II. Classification: Hydantoin

  1. Phenytoin (Dilantin)
  2. Fosphenytoin (Cerebyx)
  3. Phenytoin congeners (limited use)
    1. Mephenytoin
    2. Ethotoin
    3. Phenacemide

III. History

  1. Phenytoin Oldest non-sedative antiepileptic drug (1938)
  2. Based on research into phenobarbital antiseizure effect

IV. Indications

  1. Partial Seizures
  2. Generalized tonic-clonic Seizures

V. Contraindications

  1. Pregnancy (See Fetal Hydantoin Syndrome)

VI. Pharmacokinetics: Phenytoin

  1. Fosphenytoin (Cerebyx) has similar pharmacokinetics to Phenytoin
  2. Hepatic metabolism
  3. Highly protein bound
  4. Onset: 10-30 minutes
  5. Half-life: 12 to 24-36 hours
    1. Average half life for moderate dosages: 24 hours
    2. Very long half-life at toxic concentrations
  6. Therapeutic level: 10-20 mcg/ml

VII. Dosing: Phenytoin or Dilantin (Adults)

  1. Status Epilepticus
    1. Dose: 20 mg/kg IV (at 1 mg/kg/min up to 50 mg/min) up to to 1000 mg maximum
    2. May repeat once with Phenytoin 5-10 mg/kg IV
    3. Maintenance with Phenytoin 50 mg/min
  2. Loading dose
    1. Oral loading regimen
      1. Dose 1: 400 mg orally
      2. Dose 2: 300-400 mg orally at 2 hours after dose 1
      3. Dose 3: 300-400 mg orally at 4 hours after dose 1
    2. Parenteral loading regimen
      1. Dose: 10-20 mg/kg (average 1 gram) IV
      2. Do not administer faster than 50 mg/min
  3. Maintenance dose
    1. Initial: 5 mg/kg to 300 mg/day divided qd to tid
  4. Titrating dose
    1. Avoid increasing dose by >25-30 mg per trial
    2. Wait for steady state (7 days) before level recheck

VIII. Dosing: Fosphenytoin or Cerebyx

  1. Status Epilepticus
    1. Dose: 20 mg/kg IV or IM (at 3 mg/kg/min up to 150 mg/min) up to 1000 mg maximum
  2. Preferred over Phenytoin for Status Epilepticus
    1. Fosphenytoin can be infused with dextrose
    2. Fosphenytoin has lower risk of arrhythmia (due to no Ethylene Glycol in base)
    3. Fosphenytoin may be given IM or delivered a faster IV rate (not tissue toxic)
      1. However onset of activity is similar to that with Phenytoin (as Fosphenytoin is converted to active Phenytoin form)

IX. Drug Interactions

  1. Drugs that increase plasma Phenytoin levels
    1. Amiodarone
    2. Clobazam
    3. Fluconazole
    4. Ranitidine
    5. Phenylbutazone
    6. Sulfonamides
    7. Benzodiazepines
    8. Anticoagulants
    9. Isoniazid
  2. Drugs that decrease Phenytoin level or free fraction
    1. Influenza Vaccine
    2. Tolbutamide
    3. Carboplatin
    4. Rifampicin
    5. Theophylline
    6. Phenobarbital
    7. Carbamazepine
  3. Phenytoin decreases plasma level of other drug
    1. Doxorubicin

X. Adverse Effects

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Cost: Medications

phenytoin (on 5/17/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
PHENYTOIN 125 MG/5 ML SUSP Generic $0.08 per ml
PHENYTOIN 50 MG INFATAB Generic $0.32 each
PHENYTOIN 50 MG TABLET CHEW Generic $0.32 each
PHENYTOIN SOD EXT 100 MG CAP Generic $0.27 each
PHENYTOIN SOD EXT 300 MG CAP Generic $1.73 each
dilantin (on 6/1/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
DILANTIN 100 MG CAPSULE Generic $0.27 each
DILANTIN 125 MG/5 ML SUSP Generic $0.08 per ml
DILANTIN 30 MG CAPSULE $0.94 each
DILANTIN 50 MG INFATAB Generic $0.32 each

Ontology: Ethotoin (C0015046)

Definition (NCI) A hydantoin anticonvulsant with anti-epileptic activity. The mechanism of action is not completely known, but is thought to be fairly similar to phenytoin. Ethotoin influences synaptic transmission by altering sodium and calcium ion influx across neuronal membranes in the repolarization, depolarization, and membrane stability phase and interferes with the calcium uptake in presynaptic terminals. This inhibits neuronal firing and results in the stabilization of neuronal membranes, thereby preventing the spread of seizure activity at the motor cortex.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C084606
SnomedCT 64463006, 371384002
LNC LP16138-7, MTHU016713
English ethotoin, 2,4-Imidazolidinedione, 3-ethyl-5-phenyl-, 3-ethyl-5-phenyl-2,4-imidazolidinedione, Hydantoin, 3-ethyl-5-phenyl-, ethotoin (medication), ETHOTOIN, ethotoin [Chemical/Ingredient], Ethylphenylhydantoin, Ethotoin (substance), Ethotoin product (product), Ethotoin product, Ethotoin
Spanish etotoína (producto), etotoína, producto (producto), etotoína, producto, etilfenilhidantoína, etotoína (sustancia), etotoína

Ontology: Hydantoins (C0020209)

Definition (MSH) Compounds based on imidazolidine dione. Some derivatives are ANTICONVULSANTS.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D006827
English Hydantoins, Imidazolidine 2,4 Diones, Imidazolidine-2,4-Diones, Hydantoins [Chemical/Ingredient], hydantoin, hydantoins
Swedish Hydantoiner
Czech hydantoiny
Finnish Hydantoiinit
Russian GIDANTOINY, ETOTOIN, ГИДАНТОИНЫ, ЭТОТОИН
Croatian Not Translated[Hydantoins]
Spanish Hidantoínas
Polish Hydantoiny pochodne
Japanese グリコリル尿素, ヒダントイン
French Hydantoïnes
German Hydantoine
Italian Idantoine
Portuguese Hidantoínas

Ontology: Mephenytoin (C0025381)

Definition (NCI) A heterocyclic organic compound with anticonvulsant property. Although the mechanism of action is not well established, mephenytoin potentially promotes sodium efflux from neurons in motor cortex, and stabilizes the threshold against hyperexcitability caused by excessive stimulation. Thus this agent reduces the membrane sodium gradient and prevents cortical seizure signal spreading. It may cause blood dyscrasias, therefore, this agent was only used after other less toxic anticonvulsants had failed.
Definition (MSH) An anticonvulsant effective in tonic-clonic epilepsy (EPILEPSY, TONIC-CLONIC). It may cause blood dyscrasias.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D008617
SnomedCT 28344001, 417526007
LNC LP16185-8, MTHU011049
English Mefenetoin, Mephenytoin, Methoin, Methyl Phenetoin, Phenetoin, Methyl, 2,4-Imidazolidinedione, 5-ethyl-3-methyl-5-phenyl-, 5 Ethyl 3 Methyl 5 Phenylhydantoin, 5-Ethyl-3-Methyl-5-Phenylhydantoin, mephenytoin, mephenytoin (discontinued) (medication), mephenytoin (discontinued), Mephenytoin [Chemical/Ingredient], 3-Methyl-5,5-phenylethylhydantoin, 3-Ethylnirvanol, Methylphenylethylhydantoin, Mephenytoin (substance), Mephenytoin (product), MEPHENYTOIN
Czech mefenytoin
Finnish Mefenytoiini
Russian METILFENETOIN, MEFENITOIN, METOIN, МЕТИЛФЕНЕТОИН, МЕТОИН, МЕФЕНИТОИН
Japanese メチルフェネトイン, メトイン, フェナントイン, メフェニトイン
Swedish Mefenytoin
Spanish Mefenitoína, Metoína, Metil Fenetoína, mefenitoína (sustancia), mefenitoína, metilfeniletilhidantoína, metoína, mefenitoína (producto)
Polish Mefenytoina, Mezantoina
Portuguese Metilfenitoína, Mefenitoína, Metoína
French Méphénytoïne
German Mephenytoin, Methoin, Methylphenetoin
Italian Mefenitoina

Ontology: Phenytoin (C0031507)

Definition (NCI) A hydantoin derivative and a non-sedative antiepileptic agent with anticonvulsant activity. Phenytoin potentially acts by promoting sodium efflux from neurons located in the motor cortex reducing post-tetanic potentiation at synapses. The reduction of potentiation prevents cortical seizure foci spreading to adjacent areas, stabilizing the threshold against hyperexcitability. In addition, this agent appears to reduce sensitivity of muscle spindles to stretch causing muscle relaxation.
Definition (MSH) An anticonvulsant that is used to treat a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.
Definition (CSP) anticonvulsant used in a wide variety of seizures; also an anti-arrhythmic and a muscle relaxant.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D010672
SnomedCT 255672002, 387220006, 40556005
CPT 1011174
LNC LP14732-9, MTHU002993
English Phenytoin, 5,5-Diphenylhydantoin, Diphenylhydantoin, Fenitoin, 2,4-Imidazolidinedione, 5,5-diphenyl-, 5,5-Diphenyl-2,4-imidazolidinedione, diphenylhydantoin, Phenytoin - chemical, Phenytoin [Chemical/Ingredient], dph, fenitoin, phenytoin, PHENYTOIN, Phenytoin - chemical (substance), DPH, Phenylhydantoin, Phenytoin product, Phenytoin (product), Phenytoin (substance)
Swedish Fenytoin
Czech fenytoin, difenylthiohydantoin, difenylhydantoin
Finnish Fenytoiini
Russian DIFENIN, FENITOIN, FENANTOIN, DIFENILTIOGIDANTOIN, DIFENILGIDANTOIN, ДИФЕНИЛГИДАНТОИН, ДИФЕНИЛТИОГИДАНТОИН, ДИФЕНИН, ФЕНАНТОИН, ФЕНИТОИН
Japanese ヒダントール, ジランチン, フェニトイン, アレビアチン, ジフェニルヒダントイン, ジフェニルヒダントインナトリウム, フェニトインナトリウム
Italian Difenilidantoina, 5,5-Difenilidantoina, Fenitoina
Croatian FENITOIN
Spanish Fenitoína, Difenilhidantoína, fenitoína - químico (sustancia), fenitoína - químico, difenilhidantoína, fenitoína (producto), fenitoína (sustancia), fenitoína
Polish Fenytoina, Dilantin, Epanutin
French Phénytoïne
German Diphenylhydantoin, Fenitoin, Phenytoin
Portuguese Difenilidantoína, Fenitoína

Ontology: phenacemide (C0070525)

Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C005396
SnomedCT 18712002, 400358006
LNC LP15178-4, MTHU002567
English (phenylacetyl)urea, benzeneacetamide, N-(aminocarbonyl)-, phenacemide, phenuron, phenacemide [Chemical/Ingredient], phenylacetylurea, Phenacemide, Phenylacetylcarbamide, Phenylacetylurea, Phenacemide (product), Phenacemide (substance), PHENACEMIDE
Spanish fenacemida (producto), fenacemida (sustancia), fenacemida, fenilacetilcarbamida, fenilacetilurea

Ontology: fosphenytoin (C0244656)

Definition (NCI) A water-soluble phosphate ester prodrug of phenytoin, a hydantoin derivative with anticonvulsant activity. Fosphenytoin is hydrolyzed to phenytoin by phosphatases. Phenytoin exerts its effect mainly by promoting sodium efflux and stabilizes neuronal membranes in the motor cortex. This leads to a suppression of excessive neuronal firing and limits the spread of seizure activity.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C043114
SnomedCT 108397000, 372484000
LNC LP61620-8, MTHU021879
English 2,4-Imidazolidinedione, 5,5-diphenyl-3-((phosphonooxy)methyl)-, (SP-4-2)-, 3-(hydroxymethyl)phenytoin phosphate ester, fosphenytoin, FOSPHENYTOIN, fosphenytoin (as phenytoin equivalent), fosphenytoin [Chemical/Ingredient], Fosphenytoin (product), Fosphenytoin (substance), Fosphenytoin
Spanish fosfenitoína (sustancia), fosfenitoína, fosfofenitoína (producto), fosfofenitoína (sustancia), fosfofenitoína

Ontology: Cerebyx (C0525944)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C043114
English Cerebyx

Ontology: Dilantin (C0699512)

Definition (CHV) a kind of epilepsy treatment drug
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D010672
English dilantin, Park Davis brand of Phenytoin, Dilantin