Clinical Information

Carbamazepine and oxcarbazepine are aromatic anticonvulsants, as are eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. Carbamazepine is US Food and Drug Administration (FDA)-approved for the treatment of epilepsy, trigeminal neuralgia, and bipolar disorder. Oxcarbazepine is FDA-approved for the treatment of partial seizures. A minority of carbamazepine- or oxcarbazepine-treated persons have cutaneous adverse reactions that vary in prevalence and severity, with some forms associated with substantial morbidity and mortality. 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%. Drug reaction with eosinophilia and systemic symptoms (DRESS) and maculopapular exanthema (MPE) may also be related to carbamazepine exposure. 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. According to the FDA label for oxcarbazepine, the rate of TEN and SJS among individuals exposed to oxcarbazepine exceeds the background incidence by a factor of 3- to 10-fold, but this is expected to be an underestimate due to underreporting. The risk for a severe cutaneous adverse reaction is highest within the first few months of initiating therapy, but may not be absent, particularly if therapy is interrupted or reinitiated.

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 and Indians; and less than 1% frequency in Japanese and Koreans. This allele may be found in other populations, but is rare. This allele is strongly associated with greater risk of SJS and TEN in patients treated with carbamazepine or oxcarbazepine and has also been associated with SJS/TEN with phenytoin use. There is limited evidence associating SJS/TEN/DRESS or MPE and other aromatic anticonvulsants, such as lamotrigine, in patients who are positive for HLA-B*15:02, but the FDA has not issued a formal warning.

The HLA-A*31:01 allele, which has a prevalence of 2% to 5% in Northern European populations, 6% among Hispanic/South American populations, and 8% among Japanese populations, has been significantly associated with greater risk of MPE, DRESS, and SJS/TEN among patients treated with carbamazepine. 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 evidence linking other aromatic anticonvulsants with SJS/TEN in the presence of the HLA-A*31:01 allele is weaker; however, an alternative medication should be chosen with caution.

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 ancestry, but it does not specifically mandate screening of patients. The FDA-approved label for oxcarbazepine indicates that testing for the presence of the HLA-B*15:02 allele should be considered in patients with ancestry including genetically at-risk populations prior to initiation of therapy.

According to the FDA label, patients who test positive for HLA-B*15:02 should not be treated with carbamazepine or oxcarbazepine unless the benefit clearly outweighs the risk. Similarly, the most recent Clinical Pharmacogenetic Implementation Consortium (CPIC) guideline, patients who are HLA-B*15:02 positive should not be prescribed carbamazepine or oxcarbazepine if alternative agents are available; however, caution should be used in selecting an alternative medication as there is weaker evidence that also links other aromatic anticonvulsants with SJS/TEN in patients positive for HLA-B*15:02. Furthermore, phenytoin and fosphenytoin are the subject of a separate CPIC guideline with recommendations to avoid phenytoin and fosphenytoin in HLA-B*15:02 positive individuals, along with additional recommendations based on CYP2C9 genotype. Patients who are HLA-A*31:01 positive should not be prescribed carbamazepine if alternative agents are available. Although very limited evidence links SJS/TEN/DRESS/MPE with other aromatic anticonvulsants when used by HLA-A*31:01-positive patients, caution is advised when selecting an alternative medication.