Carbamazepine

Carbamazepine is used to treat epilepsy and trigeminal neuralgia, and is used as a prophylaxis for manic-depressive psychosis in patients unresponsive to lithium therapy.

• Variants in the HLA-B*15:02 and HLA-A*31:01 alleles have distinct ethnic and geographical distributions, which are important to consider when evaluating population risk. Adverse reactions are estimated to occur in between 1 and 6 per 10,000 new users of carbamazepine in countries with mainly White populations, but the risk in some Asian populations is estimated to be around 10 times higher.
• HLA-B*15:02 predicts the risk of severe carbamazepine-associated cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Reactions usually occur within the first three months of treatment. The frequency of HLA-B*15:02 is highest in East Asian (6.9%), Oceanian (5.4%) and South and Central Asian (4.6%) populations. However, not all East Asian populations have this allele in such high frequencies. For example, the HLA-B*15:02 frequency is much lower in patients with Japanese ethnicity (less than 1%).
• HLA-A*31:01 is also associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. It also carries an increased risk of drug rash with eosinophilia and less severe acute generalised exanthematous pustulosis and maculopapular rash. Reactions usually occur within the first three months of treatment. Variants in the HLA-A*31:01 allele occur in White populations (3%) and in Hispanic and South American populations (6%), and occur in high frequencies in some East Asian populations, specifically Japanese (8%), South Korean (5%) and South and Central Asian populations (2%).
• While these frequencies are helpful in determining broad population risks, they cannot replace genotyping on an individual basis.

• The summary of product characteristics for Tegretol (carbamazepine) indicates that patients of Han Chinese and Thai origin should, wherever possible, be screened for variants in the HLA-B*15:02 allele. However, it also states that there is currently insufficient data to recommend HLA-A*31:01 screening before starting carbamazepine treatment.
• In 2008, a drug safety update was issued by the Medicines and Healthcare products Regulatory Agency recommending that patients of Han Chinese, Hong Kong Chinese and Thai origin should be screened for HLA-B*15:02 prior to starting carbamazepine treatment.
• At the time of writing, testing for variants in the HLA-B*15:02 and HLA-A*31:01 alleles is not included in the National Genomic Test Directory, although testing may be available via your regional Genomic Laboratory Hub or other local laboratories (such as histocompatibility or immunogenetics laboratories).
• For HLA testing (and other DNA-based tests), an EDTA sample is required.
• Patients may present with information about their HLA-B*15:02 or HLA-A*31:01 status from other healthcare systems, clinical trials or direct-to-consumer genomic testing services (caution should be exercised when interpreting results from non-validated genomic tests).
• The Clinical Pharmacogenetics Implementation Consortium has produced prescribing recommendations for carbamazepine (and oxcarbazepine) in HLA-B*15:02 and HLA-A*31:01 genotypes.
• For more information about genomic testing for variants in the HLA-B*15:02 and HLA-A*31:01 alleles and how results can affect patient management, see Presentation: Patient of Asian ethnicity requiring carbamazepine and Results: Patient requiring carbamazepine with a known variant in the HLA-B*15:02 or HLA-A*31:01 allele.

For clinicians

• Clinical Pharmacogenetics Implementation Consortium: Guideline for HLA genotype and use of carbamazepine and oxcarbazepine: 2017 update (PDF, eight pages)
• Electronic Medicines Compendium: Tegretol 100mg tablets
• Medicines and Healthcare products Regulatory Agency: Drug safety update: Carbamazepine, oxcarbazepine and eslicarbazepine: Potential risk of serious skin reactions
• NHS England: National Genomic Test Directory

References:

• Khoo ABS, Ali FR, Yiu ZZN and others. ‘Carbamazepine induced Stevens-Johnson syndrome’. British Medical Journal Case Reports 2016. DOI: 1136/bcr-2016-214926

For patients

• Medicines for Children: Oral carbamazepine for preventing seizures (PDF, two pages)
• SJS Awareness UK: Stevens-Johnson syndrome and toxic epidermal necrolysis factsheet (PDF, two pages)