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Test ID: CARBR Carbamazepine Hypersensitivity Pharmacogenomics, Varies


Specimen Required


Multiple genotype tests can be performed on a single specimen after a single extraction. See Multiple Genotype Test List in Special Instructions for a list of tests that can be ordered together. 

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

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 Stability Information: Ambient (preferred) 9 days/Refrigerated 30 days

 

Specimen Type: Saliva

Supplies: Saliva Swab Collection Kit (T786)

Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.

Specimen Volume: 1 swab

Collection Instructions: Collect and send specimen per kit instructions.

Specimen Stability Information: Ambient 30 days

 

Specimen Type: Extracted DNA

Container/Tube: 2 mL screw top tube

Specimen Volume: 100 mcL (microliters)

Collection Instructions:

1. The preferred volume is 100 mcL at a concentration of 50 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred) 1 year/Ambient/Refrigerated


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 1of the following forms with the specimen:

-Therapeutics Test Request (T831)

-Neurology Specialty Testing Client Test Request (T732)

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, V

Specimen Type

Varies

Specimen Minimum Volume

0.35 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Clinical Information

Carbamazepine and oxcarbazepine are aromatic anticonvulsants, as are eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. Carbamazepine is 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.

 

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 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 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 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) Performed

Monday, Wednesday through Friday

Report Available

1 to 5 days

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 US Food and Drug Administration.

CPT Code Information

81381 x 2

LOINC Code Information

Test ID Test Order Name Order LOINC Value
CARBR Carbamazepine PGx Panel, V 94855-4

 

Result ID Test Result Name Result LOINC Value
610657 HLA-A*31:01 Genotype 79712-6
610658 HLA-B*15:02 Genotype 57979-7
610659 Carbamazepine PGx Panel Phenotype 93308-5
610660 Interpretation 69047-9
610661 Additional Information 48767-8
610662 Method 85069-3
610663 Disclaimer 62364-5
610664 Reviewed by 18771-6
Mayo Clinic Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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