Phenytoin - CYP2C9 and HLA-B

The drug phenytoin (Dilantin® or Phenytek® and generics) is part of the drug class known as anticonvulsants. Phenytoin is used to prevent and control seizures, including in patients who undergo neurosurgery. Seizures are caused by sudden, uncontrolled outbursts of electrical activity in the brain, which cause physical symptoms such as muscle spasms in various regions of the body (convulsions). Phenytoin functions to reduce abnormal electrical activity in the brain, thereby reducing the potential for convulsive episodes. When a patient is prescribed this drug, the dosing regimen must be carefully monitored as there is a large variability in response to this medication. This variability in response is explained by different genetic mutations in key enzymes, which are chemicals made by your body, that are responsible for processing or metabolizing phenytoin.

There are two genes that are essential to processing phenytoin in the body. The first gene is responsible for production of the CYP2C9 (pronounced “sip-two- see-nine”) enzyme, which is involved in the metabolism of many common drugs. Phenytoin is one such drug that interacts with the CYP2C9 enzyme, and in doing so the drug is converted to inactive forms that are eventually eliminated from the body. Genetic variation of CYP2C9 is most common in North African and European populations, whereas it is extremely rare in Asian populations.

HLA-B is the second gene, and it is a gene that belongs to a broader class of genes that play a critical role in the immune system related to recognizing an infection. The HLA-B gene, specifically, is responsible for producing proteins found on the surface of most cells. These proteins let your immune system know that these cells are normal. Should the immune system identify foreign viral or bacterial peptides, it triggers self-destruction of the infected cell. The HLA-B gene has many possible variations. The specific gene of interest is called HLA-B*1502. Having the HLA-B*1502 allele has been found to occur almost exclusively in people of Asian descent. The HLA-B*1502 allele is present in 10-15% or more of patients in parts of China, Thailand, Malaysia, Indonesia, the Philippines, and Taiwan. However, only about 2-4% of South Asians, including Indians, and less than 1% of those of Japan and Korean descent are likely to have the HLA-B*1502 allele.

Variations in the genes responsible for encoding CYP2C9 cause differences in individual response to phenytoin. Variation in the CYP2C9 gene can results in a decreased ability to break down (or metabolize) the drug, resulting in a higher concentration of the active form present in the body. This can cause toxicity which can damage the brain and lead to a variety of related complications. Patients with CYP2C9 gene variation require lower doses of phenytoin to avoid toxic adverse effects. Patients who are “intermediate metabolizers” should have a 25% reduction in the starting maintenance dose. “Poor metabolizers” should have a 50% reduction in the starting maintenance dose.

Phenytoin is contraindicated in individuals with HLA-B*1502 because there is a strong association between the presence of HLA-B*1502 and the risk of developing Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Both of these are very serious skin reactions. Use of this drug should be avoided if a patient is found to be a carrier of HLA-B*1502 regardless of any other factor. For individuals who test positive for HLA-B*1502, the recommendation is to use an alternative anticonvulsant. Medications similar in molecular structure to phenytoin, such as fosphenytoin, carbamazepine, oxcarbazepine, eslicarbazepine acetate, and lamotrigine should also be avoided or used with caution in patients with the HLA-B*1502 allele because they have also been found to have an increased risk of developing SJS and TEN. Individuals who test negative for HLA-B*1502, on the other hand, can be given phenytoin according to normal dosing recommendations because these individuals do not possess a high risk of developing SJS and TEN.

A 35 year old male Caucasian, Brian, was admitted to the hospital via ambulance for status epilepticus. He was stabilized and then treated with IV lorazepam to stop the seizure. He was then initiated on IV phenytoin to control any extra episodes. Upon conducting a medication history with a family member, it was found that Brian had a history of seizures when he was a child and they have gone largely untreated. The next day, the patient broke out in a severe rash characterized by blisters and skin becoming detached. He was diagnosed with a phenytoin-induced reaction of Stevens-Johnson syndrome. Following treatment of SJS, he was switched to valproic acid for maintenance therapy. Lab tests later came back and showed that this patient was a HLA-B*1502 carrier and a CYP2C9 extensive metabolizer. Had this information been known prior to the neurologic emergency that got him admitted to the ER, the providers would have avoided phenytoin as well as carbamazepine as these are associated with a higher incidence of SJS in HLA-B*1502 carriers.

CYP2D6 and HLA-B testing does not completely rule out the risks of taking phenytoin, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximize benefit, and minimize harm.

The links below provide access to important articles and information relative to phenytoin. The links are to external websites and will be checked regularly for consistency.

• Phenytoin Prescribing Information
• Phenytoin Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Phenytoin

Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23.

Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. 2015. Phenytoin; [2014 Aug 6; cited 2015 Mar 01]; [2 screens]. Available from: http://www.clinicalpharmacology-ip.com/Forms/drugoptions.aspx?cpnum=484&n=Phenytoin&t=0/.

Extended phenytoin sodium. DailyMed. 2015-08. URL: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e467c02-49a0-4b62-b537-430fdfa4f10e. Accessed: 2015-11-23.

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2015. Extended Phenytoin Sodium; [cited 2015 Nov 23]; [about 4 screens]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e467c02-49a0-4b62-b537-430fdfa4f10e/.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2015. Phenytoin; [cited 2015 March 1]; [about 4 screens]. Available from: https://www.pharmgkb.org/chemical/PA450947/.