Carbamazepine hypersensitivity

SJS/TEN and HLA-B*1502 Allele

Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*15:02. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*15:02. 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. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA- B*15:02 is present in <1% of the population in Japan and Korea.

HLA- B*15:02 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating carbamazepine therapy, testing for HLA-B*15:02 should be performed in patients with ancestry in populations in which HLA-B*15:02 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA- B*15:02 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Carbamazepine should not be used in patients positive for HLA-B*15:02 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.

Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on carbamazepine.

The HLA-B*15:02 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Limited evidence suggests that HLA-B*15:02 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*15:02 positive patients, when alternative therapies are otherwise equally acceptable.

Hypersensitivity Reactions and HLA-A*31:01 Allele

Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*31:01, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms.

HLA-A*31:01 is expected to be present in the following approximate frequencies: greater than 15% in patients of Japanese and Native American ancestry; up to about 10% in patients of Han Chinese, Korean, European, and Latin American ancestry; and up to about 5% in African-Americans and patients of Indian, Thai, Taiwanese, and Chinese (Hong Kong) ancestry.

The risks and benefits of carbamazepine therapy should be weighed before considering carbamazepine in patients known to be positive for HLA-A*31:01.

General Information on HLA Genotyping and Hypersensitivity

Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*15:02-positive and HLA- A*31:01-positive patients treated with carbamazepine will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B*15:02-negative and HLA-A*31:01-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.

Please review the complete therapeutic recommendations that are located here: (1).

The therapeutic recommendations for HLA-B*15:02 and carbamazepine remain unchanged from the original guideline (3) but in this update they are now also applicable to oxcarbazepine (4). These recommendations hold irrespective of the patient’s region of origin or ethnic group. For patients who are HLA-B*15:02 negative, carbamazepine or oxcarbazepine may be prescribed per standard guidelines. If a patient is carbamazepine-naïve or oxcarbazepine-naïve and HLA-B*15:02 positive, carbamazepine and oxcarbazepine should be avoided, respectively, due to the greater risk of SJS/TEN. Other aromatic anticonvulsants, including eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital, have very limited evidence, if any, linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used when choosing an alternative agent. With regular dosing, carbamazepine- or oxcarbazepine-induced SJS/TEN usually develops within the first 4–28 days of therapy; therefore, patients who have been continuously taking carbamazepine or oxcarbazepine for longer than 3 months without developing cutaneous reactions are at extremely low risk (but not zero) of carbamazepine- or oxcarbazepine-induced adverse events in the future, regardless of HLA-B*15:02 status.

For patients who are HLA-A*31:01 negative, carbamazepine may be prescribed per standard guidelines (Table 3). If a carbamazepine-naïve patient also received testing for HLA-B*15:02 and is positive for this allele, carbamazepine should be avoided regardless of the HLA-A*31:01 genotype result. If a patient is carbamazepine-naïve and HLA-A*31:01 positive, and if alternative agents are available, carbamazepine should be avoided due to the greater risk of SJS/TEN, DRESS, and MPE. Other aromatic anticonvulsants, including oxcarbazepine, have very limited evidence, if any, linking SJS/TEN, DRESS, and/or MPE with the HLA-A*31:01 allele, and thus no recommendation can be made with respect to choosing another aromatic anticonvulsant as an alternative agent. If alternative agents are not available, consider the use of carbamazepine with increased frequency of clinical monitoring. Discontinue therapy at the first evidence of a cutaneous adverse reaction. As previously mentioned, since the latency period for cutaneous adverse drug reactions is known, if the patient is HLA-A*31:01 positive and has previously used carbamazepine for longer than 3 months without incidence of a cutaneous adverse reaction, cautiously consider use of carbamazepine.

Please review the complete therapeutic recommendations that are located here: (4).

Recommendation 1.1: Genetic testing for HLA- B*15:02 is recommended for all carbamazepine (CBZ)-naive patients before initiation of carbamazepine therapy (Level A – strong in patients originating from populations where HLA- B*15:02 is common, its frequency unknown or whose origin is unknown; Level C – optional in patients originating from populations where HLA-B*15:02 is rare). Genetic testing for HLA-A*31:01 is recommended for all carbamazepine-naive patients before initiation of carbamazepine therapy (Level B – moderate in all patients; Table 6).

Recommendation 1.2: In patients who have previously taken carbamazepine for > 3 months without any adverse effects, and in whom reinitiation of carbamazepine is considered, genetic testing is NOT recommended (B). In patients who have previously taken carbamazepine for a shorter period, genetic testing should be considered (B).

Recommendation 1.3: In patients who have previously experienced a hypersensitivity reaction (HSR) potentially related to carbamazepine, genetic testing is recommended as part of the differential diagnosis and for the direction of future therapy (B).

Recommendation 1.4: In patients for whom no alternative treatment options are available, genetic testing is recommended to ensure increased alertness to hypersensitivity symptoms in positive patients (B).

Recommendation 2.1: Genetic testing for HLA- B*15:02 is most beneficial in patients originating from a population where HLA-B*15:02 is common (e.g., Chinese, Thai, Indian, Malay, Filipino, Indonesian; A). Nevertheless, genotyping for HLA-B*15:02 should be considered in ALL patients, irrespective of their ancestry, as the safest option (C).

Recommendation 2.2: HLA-A*31:01 is common in most populations studied so far. Therefore, genetic testing for this variant is recommended in patients of all ancestries (B).

Recommendation 3.1: In patients who are positive for HLA-B*15:02 or HLA-A*31:01, alternative medications should be used as first-line therapy (A). Consideration in the choice of alternative medications should be given to the possibility of cross-reactivity with structurally similar antiepileptic drugs (AED) (oxcarbazepine, lamotrigine, phenytoin, phenobarbital, primidone).

Recommendation 3.2: In patients who are negative for HLA-B*15:02 and HLA-A*31:01, carbamazepine can be used as first-line therapy (A). However, the occurrence of a hypersensitivity reaction cannot be excluded based on a negative genetic test result.

Please review the complete therapeutic recommendations that are located here: (5).