Serious adverse skin reactions associated with carbamazepine

Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are life-threatening adverse skin reactions, with mortality rates of up to 5% and 40% respectively. Drugs are most often implicated as the suspected cause of SJS and TEN in adults and elderly persons.

Carbamazepine, (CBZ) indicated for the treatment of epilepsy, neuropathic pain and bipolar disorder, is known to be associated with an increased risk of causing adverse cutaneous skin reactions, including SJS and TEN. This increased risk has been observed in the local population through the relatively higher numbers of SJS and TEN that have been reported in association with the drug over the years. More recently, studies have been published which demonstrate a plausible genetic association with CBZ-induced SJS and TEN among Asian patients, in particular, Han Chinese and Thais.

Local ADR reports of SJS and TEN

Between 2003 and 2008, the Pharmacovigilance (PV) Branch of HSA received 290 cases of drug-induced SJS and TEN. CBZ was one of the most commonly suspected causative agents, accounting for 53 cases (18%) (in 2008 alone, 15 cases of SJS-TEN were reported in association with CBZ). These 53 reports involved patients aged one to 88 years. The CBZ dosages ranged from 100 - 600mg daily. The onset of adverse reactions ranged from one day to three months after starting therapy.

Other drugs such as allopurinol, phenytoin and cotrimoxazole were also reported to be associated with a higher number of SJS/TEN, accounting for 9.3%, 9.6% and 12.1% of the total local SJS/TEN reports received respectively.

Association observed between the HLA-B*1502 allele and CBZ-induced SJS and TEN

Recently, CBZ-induced SJS and TEN have been found to be associated with the HLA-B*1502 allele among Han Chinese (in Taiwan and Hong Kong) and Thais.^2,3,4 In the Taiwan study, while 59 out of the 60 patients with CBZ-induced SJS/TEN had the HLA-B*1502 allele, only 4% of the CBZ-tolerant patients were found to carry the allele. Out of the 144 CBZ-tolerant patients, who had been on CBZ for at least three months and at a higher dose of CBZ, none reported any SJS nor TEN.³

Also, the allele HLA-B*1502 was not observed in patients with other forms of CBZ-induced cutaneous reactions such as hypersensitivity syndrome or maculopapular eruptions, suggesting that the genetic association is phenotype-specific. A case series in Hong Kong found four out of four cases of SJS/TEN to be associated with CBZ in patients positive for HLA-B*1502.⁴

A European study from the RegiSCAR group⁵ found that out of the 12 patients with CBZ-induced SJS/TEN, all four who were positive for the HLA-B*1502 allele were of Asian origin. It further suggested that the genetic link may be specific to patients with Asian ancestry such as the Han Chinese.

An analysis of worldwide post-marketing cases reported to the World Health Organisation (WHO) also pointed to a much higher reporting rate of SJS/TEN, about 10 times, higher in some Asian countries.⁶

Regulatory Actions taken to date

Based on the above findings and the post-marketing ADRs reported by the manufacturers of carbamazepine, the US Food and Drug Administration (FDA) concluded in December 2007, that the risk of SJS/ TEN from CBZ is significantly increased in Asian patients positive for the HLA-B*1502 allele⁶. Recognising the wide variability in rates of HLA-B*1502 even within ethnic groups, the difficulty in ascertaining ethnic ancestry, as well as the likelihood of mixed ancestry, FDA recommended that screening for HLA-B*1502 should be performed for most patients of Asian ancestry. Patients of any ethnicity or genotype, including HLA-B*1502 positive, who have been taking carbamazepine for more than a few months are at low risk of SJS/TEN from carbamazepine.⁶

The local package insert for Tegretol® has also been updated by the manufacturer to reflect the association observed between HLA-B*1502 allele and CBZ-induced SJS, the prevalence of this allele in vaious Asian population as well as a recommendation to consider testing for the presence of HLA-B*1502 allele in patients with Asian ancestry prior to prescribing Tegretol®. In addition, it is also stated that the use of carbamazepine should be avoided in tested patients who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks. However, it is not known if a patient whotests positive for HLA-B*1502 would develop SJS/TEN when alternative anti-epileptics are used.

Currently, the Health Sciences Authority's (HSA) Tissue Typing Laboratory (Tel: 62130632, 62130633) is the only accredited lab in Singapore thatoffers HLA testing as part of their diagnostic services. Prescribers may send their patients' samples for a preliminary test to check for the presence of the HLA-B15 serotype (HLA-B Low Resolution), and then proceed to test for the presence of the HLA-B*1502 allele (HLA-B High Resolution) if this is positive. Alternatively, prescribers could also proceed directly to test for the presence of the HLA-B*1502 allele. The turnaround time is estimated to be between three to seven working days.

Pharmacogenetics initiative by HSA

In an effort to understand the relevance of genetic association with adverse drug reactions among the diverse ethnic groups (Chinese, Malays and Indians) in the local population, HSA is embarking on a pharmacogenetics-based pharmacovigilance programme together with scientific collaborators from the various public institution hospitals and research institutes. The study is aimed at investigating the significance of the genetic association of the HLA-B*1502 allele to CBZ-induced serious skin reactions in the local context and also to uncover other possible genetic associations that may be responsible for the adverse drug- induced skin reactions observed locally.

References:

1. Yearbook of Statistics Singapore, 2008

2. Epilepsia 2008, 49(12):2087-2091

3. Pharmacogenet. Genomics 2006, 16(4):297-306

4. Epilepsia 2007, 48(5):1015-1018

5. Pharmacogenomics J. 2006, 6(4), 265-268

6. http://www.fda.gov/Drugs/DrugSafety/PostmarketdrugsafetyinformationforPatientsandProviders/ucm124718.htm