This section contains excerpted
1
information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
2018 Statement from the US Food and Drug Administration (FDA)
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).
2015 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)
HLA-B*15:02: CARBAMAZEPINE
Patients with this genetic variation have a severely increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced SJS/TEN in these patients is 1.8-3.4%.
Recommendation:
- choose an alternative if possible
HLA-A*31:01: CARBAMAZEPINE
Patients with this genetic variation have an increased risk of experiencing the life-threatening cutaneous adverse events DRESS and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced DRESS in these patients is 0.89%.
Recommendation:
- carefully weigh the risk of DRESS and SJS/TEN against the benefits
- if an alternative is an option, choose an alternative
HLA-B*15:11: CARBAMAZEPINE
Patients with this genetic variation have an increased risk of experiencing the life-threatening cutaneous adverse event Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The risk of carbamazepine-induced SJS/TEN in patients with the HLA-B*15:02 allele, which carries a 4.6-6.6 times higher risk than the HLA-B*15:11 allele, is 1.8-3.4%. This would equate to a risk of carbamazepine-induced SJS/TEN in these patients of 0.27-0.73%.
Recommendation:
- carefully weigh the risk of SJS/TEN against the benefits
- if an alternative is an option, choose an alternative
Please review the complete therapeutic recommendations that are located here: (2)
.
2017 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC)
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).
2014 Recommendations from the Canadian Pharmacogenomics Network for Drug Safety (CPNDS)
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.
Table 7. Grading scheme used for clinical practice recommendations| Table adapted from: Amstutz, U., N.H. Shear, M.J. Rieder, S. Hwang, 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(4): p. 496-506 (5). |
| Level | Strength | Evidence basis |
|---|
| A | Strong | Based on strong scientific evidence; benefits clearly outweigh risks |
| B | Moderate | Based on reduced confidence scientific evidence and expert opinion;
benefits likely to outweigh risks |
| C | Optional | Based mainly on expert opinion,
for use with evidence development in a research context |
Please review the complete therapeutic recommendations that are located here:
(5).
Table 3. CPIC (2016) Recommendations for Carbamazepine Therapy based on HLA-B and HLA-A Genotype.| DRESS, drug reaction with eosinophilia and systemic symptoms; MPE, maculopapular exanthema; N/A, not applicable; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.a
If only HLA-B*15:02 was tested, assume HLA-A*31:01 is negative and vice versa. b
HLA-B*15:02 has a 100% negative predictive value for carbamazepine-induced SJS/ TEN, and its use is currently recommended to guide the use of carbamazepine and oxcarbazepine only. Because there is a much weaker association and less than 100% negative predictive value of HLA-B*15:02 for SJS/TEN associated with other aromatic anticonvulsants, using these drugs instead of carbamazepine or oxcarbazepine in the setting of a negative HLA-B*15:02 test in Southeast Asians will not result in prevention of anticonvulsant-associated SJS/TEN.c
In addition to HLA-B*15:02, the risk for carbamazepine-induced SJS/TEN has been reported in association with the most common B75 serotype alleles in Southeast Asia, HLA-B*15:08, HLA-B*15:11, and HLA- B*15:21. Although not described, the possibility of carbamazepine-induced SJS/TEN in association with less frequently carried B75 serotype alleles, such as HLA- B*15:30 and HLA-B*15:31, should also be considered. d
Aromatic anticonvulsants include carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, and phenobarbital. |
| This table is adapted from Phillips EJ, Sukasem C, Whirl-Carrillo M, Müller DJ, Dunnenberger HM, Chantratita W, Goldspiel B, Chen YT, Carleton BC, George ALJ, Mushiroda T, Klein T, Gammal RS, and Pirmohamed M. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clinical pharmacology and therapeutics (4). |
| Genotypea
| Implication | Therapeutic recommendation | Classification of recommendations | Considerations for other aromatic anticonvulsants |
|---|
| HLA-B*15:02 negative and HLA-A*31:01 negative | Normal risk of carbamazepine-induced SJS/TEN, DRESS, and MPE | Use carbamazepine per standard dosing guidelines.b
| Strong | N/A |
| HLA-B*15:02 negative and HLA-A*31:01 positive | Greater risk of carbamazepine-induced SJS/TEN, DRESS, and MPE | If patient is carbamazepine-naïve and alternative agents are available, do not use carbamazepine. | Strong | Other aromatic anticonvulsantsd
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 patient is carbamazepine-naïve and alternative agents are not available, consider the use of carbamazepine with increased frequency of clinical monitoring. Discontinue therapy at first evidence of a cutaneous adverse reaction. | Optional | N/A |
| The latency period for cutaneous adverse drug reactions is variable depending on phenotype; however, all usually occur within three months of regular dosing. Therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine. | Optional | Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.d
|
| HLA-B*15:02 positivec
and any HLA-A*31:01 genotype (or HLA-A*31:01 genotype unknown) | Greater risk of carbamazepine-induced SJS/TEN | If patient is carbamazepine-naïve, do not use carbamazepine. | Strong | Other aromatic anticonvulsantsd
have weaker evidence linking SJS/TEN with the HLA-B*15:02 allele; however, caution should still be used in choosing an alternative agent. |
| The latency period for drug-induced SJS/TEN is short with continuous dosing and adherence to therapy (4-28 days), and cases usually occur within three months of dosing; therefore, if the patient has previously used carbamazepine consistently for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of carbamazepine in the future. | Optional | Previous tolerance of carbamazepine is not indicative of tolerance to other aromatic anticonvulsants.d
|
Table 6. CPIC (2017). Assignment of likely HLA-B and HLA-A genotype| a
. Where *X 5 any HLA-B allele other than HLA-B*15:02. b
Where *Y 5 any HLA-A allele other than HLA-A*31:01. |
| Table is adapted from Phillips EJ, Sukasem C, Whirl-Carrillo M, Müller DJ, Dunnenberger HM, Chantratita W, Goldspiel B, Chen YT, Carleton BC, George ALJ, Mushiroda T, Klein T, Gammal RS, and Pirmohamed M. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clinical pharmacology and therapeutics (4). |
| Genotype | Definition | Examples of diplotypes |
|---|
| HLA-B*15:02 negative | Homozygous for an allele other than HLA-A*15:02 | *X/*Xa
|
| HLA-B*15:02 positive | Heterozygous or homozygous variant | *15:02/*Xa
, *15:02/*15:02 |
| HLA-A*31:01 negative | Homozygous for an allele other than HLA-A*31:01 | *Yb
/*Yb
|
| HLA-A*31:01 positive | Heterozygous or homozygous variant | 31:01/*Yb
, *31:01/*31:01 |
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The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations where necessary, other author insertions are shown in square brackets.