Genetic testing to avoid phenytoin hypersensitivity and toxicity
Genetic testing can identify individuals at increased risk of developing a severe cutaneous adverse reaction to phenytoin, or who require lower maintenance doses to avoid toxicity. Variations in a number of genes can have a significant impact on the patient’s response to standard dosing with phenytoin. Testing for these variants can identify patients at increased risk of a hypersensitivity reaction or who may develop toxicity on standard dosing. A recent publication from the Clinical Pharmacogenomics Implementation Consortium (CPIC) provides explicit guidance about prescribing for patients with these variants.1
Hypersensitivity to phenytoin
The HLA-B*15:02 variant is associated with an increased risk of developing a severe cutaneous adverse reaction (SCAR) to phenytoin. The frequency of people with this variant ranges from less than one per thousand (Caucasians) to 45 per thousand (for example, Asians) in different ethnic groups.2 The association between this HLA variant and SCAR is not absolute, with the sensitivity and specificity of an HLA test for the occurrence of SCAR being well below 100%. That said, the SCAR associated with HLA*15:02 and phenytoin can be severe, for example, Stevens-Johnson syndrome/toxic epidermal necrolysis. CPIC makes the following recommendation:
– For patients who are phenytoin-naïve and who have the HLA*15:02 variant, avoid phenytoin. Carbamazepine (and derivatives) should also be avoided as the association of this HLA variant with SCAR is even stronger with carbamazepine.
If the patient has previously used phenytoin continuously for at least 3 months without evidence of hypersensitivity, the risk of subsequently developing a SCAR is low. SCAR in response to phenytoin typically presents within 3 months of commencing therapy. Note that absence of the HLA*15:02 variant makes SCAR less likely, but does not exclude this possibility.
Toxicity from standard doses of phenytoin
Variants in the CYP2C9 gene can significantly alter the rate at which phenytoin is metabolised. There is no need to modify the loading dose (based on body weight), but the maintenance dose may need to be reduced. CPIC makes the following recommendation:
– For patients who are poor- to intermediate-metabolisers of phenytoin (Activity Score ≤1), the initial maintenance dose should be reduced by 25–50%, with subsequent doses being based on therapeutic drug monitoring.
Screening for the HLA-B*15:02 variant is available nationally through Sonic Genetics (click here for test details). Testing for CYP2C9 variants is included in the Sonic PGx Panel (click here for test details).
Therapeutic drug monitoring of phenytoin is available through Sonic Healthcare pathology practices, and is Medicare-rebated.