Annotation of DPWG Guideline for lamotrigine and HLA-B

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Summary

Avoid lamotrigine in patients with HLA-B*15:02 if an alternative is available. If avoidance is not possible, advise to report any rash immediately.

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Important information about alleles in DPWG guidelines.

Annotation

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Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs. European journal of human genetics (2024)

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group published a paper with the guidelines as per the May 2021 guidelines including more details and scoring the clinical implementation [Article:39676086].

The phenotype name was changed from HLA-B*1502 to HLA-B*1502 positive, which is reflected in the table below. The "Description" section in the table below was updated based on content from Supplementary table 18.

The Clinical Implication Score for HLA-B*15:02-lamotrigine and HLA-B*15:02-oxcarbazepine is “beneficial” in patients of Asian descent other than Japanese descent, based on the criteria and corresponding scores given by the DPWG, for detailed information see Supplementary table 20d.

May 2021

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for lamotrigine based on HLA-B*15:02.

Wording in table taken from the Dutch guidelines May 2021 update.

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Allele/Genotype/Phenotype	Drug	Description	Recommendation
HLA-B*1502 positive	lamotrigine	The life-threatening cutaneous side effect Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in the first three months occurs more often in patients with this genetic variation. Based on the estimated risk for all patients and the increase by a factor 2.4-7.9 for patients with this genetic variation, the risk of lamotrigine-induced SJS/TEN in patients with HLA-B*1502 is estimated at 0.24-0.79%.	- Carefully weigh the risk of SJS/TEN against the benefits. - Avoid lamotrigine if an alternative is possible. Carbamazepine carries a much higher risk of SJS/TEN in these patients and is therefore not an alternative. A similar risk has been reported for phenytoin as for lamotrigine. The same applies to oxcarbazepine, but the most severe forms (SJS/TEN overlap and TEN) have not been observed with oxcarbazepine. - If it is not possible to avoid lamotrigine, advise the patient to report any skin rash immediately.

Read for more information about this recommendation, Read about gene information from DPWG

Preemptive genotyping

Excerpts from the DPWG risk analysis document for lamotrigine and HLA:

HLA-B*1502 has not been detected in a sample of 1350 Dutch persons (Allele Frequency Net Database: http://www.allelefrequencies.net). For this reason, the KNMP Pharmacogenetics Working Group does not consider genotyping of Dutch patients in general before starting lamotrigine to be useful. However, the HLA-B*1502 frequency is high in Asians, except for Japanese and Koreans. In Japanese the HLAB*1502 frequency is very low (< 0.1%). In Korea, it is less than 1% in some populations and more than 1% in other populations, with a mean of approximately 2% according to the SmPC of carbamazepine. The KNMP Pharmacogenetics Working Group considers genotyping of patients of Asian descent other than Japanese descent before starting lamotrigine to be beneficial for drug safety. It is advised to consider genotyping these patients before (or directly after) drug therapy has been initiated to guide drug selection.

PharmGKB ID

PA166265341