Clinical Information

Carbamazepine is sometimes prescribed for the treatment of epilepsy, as well as trigeminal neuralgia and bipolar disorder. A minority of carbamazepine-treated persons have cutaneous adverse reactions that vary in prevalence and severity, with some forms associated with substantial morbidity and mortality. More severe reactions, such as the hypersensitivity syndrome, are associated with mortality of up to 10% and include symptoms such as rash, fever, eosinophilia, hepatitis, and nephritis. The most severe reactions, such as the Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are characterized by a blistering rash affecting a variable percentage of the body-surface area. TEN is the rarest of these phenotypes and is associated with mortality of up to 30%. According to the FDA-approved label for carbamazepine, the estimated incidence of SJS-TEN is 1 to 6 cases in 10,000 persons of European ancestry who are exposed to the drug. The rate of SJS-TEN as a result of carbamazepine exposure is about 10 times higher in some Asian countries.

Clinical studies have demonstrated associations between some human leukocyte antigen (HLA) genotypes and drug-associated cutaneous adverse reactions. The presence of the HLA-B*15:02 allele varies throughout Asia: 10% to 15% frequency in Chinese, 2% to 4% frequency in Southeast Asians, including Indians, and <1% frequency in Japanese and Koreans.

The HLA-A*31:01 allele, which has a prevalence of 2% to 5% in Northern European populations, has been significantly associated with drug-associated cutaneous adverse reactions. In the absence of HLA-A*31:01, the risk for drug-associated cutaneous adverse reactions is 3.8%, but in the presence of this allele, the risk increases to 26%.  

The FDA-approved label for carbamazepine states that the screening of patients in genetically at-risk populations (ie, patients of Asian descent) for the presence of the HLA-B*15:02 allele should be carried out prior to initiating treatment with carbamazepine. The FDA-approved label also notes the association of HLA-A*31:01 allele with drug-associated cutaneous adverse reactions regardless of ethnicity but does not specifically mandate screening of patients. For patients who are HLA-B*15:02 and HLA-A*31:01 positive, oxcarbazepine, phenytoin, fosphenytoin, eslicarbazepine acetate, and lamotrigine may also be associated with drug-associated cutaneous adverse reactions so these medications may need to be avoided as well.