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Pharmacogenetics - The Rational for Patients of Asian Descent Having HLA Genetic Testing Before Using Carbamazepine

Summary:

  • Carbamazepine (Carbatrol; Equetro; Tegretol) is an anticonvulsant commonly used for the treatment of acute manic and mixed episodes associated with bipolar I disorder, epilepsy, and trigeminal neuralgia that is associated causing hypersensitivity reactions that most commonly involves the skin that can include Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN).
  • Patients of Asian descent (specifically Han Chinese) are at greatest risk for developing SJS and/or TEN when treated with carbamazepine and have a high association for being for the human leukocyte antigen (HLA)-B*1502 allele.   While not confirmed patients from India, Singapore, Malaysia and possibly Thailand appear to also have higher incidences for this adverse drug reaction.
  • As such, the FDA required all of the manufacturers to add a black box warning to their product package inserts that not only informed healthcare providers about this adverse drug reaction, but to also state that, "patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to initiating carbamazepine."  The "at-risk populations" referenced here refers to several Asian countries not just the Han Chinese from Taiwan.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewer:
  Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed:
August 2015

Explanation

  • The use of carbamazepine (Carbatrol; Equetro; Tegretol) is common for the treatment of acute manic and mixed episodes associated with bipolar I disorder, epilepsy, and trigeminal neuralgia.1,2 Unfortunately, carbamazepine is associated with a number of problems and/or side effects one of which includes hypersensitivity reactions that most commonly involves the skin, but is also associated with other organs (liver, kidneys) as well.3  Many patients will typically exhibit a triad of fever, rash, and lymphadenopathy, but are also known to have eosinophilia and atypical lymphocytosis.3,4  As it relates to the hypersensitivity reaction involving the skin, the condition can range from a mild skin rash (generalized exanthematous eruptions) to the development of life-threatening skin reactions that include Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN).3-6  While the incidence in the general population is low, the development of SJS and TEN can lead to an increase in morbidity and mortality.5-7  

    Are there any risk factors that predispose patients to carbamazepine induced SJS and/or TEN?
    Yes.  It appears that patients of Asian descent (specifically Han Chinese) are at greatest risk for developing SJS and/or TEN when treated with carbamazepine.8-14  Case-controlled studies have now shown a high association of these patients to also be positive for the human leukocyte antigen (HLA)-B*1502 allele.8,9  As a short review, HLA-B is one type of the class I human major histocompatibility complexes that are used to present antigens (short peptide fragments of self and non-self) to cytotoxic CD8+ T-lymphocytes (or natural killer cells) of the immune system.  When circulating CD8+ T-lymphocytes come in proximity to nucleated cells with antigen bound to HLA-B, the T-cell receptors on these CD8+ T-lymphocytes will interact with the HLA-B proteins to "read" the antigen being presented.  If the CD8+ T-cells "see" or "read" the antigen being presented as foreign or "non-self", it will then become activated with the final result being death to that cell.  Therefore, the interaction between the antigen (peptide) and the HLA-B molecule can influence how the CD8+ T-lymphocyte will respond.  Certain genotypes (or variations) for the HLA-B proteins may then cause the immune system to see combination of the antigen bound HLA-B complex as something foreign enough to feel the need to kill or clear that cell from the body.  It is important to know that patients of Asian descent with the HLA-B*1502 allele and who are taking carbamazepine have an estimated odds ratio (OR) of 1357 (95% confidence interval: 193.2 - 8838.3; p<1.6 x 10-21).9  Assuming a 0.25% incidence of carbamazepine-induced SJS and/or TEN in newly prescribed patients and a 3% false positive rate for HLA-B*1502, the estimated performance of screening tests in this population of high risk patients would be a 98.3% sensitivity, 97% specificity, 7.7% positive predictive value and a 100% negative predictive value.14  While additional studies are needed, this adverse drug reaction appears to also put patients from India, Singapore, Malaysia and possibly Thailand at increased risk due to their greater likelihood of having the HLA-B*1502 allele.11-14   

    The above information led the FDA to require all of the manufacturers add a black box warning to their product package inserts that not only informed healthcare providers about this adverse drug reaction but to also state that,  "patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 allele prior to initiating carbamazepine."8  The "at-risk populations" referenced here refers to several Asian countries not just the Han Chinese from Taiwan. 

    Why is the FDA's recommendation limited to patients of Asian descent? 
    Interestingly, two studies of Caucasians of non-Asian ancestry who were positive for the HLA-B*1502 allele failed to show a correlation between the development of SJS and/or TEN while taking carbamazepine.15,16  This suggests that something else in addition to having HLA-B*1502 alleleis related to the increased risk for developing carbamazepine-induced SJS and/or TEN.  Until further evidence becomes available it does not appear that the screening of patients with no Asian ancestry is of significant value.  

    In most cases this adverse reaction will start in the first 8 weeks of carbamazepine therapy.6  If a patient develops this adverse drug reaction (regardless of the type of HLA-B) while on carbamazepine, immediate discontinuation of carbamazepine is essential.17,18 While no single treatment intervention is most effective, many patients with SJS and/or TEN will require admission to the intensive care unit (ICU) or burn unit where the use of corticosteroids, cyclosporin and intravenous immunoglobulin are sometimes used to modulate the immune system.18  This article, in addition to several others at EBM Consult not only reveal the growing complexity in drug therapy, but how among many patient specific factors, the influence of a patient's genotype can also contribute to the safety and efficacy of drug therapy.

    References:

    1. Carbamazepine extended release capsules (Carbatrol) product package insert.  Schire US Inc.  Wayne, PA.  April 2009.
    2. Carbamazepine extended release capsules (Equetro) product package insert.  Validus Pharmaceuticals Inc.  Parsippany, NJ.  December 2007.
    3. Vittorio CC, Muglia JJ.  Anticonvulsant hypersensitivity syndrome.  Arch Intern Med  1995;155:2285-90. 
    4. Shear NH, Spielberg SP.  Anticonvulsant hypersensitivity syndrome.  In vitro assessment of risk.  J Clin Invest 1988;82:1826-32.  
    5. Tennis P, Stern RS.  Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study.  Neurology  1997;49:542-6.  
    6. Rzany B, Correia O, Kelly JP et al.  Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study.  Study group of the International Case Control Study on Severe Cutaneous Adverse Reactions.  Lancet  1999;353:2190-4.  
    7. Roujeau JC, Stern RS.  Severe adverse cutaneous reactions to drugs.  N Engl J Med  1994;331:1272-85.  
    8. United States Food and Drug Administration.  Carbamazepine (marketed as Carbatrol, Equetro, Tegreto and generics).  MedWatch The FDA Safety Information and Adverse Event Reporting Program.  December 12, 2007.  Last accessed on 08/06/2009.  
    9. Chung WH, Hung SI, Hong HS et al.  Medical genetics: a marker for Stevens-Johnson syndrome.  Nature  2004;428:486.  
    10. Hung SI, Chung WH, Jee SH et al.  Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions.  Pharamcogenet Genomics  2006;16:297-306.  
    11. Devi K, George S, Criton S et al.  Carbamazepine-the commonest cause of toxic epidermal necrolysis and Stevens-Johnson syndrome: a study of 7 years.  Indian J Dermatol Venereol Leprol  2005;71:325-8.  
    12. Sharma VK, Sethuraman G, Kumar B et al.  Cutaneous adverse drug reactions: clinical pattern and causative agents-a 6 year series from Chandigarh, India.  J Postgrad Med  2001;47:95-9.  
    13. Kamaliah MD, Zainai D, Mokhtar N et al.  Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in northeastern Malaysia.  Int J Dermatol  1998;37:520-3.  
    14. Ferrell PB Jr., McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations.  Pharmacogenomics  2008;9:1543-6.  
    15. Alfirevic A, Jorgensen AL, Williamson PR et al.  HLA-B locus in Caucasian patients with carbamazepine hypersensitivity.  Pharmacogenomics  2006;7:813-8.  
    16. Lonjou C, Thomas L, Borot N et al.  A marker for Stevens-Johnson syndrome...:ethnicity matters.  Pharmacogenomics J  2006;6:265-8.  
    17. Garcia-Doval I, LeCleach L, Bocquet H et al.  Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?  Arch Dermatol  2000;136:323-7.  
    18. Khalili B, Bahna SL.  Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis.  Ann Allergy Asthma Immunol  2006;97:272-80.

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MESH Terms & Keywords

  • Carbamazepine, Tegretol, Carbatrol, Equetro, Anticonvulsant, HLA Mutations, Genetic Testing, Pharmacogenetics