From 2003 to 2012, HSA received an average of 15 reports of CBZ-induced SJS/TEN per year. Since April 2013, more than 2,700 patients have been genotyped for HLA-B*1502, of which 11% were found to carry the HLA-B*1502 allele. HSA has recently received one report of CBZ-induced SJS among all the patients screened for the allele. This suspected case of CBZ-induced SJS occurred in a patient who was genotyped negative. The patient developed SJS 32 days after the initiation of CBZ. A concomitant drug, gabapentin, was initiated 68 days prior to the reaction.
HLA-B*1502 has not been shown to be a risk predictor of CBZ-induced DRESS. HSA has received two reports of CBZ-induced DRESS in patients who were genotyped negative. CBZ was the only suspected drug in both cases. The time-to-onset was 31 and 44 days, respectively.
While genotyping for HLA-B*1502 has successfully mitigated the risk of CBZ-induced SJS/TEN locally, these three cases of CBZ-induced SCAR are a reminder of the need to remain vigilant for SCAR even among those who tested negative for HLA-B*1502 as non-genetic factors may be involved in the development of SCAR.
HSA’s Advisory
Genotyping for the HLA-B*1502 allele prior to the initiation of CBZ therapy in new patients of Asian ancestry is the standard of care in Singapore. HLA-B*1502 genotyping test has proven highly effective in distinguishing high-risk patients from low-risk patients who are able to continue to use this cost-effective medicine.
Healthcare professionals are reminded of the following:
- HLA-B*1502 genotype testing specifically identifies patients at high risk of developing CBZ-induced SJS/TEN, but not CBZ-induced DRESS.
- HLA-B*1502 test results should be obtained prior to prescribing CBZ. This is because of the possibility of development and progression of SJS/TEN in susceptible patients even after prompt discontinuation of the drug.
- The use of CBZ should be avoided and treatment alternatives are strongly recommended in patients who are found to be positive for HLA-B*1502. As a precaution, these patients should also not be prescribed phenytoin, as there is preliminary data suggesting a suspected association between HLA-B*1502 and phenytoin-induced SJS/TEN.
- Genetic testing should not substitute for appropriate clinical vigilance and patient management. Although reported to be rare, patients who test negative for HLA-B*1502 may still be at risk of developing CBZ-induced SCAR, including DRESS. The role of other factors which may contribute to the development of SCAR in these patients, such as drug dose, concomitant medications and co-morbidities, have not been studied.
- Clinical vigilance for CBZ-induced SCAR including DRESS should continue, especially during the first 12 weeks following initiation of CBZ therapy
Healthcare professionals are encouraged to report any suspected serious ADRs relating to CBZ use to the Vigilance and Compliance Branch.
References
- Pharmacogenomics J. 2014; 14: 316-21
- Neurology 2012; 79: 1259-67
- https://www-hsa-gov-sg.cwp.sg/announcements/safety-alert/recommendations-for-hla-b-1502-genotype-testing-prior-to-initiation-of-carbamazepine-in-new-patients