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Test Catalog

Test ID: CARPO    
Carbamazepine Hypersensitivity Pharmacogenomics, Saliva

Useful For Suggests clinical disorders or settings where the test may be helpful

Identifying individuals with increased risk of carbamazepine- or oxcarbazepine-associated cutaneous adverse reactions

 

Genotyping patients who prefer not to have their blood drawn

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

Detection of the HLA-B*15:02 allele (HLA00165) in the HLA-B gene (NM_005514).

 

Detection of the HLA-A*31:01 allele (HLA00097) in the HLA-A gene (NM_001242758).

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Carbamazepine is an aromatic anticonvulsant. Oxcarbamazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital are also in this category. Carbamazepine is FDA-approved for the treatment of epilepsy, 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%. 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.

 

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 less than 1% frequency in Japanese and Koreans. 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 very limited evidence associating SJS/TEN/DRESS or MPE and other aromatic anticonvulsants in patients who are positive for HLA-B*15:02.

 

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 ethnicity but 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 most recent Clinical Pharmacogenetic Implementation Consortium (CPIC) guideline, patients who are HLA-B*15:02 positive should not be prescribed carbamazepine or oxcarbamazepine 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 is the subject of a separate CPIC guideline with recommendations to avoid phenytoin 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. However, although very limited evidence links SJS/TEN/DRESS/MPE with other aromatic anticonvulsants among HLA-A*31:01-positive patients, caution should be used in selecting an alternative medication.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Rare, reported or unreported HLA-A and HLA-B alleles may occur and may interfere with this assay resulting in a false-positive or false-negative call. Examples of alleles that may interfere include other HLA-A*31 alleles (including HLA-A*31:01:23), HLA-B*15:13, HLA-B*15:31, HLA-B*15:55, HLA-B*15:88, HLA-B*15:89, HLA-B*18:20, HLA-B*15:112, HLA-B*15:121, HLA-B*15:144, and HLA-B*15:170. However, most of these alleles are rare and exist only in specific ethnicities and it is not known if any of these subtypes are associated with hypersensitivity. For example, HLA-B*15:13, while rare, has been observed more in Asian populations than other populations.

 

Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic hematopoietic stem cell transplantation (AHSCT). Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. The impact of AHSCT on risk of adverse cutaneous reactions is not defined in the literature.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Phillips EJ, Sukasem C, Whirl-Carrillo M, et al: Clinical Pharmacogenetics Implementation Consortium guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther 2018;103(4):574-581

2. Caudle KE, Rettie AE, Whirl-Carrillo M, et al: Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharacol Ther 2014;96(5):542-548

3. McCormack M, Alfirevic A, Bourgeois S, et al: HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011;364:1134-1143

4. Amstutz U, Shear NH, Rieder MJ, et al: Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia 2014;55:496-506 

5. Caudle KE, Rettie AE, Whirl-Carrillo M, et al: Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing. Clin Pharmacol Ther 2014;96(5):542-548

Special Instructions Library of PDFs including pertinent information and forms related to the test