Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing

Abstract

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA-B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA-B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost-effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org.

Figure 1

Algorithm for suggested clinical actions based on HLA‐B*15:02 and CYP2C9 genotypes. ^aIf patient has previously used phenytoin for longer than 3 months without incidence of cutaneous adverse reactions, reinitiate phenytoin with caution. Adjust dose based on CYP2C9 genotype if known. ^bCarbamazepine should not be used as an alternative. ⁴ Alternative medications such as oxcarbazepine, eslicarbazepine acetate, and lamotrigine have some evidence linking SJS/TEN with the HLA‐B*15:02 allele, and thus caution should be used in choosing alternatives to phenytoin (see Supplementary Material online for details). ^cRecommended maintenance dose based on patient's clinical characteristics. EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; SJS/ TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis.