Phenytoin and Skin-related Side Effect in Particular HLA-aplotipe Population

Author: Luca Bresciano
Date: 11/12/2014


Luca Bresciano & Lucia Caramellino


Phenytoin is a hydantoin-derivative anticonvulsant drug used primarily in the management of complex partial seizures and generalized tonic-clonic seizures. Phenytoin is also used to prevent seizures following neurosurgery.
Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage-gated sodium channels. Additionally, phenytoin is a class 1b antiarrhythmic that can be used to treat cardiac arrhythmias when conventional options have failed or after cardiac glycoside intoxication.
Phenytoin targets voltage-gated sodium channels in the brain. Voltage-gated sodium channels are heteromeric complexes consisting of a large glycosylated alpha subunit (approximately 260 kD) and 2 smaller beta subunits (33-39 kD).
The voltage-gated sodium channels are coded for by the SCN family of genes, which has members expressed in heart and skeletal muscle as well as the peripheral and central nervous systems. Phenytoin binds the channel preferentially in the open formation. It is thought that phenytoin blocks sodium channels poorly at slow firing rates allowing normal brain activity but suppresses the high frequency repetitive firing characteristic of seizures.


Hydantoin, is a heterocyclic organic compound with the formula CH2CNHCNH. It is a colorless solid that arises from the reaction of glycolic acid and urea. It is an oxidized derivative of imidazolidine.
In a more general sense, hydantoins can refer to a groups and a class of compounds with the same ring structure as the parent.
Phenytoin, which derivated from hydantoin, has two phenyl groups substituted onto the number 5 carbon in a hydantoin molecule.
Phenytoin is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2, 4-imidazolidinedione, having the following structural formula:


  • Seizures
    • Grand mal - Tonic–clonic seizure
    • Partial seizures
    • Absence seizures
    • Seizures during surgery
    • Status epilepticus
  • Other
    • Cardiac dysrhythmia
    • Digoxin toxicity
    • Trigeminal neuralgia
    • Wound healing


The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with recommended doses of 300 mg/day.
When serum level determinations are necessary, they should be obtained at least 5 to 7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration.
Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin.
In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.
Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.


Phenytoin produces its anticonvulsant activity through blocking sustained high frequency repetitive firing of action potentials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady state inactivation.
Sodium channels exist in three main conformations:

  1. Resting state
  2. Open state
  3. Inactive state

Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissociate from the inactive channel, there is a time dependent block of the channel. Since the fraction of inactive channels is increased by membrane depolarization as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials.
The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses which prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures.


Several studies have reported associations between genomic variation and dose, metabolic ratios or plasma drug levels; relatively few have explored their roles in drug resistance and adverse drugs reactions (ADRs).
Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability partly due to genetic variations in CYP2C9. Furthermore, the variant allele of human leukocyte antigen B (HLA-B*15:02) is associated with an increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in response to phenytoin treatment.

Hepatic CYP2C9 enzyme contributes to the metabolism of many clinically relevantdrugs, including phenytoin.
The CYP2C9 gene is highly polymorphic, having more than 50 known variant alleles. Individuals homozygous for the reference CYP2C9 allele (CYP2C9*1) have the “normal metabolizer” phenotype.
Each named CYP2C9 star (*) allele is defined by a genotype at one or more specific single-nucleotide polymorphisms (SNPs) with variable enzyme activity.
The two most common variants with reduced enzyme activity in Europeans are CYP2C9*2 and CYP2C9*3.

Clinical genotyping test results for HLA-B*15:02 are interpreted as “positive” if one or two copies of HLA-B*15:02 are present or “negative” if no copies of HLA-B*15:02 are present. The allele frequencies of HLA-B vary greatly among populations. Specifically, HLA-B*15:02 is most prevalent in Oceania, East Asian and South/Central Asian populations ranging from 1% to over 10%. It is less frequent in European populations (0-1%) and apparently absent in several African populations. The global average derived from over 46,000 individuals is 1.37%.
Phenytoin and its prodrug fosphenytoin are one of the mainstays of treatment for both focal and generalized convulsive status epilepticus. Dosing is complex owing to its highly unusual pharmacokinetics and requiring adjustments be made in line with patient weight, sex, and age. Outpatient therapy is generally initiated at 5-7 mg/kg/day in adults (slightly higher in children) and may be given once daily (or twice daily in children). Starting dose must be lower in the setting of hepatic impairment. Careful dose adjustments must then be made, generally 30 - 40 mg at a time in 2-week intervals in adults, to stabilize the level within the typical therapeutic range (10 - 20 ug/dL). In urgent situations such as status epilepticus, intravenous loading doses of 15-20 mg/kg are given, followed by maintenance doses, IV or oral, as above. Acute doserelated side effects include sedation, ataxia, dizziness, nystagmus, nausea, and cognitive impairment. The drug is highly allergenic, and rashes ranging from mild eruptions to lifethreatening hypersensitivity reactions may be seen. HLA-B*15:02 is associated with the phenytoin-induced SJS and TEN.
SJS is characterized by epidermal detachment involving up to 10% of body surface area (BSA) while TEN usually affects more than 30% of the BSA. Subacutely, hematologic and hepatic toxicity can occur; the latter is likely a hypersensitivity reaction itself, as it is usually accompanied by rash (7), while the former may consist of leukopenia or pancytopenia. Substantial evidence links CYP2C9 and HLA-B*15:02 genotype with phenotypic variability.

Therapeutic Recommendations

HLA-B*15:02 recommendations. The FDA warning for phenytoin states, “Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLAB* 15:02” due to the increased risk of SJS/TEN in patients of Asian ancestry.” The evidence linking HLA-B*15:02 to phenytoin-induced SJS/TEN was generated in individuals of Asian ancestry as the frequency of HLA-B*15:02 is very low in other populations. However, it may also occur in other populations throughout the world yet to be studied and patients may be unaware of or fail to disclose more distant Asian ancestry in their families. Therefore, regardless of the CYP2C9 genotype and individual's ancestry or age, if the HLA-B*15:02 test result is “positive”, the recommendation is to consider using an anticonvulsant other than carbamazepine and phenytoin unless the benefits of treating the underlying disease clearly outweigh the risks.

Phenotype/GenotypeHLA-B*15:02 carrier
Genotype: 1 or 2 *15:02 alleles; "positive"
HLA-B*15:02 non-carrier
Genotype: No HLA-B*15:02 alleles reported; "negative"
CYP2C9 Extensive Metabolizer
normal activity ~91% of patients
Genotype: An individual carrying 2 normal activity alleles
Example diplotype: *1/*1
Implication: Increased risk of phenytoin-induced SJS/TEN.
Therapeutic Recommendation: If patient is phenytoin-naive , do not use phenytoin/fosphenytoin.
Strength of Recommendation: STRONG
Implication: Normal phenytoin metabolism.
Therapeutic Recommendation: Initiate therapy with recommended maintenance dose .
Strength of Recommendation: STRONG
CYP2C9 Intermediate Metabolizer
heterozygote ~8% of patients
Genotype: An individual carrying one normal activity allele plus one decreased function allele
Example diplotypes: *1/*3, *1/*2
Implication: Increased risk of phenytoin-induced SJS/TEN.
Therapeutic Recommendation: If patient is phenytoin-naive , do not use phenytoin/fosphenytoin.
Strength of Recommendation: STRONG
Implication: Reduced phenytoin metabolism, higher plasma concentrations will increase probability of toxicities.
Therapeutic Recommendation: Consider 25% reduction of recommended starting maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring and response.
Strength of Recommendation: MODERATE
CYP2C9 Poor Metabolizer
homozygous variant ~1% of patients
Genotype: An individual carrying 2 decreased function alleles
Example diplotypes: *2/*2, *3/*3, *2/*3
Implication: Increased risk of phenytoin-induced SJS/TEN.
Therapeutic Recommendation: If patient is phenytoin-naive, do not use phenytoin/fosphenytoin.
Strength of Recommendation: STRONG
Implication: Reduced phenytoin metabolism, higher plasma concentrations will increase probability of toxicities.
Therapeutic Recommendation: Consider 50% reduction of recommended starting maintenance dose. Subsequent maintenance doses should be adjusted according to therapeutic drug monitoring and response.
Strength of Recommendation: STRONG

Another potential risk would be an error in genotyping. Also, many commercially available genotyping tests do not detect alleles that are rare or de novo variants. Other alleles are not well characterized, resulting in uncertainty when predicting the phenotype for some genetic test results.
Moreover, because not all phenytoin-induced adverse events are attributed to HLA-B*15:02 or CYP2C9 metabolizer status, clinicians should carefully monitor all patients according to standard practices.


  • Cardiovascular
    Severe hypotension and cardiac arrhythmias seen with rapid infusion of IV phenytoin.
  • Neurologic
    At therapeutic doses, phenytoin may produce nystagmus on lateral gaze. At toxic doses, patients experience verticalnystagmus, diplopia, sedation, slurred speech, cerebellar ataxia, and tremor.
  • Hematologic
    It has been suggested that phenytoin causes a reduction in folic acid levels, predisposing patients to megaloblastic anemia.
  • Teratogenicity
    Phenytoin is a known teratogen. The syndrome consists of craniofacial anomalies (broad nasal bridge, cleft lip and palate, microcephaly) and a mild form of mental retardation.
  • Gingival
    Phenytoin has been associated with drug-induced gingival enlargement (overgrowth of the gums), probably due to above-mentioned folate deficiency.
  • Dermatologic
    Hypertrichosis, purple glove syndrome, rash, exfoliative dermatitis, pruritis, hirsutism, and coarsening of facial features
    Phenytoin therapy has been linked to the life-threatening skin reactions Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
  • Autoimmune disease
    Phenytoin has been known to cause drug-induced lupus.
  • Immunodeficiency disease
    Phenytoin is also associated with induction of reversible IgA deficiency.
  • Suicidal behavior and ideation
    Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide.
  • Effects on bone
    Chronic phenytoin use has been associated with decreased bone density and increased bone fractures.


  • Monitoring plasma concentrations
    Narrow therapeutic index. Anticonvulsant effect: 10–20 µg/mL; Antiarrhythmic effect: 10–20 µg/mL
  • Avoid giving intramuscular formulation unless necessary due to skin necrosis and local tissue destruction.
  • Geriatric
    May show earlier signs of toxicity.
  • Obese
    Use ideal body weight for dosing calculations.
  • Pregnancy
    Due to risk of fetal hydantoin syndrome and fetal hemorrhage. However, optimal seizure control is very important during pregnancy so drug may be continued if benefits outweigh the risks. Due to decreased drug concentrations during pregnancy, dose of phenytoin may need to be increased if only option for seizure control.
  • Breast feeding
    The manufacturer does not recommend breast feeding because low concentrations of phenytoin is excreted in breast milk.
  • Hepatic Impairment
    Do not use oral loading dose. Consider using decreased maintenance dose.
  • Renal Impairment
    Do not use oral loading dose. Can begin with standard maintenance dose and adjust as needed.
  • IV use is contraindicated in patients with sinus bradycardia, SA block, second- or third-degree AV block, Adams-Stokes syndrome, or have known hypersensitivity to phenytoin or any ingredient in the respective formulation or to other hydantoins.
PharmGKBClinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C9 and HLA-B Genotype and Phenytoin Dosing
DILATIN - PfizerFull prescribing information
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