Impact of genetic variation on response to therapy
Carbamazepine is known to cause immune-mediated cutaneous hypersensitivity reactions including maculopapular exanthema (MPE), drug hypersensitivity syndrome (HSS) also known as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The HLA alleles HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 are predisposing factors for these hypersensitivity reactions.
SJS, TEN and DRESS are life-threatening adverse events and should be avoided if possible.
The UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx) provides recommendations for carriers of HLA-B or HLA-A variant alleles associated with increased risk of severe cutaneous adverse drug reactions that are summarised as follows:
- Carbamazepine should be avoided in carriers of HLA-B*15:02
- Carbamazepine should be avoided in carriers of HLA-B*15:11 or HLA-A*31:01 if an alternative is possible.
The MHRA and the SmPC for carbamazepine advise that carbamazepine should be avoided in individuals of Thai or Han Chinese ethnic origin who are known to be HLA-B*15:02 positive unless there is no other therapeutic option, and in individuals of European descent or Japanese origin who are known to be HLA-A*31:01 positive unless the benefits are thought to outweigh the risks.
Testing recommendations
UK CERSI-PGx recommend that any treatment naïve patient, regardless of ancestry or indication for treatment, who is about to be prescribed carbamazepine, should undergo pharmacogenetic testing to identify all clinically relevant HLA alleles to reduce the risk of immune-mediated hypersensitivity reactions. Patients who have previously taken carbamazepine for less than 3 months should also undergo pharmacogenetic testing.
The SmPC for carbamazepine states that whenever possible, individuals of Han Chinese or Thai origin should be screened for the HLA-B*15:02 allele before starting treatment, and that testing may be considered in “genetically at risk” populations including individuals of Filipino or Malay origin.
A 2008 MHRA Drug Safety Update recommends that individuals of Han Chinese, Hong Kong Chinese or Thai origin should be screened for HLA-B*15:02 before prescription of carbamazepine.
Therapeutic recommendations
Carriers of HLA-B*15:02 (regardless of ancestry):
- Greatly increased risk of severe cutaneous adverse drug reactions including SJS/TEN.
- Avoid carbamazepine.
Carriers of HLA-A*31:01 or HLA-B*15:11 (regardless of ancestry):
- Increased risk of severe cutaneous adverse drug reactions including SJS/TEN.
- Avoid carbamazepine unless no suitable alternative is available and consider only if the benefits are thought to outweigh the risks.
- If no suitable alternative is available, increase monitoring and advise patients on what action to take if a skin rash occurs.
Further information
Risk of carbamazepine-induced SJS/TEN in carriers of HLA-B or HLA-A variant alleles
The Dutch Pharmacogenetics Working Group (DPWG) report that the risk of carbamazepine-induced SJS/TEN in HLA-B*15:02 carriers is 1.8 – 7.7% (between 1 in 56, and 1 in 13). The DPWG report that for HLA-A*31:01 carriers the risk of DRESS is 0.89% (1 in 112), and in HLA-B*15:11 carriers the risk of carbamazepine-induced SJS/TEN is 0.18-4.8% (between 1 in 556, and 1 in 21).
The SmPC for carbamazepine states that the presence of the HLA-A*31:01 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in the general population to 26.0% among subjects of Northern European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%.
Carbamazepine-induced serious cutaneous adverse events occur more frequently in the first 3 months post initiation of therapy. Even though the incidence and risk are low, SJS/TEN/DRESS is a life-threatening adverse event and should be avoided if possible.
Ancestry and ethnicity
The evidence linking HLA-B*15:02 and HLA-B*15:11 to carbamazepine-induced SJS/TEN has been generated primarily in individuals of Asian ancestries, which is due to the frequency of HLA-B*15:02 and HLA-B*15:11 being higher in Asian populations than in other populations. The evidence linking HLA-A*31:01 has been generated in Asian and European populations. However, all HLA-B or HLA-A variant alleles may occur individuals of any ancestry. It is recommended to avoid carbamazepine in all individuals who are carriers of clinically relevant HLA-B or HLA-A variant alleles, regardless of ancestry.
Alternative anti-epileptic agents
There is an association between HLA-B*15:02 and SJS/TEN induced by phenytoin, fosphenytoin, oxcarbazepine, eslicarbazepine and lamotrigine, although the risk is 10-fold lower than the risk with carbamazepine.
Oxcarbazepine and eslicarbazepine should also be avoided in HLA-B*15:02 carriers, and in HLA-A*31:01 or HLA-B*15:11 carriers if an alternative is possible.
Phenytoin, fosphenytoin, and lamotrigine should also be avoided in HLA-B*15:02 carriers unless no suitable alternative is available.
There is also limited evidence linking an increased risk of SJS/TEN and phenobarbital in HLA-B*15:02 carriers and it is recommended that phenobarbital and primidone (which is partially metabolised into phenobarbital) should be avoided in HLA-B*15:02 carriers unless no suitable alternatives are available and the benefit is thought to outweigh the risks.
Users should refer to individual monographs and the SmPCs for alternative agents for further information.
References
Novartis Pharmaceuticals UK Ltd (2025) Tegretol 100mg tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/1040/smpc (Accessed online 13th May 2025).
Medicines and Healthcare products Regulatory Agency (2014). Carbamazepine, oxcarbazepine and eslicarbazepine: potential risk of serious skin reactions. Drug Safety Update. Available at: https://www.gov.uk/drug-safety-update/carbamazepine-oxcarbazepine-and-eslicarbazepine-potential-risk-of-serious-skin-reactions (Accessed online 13th May 2025).
Medicines and Healthcare products Regulatory Agency and the Commission on Human Medicines. Drug Safety Update April 2008, vol 1, issue 9.
Clinical Pharmacogenetics Implementation Consortium (CPIC®) (2021). CPIC® Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Available at: https://cpicpgx.org/guidelines/guideline-for-carbamazepine-and-hla-b/ (Accessed online 13th May 2025).
Manson L.E.N et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs. European Journal of Human Genetics (2024) 32:903–911; https://doi.org/10.1038/s41431-024-01572-4.
Galloway L, Dello Russo C, Bass N, et al. HLA genotype testing for carbamazepine, oxcarbazepine and eslicarbazepine: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx). Br J Clin Pharmacol. 2026;1-20. doi:10.1002/bcp.70559
