Carbamazepine Therapy and Genotype

Carbamazepine (brand names include Carbatrol, Epitol, Equetro, and Tegretol) is an effective antiseizure drug that is often used as a first-line agent in the treatment of epilepsy. Carbamazepine is also used to treat bipolar disorder and to relieve pain in trigeminal neuralgia. Hypersensitivity reactions associated with carbamazepine can occur in up to 10% of patients, and typically affect the skin. Some of these reactions are mild, as in the case of maculopapular exanthema (MPE); however, conditions such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are potentially life-threatening. The risk of hypersensitivity is increased by the presence of specific human leukocyte antigen ( alleles. The allele is strongly associated with carbamazepine-induced SJS/TEN in populations where this allele is most common, such as in Southeast Asia. According to the FDA-approved drug label for carbamazepine, testing for should be done for all patients with ancestry in populations with increased frequency of , prior to initiating carbamazepine therapy (Table 1). The label states that greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. The label states that South Asians, including Indians, appear to have intermediate prevalence of , averaging 2 to 4%, but higher in some groups. In Japan and Korea, the is present in less than 1% of the population. In individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans), the allele is largely absent. These prevalence rates of may be used to guide which patients should be screened. However, the FDA cautions to keep in mind the limitations of prevalence rate data when deciding which patients to screen. This is because of the wide variability in rates (even within ethnic groups), the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry (1). The FDA label also states that carbamazepine should not be used in patients who are positive for unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN. The allele may also be a risk factor for SJS/TEN but is more strongly associated with other carbamazepine-induced reactions, such as DRESS and MPE. is found in most populations, worldwide. is another allele that has been linked with SJS/TEN. The FDA states that the risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for , but does not discuss (1). Carbamazepine dosing guidelines based on genotype have been published by the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) (2, 3, 4, 5). DPWG recommendations include avoiding the use of carbamazepine and selecting an alternative, if possible, for individuals positive for , and (Table 2). CPIC recommendations include not using carbamazepine in carbamazepine-naïve patients who are positive for and any genotype (or genotype unknown) (Table 3). CPNDS recommends genetic testing for all carbamazepine-naïve patients before they start treatment, with a moderate level of evidence for testing, and strong to optional evidence for testing (based on the frequency of in the population the patient originates from, and if this is known or not) (Table 4).