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Test ID: CARPB Carbamazepine Hypersensitivity Pharmacogenomics, Blood

Useful For

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

Method Name

Qualitative Allele-Specific Real-Time Polymerase Chain Reaction (PCR)

Reporting Name

Carbamazepine PGx Panel, B

Specimen Type

Whole Blood EDTA


Specimen Required


Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.


Specimen Minimum Volume

0.35 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)
  Refrigerated 

Clinical Information

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

An interpretive report will be provided.

Interpretation

The presence of the HLA-B*15:02 and/or HLA-A*31:01 allele confers increased risk for hypersensitivity to carbamazepine. The presence of the HLA-B*15:02 allele also confers increased risk for hypersensitivity to oxcarbazepine and phenytoin.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Clinical Reference

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

Day(s) and Time(s) Performed

Monday, Wednesday through Friday, 8 a.m.

Analytic Time

1 day (not reported Saturday or Sunday)

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81381 x 2

LOINC Code Information

Test ID Test Order Name Order LOINC Value
CARPB Carbamazepine PGx Panel, B In Process

 

Result ID Test Result Name Result LOINC Value
37296 HLA-A3101 Genotype 79712-6
37297 HLA-B1502 Genotype 57979-7
37298 Carbamazepine PGx Panel Phenotype In Process
37299 Carbamazepine PGx Panel Interpretation In Process
37407 Reviewed by 18771-6

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

-Neurology Specialty Testing Client Test Request (T732)

-Pharmacogenomics Test Request (T797)

Mayo Clinic Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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