Impact of genetic variation on response to therapy
The SmPC for phenytoin provides special warnings and precautions in use related to HLA-B and CYP2C9 gene variants which are summarised as follows:
- Limited evidence suggests that HLA-B*15:02 (an inherited allelic variant of the HLA-B gene) may be a risk factor for the development of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin.
- Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B*15:02 positive patients when alternative therapies are available.
- Studies in Taiwanese, Japanese, Malaysian and Thai patients have identified an increased risk of severe cutaneous adverse drug reactions in carriers of the decreased function CYP2C9*3 variant.
- Patients who are carriers of the decreased function CYP2C9*2 or CYP2C9*3 variants (intermediate or poor metabolisers of CYP2C9 substrates) may be at risk of increased phenytoin plasma concentrations and subsequent toxicity.
A 2014 MHRA Drug Safety Alert advises that phenytoin should be avoided in individuals of Thai or Han Chinese ethnic origin who are known to be HLA-B*15:02 positive unless the benefits are thought to outweigh the risks.
Testing recommendations
At the time of publication, there are no UK recommendations for CYP2C9 genotype testing to guide dosing or for HLA-B genotyping to determine the risk of severe cutaneous reactions with phenytoin.
Therapeutic recommendations
Carriers of HLA-B*15:02 (regardless of ancestry):
- Increased risk of severe cutaneous adverse drug reactions including SJS/TEN.
- Avoid phenytoin unless no suitable alternative is available and consider only if the benefits are thought to outweigh the risks (See further information).
- If no suitable alternative is available, increase monitoring and advise on action to take if a skin rash occurs.
CYP2C9 Unknown metaboliser status
- Initiate standard starting or loading dose.
- Monitor efficacy and side effects and titrate according to response and therapeutic drug monitoring.
CYP2C9 Normal metaboliser status: Activity score 2.0
Some examples of CYP2C9 genotypes include: *1/*1
- Initiate standard starting or loading dose.
- Monitor efficacy and side effects and titrate according to response and therapeutic drug monitoring.
CYP2C9 Intermediate metabolisers: Activity score 1.5
Some examples of CYP2C9 genotypes include: *1/*2
- Predictive of slightly higher plasma exposure than normal metabolisers but this does not appear to translate into increased side effects.
- Initiate standard starting or loading dose.
- Monitor efficacy and side effects and titrate according to response and therapeutic drug monitoring.
CYP2C9 Intermediate metabolisers: Activity score 1.0
Some examples of CYP2C9 genotypes include: *1/*3, *2/*2
- Predictive of higher plasma exposure than normal metabolisers.
- Increased potential for toxicity.
- Initiate standard starting or loading dose, consider a 25% reduction in maintenance dose.
- Monitor efficacy and side effects and titrate according to response and therapeutic drug monitoring.
CYP2C9 Poor metabolisers: Activity score 0.5 or 0.0
Some examples of CYP2C9 genotypes include: *2/*3, *3/*3
- Predictive of higher plasma exposure than normal metabolisers.
- Increased potential for toxicity.
- Initiate standard starting or loading dose, consider a 50% reduction in maintenance dose.
- Monitor efficacy and side effects and titrate according to response and therapeutic drug monitoring.
Further information
Drug metabolism and drug interactions
Phenytoin is metabolised by CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions. Variants in CYP2C19 may also contribute to altered phenytoin metabolism although studies evaluating the effect of multiple gene variation and phenytoin dose requirements are limited. Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Patients should be carefully monitored according to standard practices and the SmPC. Consult the SmPC for a list of drug interactions.
Risk of phenytoin-induced SJS/TEN in HLA-B*15:02 carriers
The Dutch Pharmacogenetics Working Group (DPWG) report that the risk of phenytoin-induced SJS/TEN in HLA-B*15:02 carriers is 0.65% (approx. 1 in 150). Phenytoin-induced SJS/TEN occurs more frequently in the first 3 months post initiation of therapy. Even though the incidence and risk are low, SJS/TEN is a life-threatening adverse event and should be avoided if possible.
Ancestry and ethnicity
The evidence linking HLA-B*15:02 to phenytoin-induced SJS/TEN has been generated primarily in individuals of Asian ancestries, which is due to the frequency of HLA-B*15:02 being higher in Asian populations than in other populations. However, HLA-B*15:02 may occur in individuals of any ancestry. Genetic ancestry can be difficult to determine. For example, patients may not always be aware of or disclose ancestry in their families. It is recommended to avoid phenytoin in all individuals who are HLA-B*15:02 positive regardless of ancestry.
Alternative anti-seizure medications
Carbamazepine should be avoided in HLA-B*15:02 carriers and has been shown to carry a 10-fold higher risk of SJS/TEN than phenytoin in HLA-B*15:02 carriers.
Oxcarbazepine, eslicarbazepine and lamotrigine should also be avoided in HLA-B*15:02 carriers unless no suitable alternative is available due to an increased risk of severe cutaneous reactions including SJS/TEN (similar risk to phenytoin).
There is also limited evidence linking an increased risk of SJS/TEN and phenobarbital in HLA-B*15:02 carriers and it is recommended that phenobarbital should be considered only if no suitable alternatives are available and the benefit is thought to outweigh the risks.
Fosphenytoin is a pro-drug of phenytoin. The anti-seizure effects of fosphenytoin are attributable to phenytoin, and the pharmacological and toxicological effects of fosphenytoin include those of phenytoin. The recommendations in this monograph apply to both phenytoin and fosphenytoin.
Users should refer to individual monographs and the SmPCs for alternative agents for further information.
References
Upjohn UK Ltd (2023) Epanutin 30mg/5ml oral suspension SmPC. Available at: https://www.medicines.org.uk/emc/product/2257/smpc (Accessed online 29th January 2026).
Pfizer Ltd (2023) Pro-Epanutin 75mg/ml concentrate for solution for infusion/solution for injection SmPC. Available at: https://www.medicines.org.uk/emc/product/2260/smpc (Accessed online 28th August 2025).
Medicines and Healthcare products Regulatory Agency (2014). Phenytoin: risk of Stevens-Johnson syndrome associated with HLA-B*1502 allele in patients of Thai or Han Chinese ethnic origin. Drug Safety Update. Available at: https://www.gov.uk/drug-safety-update/phenytoin-risk-of-stevens-johnson-syndrome-associated-with-hla-b-1502-allele-in-patients-of-thai-or-han-chinese-ethnic-origin (Accessed online 11th February 2025).
Medicines and Healthcare products Regulatory Agency (2014). Carbamazepine, oxcarbazepine and eslicarbazepine: potential risk of serious skin reactions. Drug Safety Update. Available at: https://www.gov.uk/drug-safety-update/carbamazepine-oxcarbazepine-and-eslicarbazepine-potential-risk-of-serious-skin-reactions
Clinical Pharmacogenetics Implementation Consortium (CPIC®) (2021). CPIC® Guideline for Phenytoin and CYP2C9 and HLA-B. Available at https://cpicpgx.org/guidelines/guideline-for-phenytoin-and-cyp2c9-and-hla-b/ (Accessed online 11th February 2025).
Cite Manson LEN et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs. Eur J Hum Genet. 2024 Aug;32(8):903-911. doi: 10.1038/s41431-024-01572-4. Epub 2024 Apr 3. PMID: 38570725; PMCID: PMC11291682.
