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Drug Reference

phenytoin

Anticonvulsant· Brands: Dilantin, Epanutin, PhenytekIVPO

Mechanism of action
Phenytoin blocks voltage-gated sodium channels in a use-dependent manner, preventing the repetitive firing of neurons during seizures. It stabilises neuronal membranes and reduces excitability by prolonging the refractory period, thereby suppressing seizure activity.
Pharmacokinetics
Phenytoin is erratically absorbed from the gastrointestinal tract and is highly protein-bound, approximately 90% to plasma albumin. It is extensively metabolised in the liver by cytochrome P450 enzymes, primarily CYP2C9 and CYP2C19, with saturable kinetics producing non-linear elimination at therapeutic doses. The half-life is dose-dependent, typically 20 to 30 hours, and increases as plasma concentrations rise. Phenytoin induces its own metabolism and that of other drugs.
Indications & dosing

Status epilepticus (loading dose)

Administer slowly, not exceeding 50 mg/min. Monitor cardiac rhythm and blood pressure.

  • adult · IV: 15–20 mg/kg Loading dose · Administer slowly, not exceeding 50 mg/min. Monitor cardiac rhythm and blood pressure.

Generalized tonic-clonic seizures (maintenance)

May be given as divided doses. Adjust according to serum levels (target 10-20 mg/L).

  • adult · PO: 300 mg OD · May be given as divided doses. Adjust according to serum levels (target 10-20 mg/L).

Partial seizures (maintenance)

May be given as divided doses. Adjust according to serum levels (target 10-20 mg/L).

  • adult · PO: 300 mg OD · May be given as divided doses. Adjust according to serum levels (target 10-20 mg/L).

Status epilepticus (loading dose)

Administer slowly, not exceeding 1-3 mg/kg/min. Monitor cardiac rhythm and blood pressure.

  • pediatric · IV: 15–20 mg/kg Loading dose · Administer slowly, not exceeding 1-3 mg/kg/min. Monitor cardiac rhythm and blood pressure.
Contraindications & precautions
  • Hypersensitivity to phenytoin or other hydantoins · Includes rash, eosinophilia, or drug-induced lupus.
  • Sinoatrial block, second- or third-degree atrioventricular block · Phenytoin can worsen conduction defects.
  • Acute porphyria · Phenytoin may precipitate acute porphyric crisis.
  • Pregnancy · Teratogenic; use only if benefits outweigh risks, consider alternatives.
  • Monitor plasma phenytoin concentration; therapeutic range is narrow (10-20 mg/L, 40-80 μmol/L).
  • Avoid abrupt withdrawal, as this may precipitate status epilepticus; taper gradually.
  • Phenytoin is a potent enzyme inducer; be alert to interactions with other drugs.
  • Use caution in patients with hepatic impairment or hypoalbuminaemia.
  • Consider folic acid and vitamin D supplementation during long-term therapy.
Adverse effects
  • Nystagmus
  • Ataxia
  • Drowsiness
  • Gingival hyperplasia
  • Hirsutism
  • Stevens-Johnson syndromeserious
  • Blood dyscrasiasserious
  • Hepatotoxicityserious
Interactions
  • omeprazolemoderateMonitor plasma phenytoin concentrations and observe for signs of toxicity when omeprazole is started, stopped, or the dose is changed. Consider reducing the phenytoin dose if levels rise. If clinically appropriate, an alternative proton pump inhibitor with less CYP2C19 inhibition, such as pantoprazole, could be substituted.
  • valproic acidmajorMonitor total and, where available, free phenytoin concentrations, as well as valproic acid levels, when initiating, adjusting, or discontinuing either drug. Consider reducing the phenytoin dose when valproic acid is added, and increase it when valproic acid is withdrawn. Observe the patient for clinical signs of phenytoin toxicity and adjust the dose accordingly.
  • carbamazepinemajorMonitor plasma concentrations of both drugs when initiating, adjusting, or stopping either drug. Adjust doses based on therapeutic drug monitoring. Consider alternative antiepileptics with fewer interactions. Monitor for signs of seizure recurrence or toxicity.
  • isoniazidmajorMonitor plasma phenytoin concentrations closely, especially within the first two weeks of concurrent therapy. Reduce the phenytoin dose as needed to maintain therapeutic levels. Advise patients to report symptoms of toxicity. If isoniazid is stopped, monitor for decreased phenytoin levels and increase the dose if required.
  • rifampicinmajorAvoid the combination if possible. If co-administration is necessary, closely monitor phenytoin plasma concentrations and observe for signs of reduced efficacy. Phenytoin dosage may need substantial upward adjustment, often by two- to three-fold, based on therapeutic drug monitoring. After stopping rifampicin, phenytoin levels may rise, requiring dose reduction to avoid toxicity. Consider alternative antiepileptics or anti-tuberculosis drugs when feasible.
  • theophyllinemajorIf coadministration is necessary, monitor serum theophylline concentrations closely. It may be necessary to increase the theophylline dose by 20 to 50 percent and adjust based on levels. Reassess after any change in phenytoin therapy. Alternative bronchodilators should be considered.
  • fluoxetinemajorIf concurrent use is required, monitor plasma phenytoin concentrations before and after initiating or discontinuing fluoxetine. Repeat levels within 1 to 2 weeks of any change, and adjust the phenytoin dose accordingly. Monitor the patient for clinical signs of phenytoin toxicity. Advise the patient to report any new neurological symptoms.
  • warfarinmajorAvoid co-prescription if possible. If necessary, monitor INR frequently and adjust warfarin dose accordingly. Monitor serum phenytoin levels and signs of toxicity, adjusting phenytoin dose as needed. Consider alternative anticonvulsants or anticoagulants that do not interact (e.g., levetiracetam for seizures, or a DOAC if appropriate).
  • fluconazolemajorMonitor phenytoin plasma concentrations and clinical signs of toxicity when starting, stopping, or changing the dose of fluconazole. Consider reducing the phenytoin dose if toxicity develops, especially with high-dose or prolonged fluconazole use. Recheck phenytoin levels after any change in the antifungal regimen and adjust the dose accordingly. Antifungal response should also be monitored to ensure adequate efficacy.
  • methadonemajorAvoid concurrent use if possible. If co-prescription is necessary, closely monitor the patient for signs of opioid withdrawal. Consider increasing the methadone dosage, with careful titration based on clinical response. Monitor plasma methadone concentrations where available, particularly after initiating or discontinuing phenytoin. Re-evaluate the methadone dose when phenytoin is stopped, as methadone levels may rise and cause toxicity. Involve the patient and relevant specialists in dose adjustments.
  • apixabanmajorAvoid co-prescription where possible. Consider alternative anticoagulants (e.g., warfarin with INR monitoring) or alternative antiepileptics (e.g., levetiracetam). If concurrent use is unavoidable, monitor for clinical signs of thrombosis and consider increasing the apixaban dose, though specific dosing recommendations are not well established.
Renal & hepatic adjustment
  • eGFR 0–300: No dose adjustment required based on eGFR. In severe renal impairment, monitor free phenytoin concentration as protein binding may be altered.
  • Hepatic impairment (mild): No dosage adjustment usually required, but monitor serum phenytoin levels.
  • Hepatic impairment (moderate): Consider reducing maintenance dose by approximately 25-50% and monitor serum levels closely.
  • Hepatic impairment (severe): Avoid or use with extreme caution; consider alternative therapy if possible. (avoid)
Monitoring, pregnancy & toxicity
  • Serum phenytoin concentration · At steady state (7-10 days after initiation or dose change), and periodically thereafter
  • Liver function tests · Baseline and every 6-12 months during maintenance
  • Full blood count · Baseline and periodically; monitor for blood dyscrasias
  • Skin reactions (e.g., rash, blisters) · During initial treatment and after any dose change
  • Neurological examination (nystagmus, ataxia) · At each visit, especially with dose changes
  • Pregnancy: Phenytoin is teratogenic (e.g., fetal hydantoin syndrome, neural tube defects). Avoid if possible in pregnancy; if used, use the lowest effective dose, monitor serum concentrations closely, and supplement with folic acid.
  • Toxicity: Nystagmus with ataxia and slurred speech · Reduce or withhold the dose; monitor serum levels; supportive care.
  • Toxicity: Acute overdose · Supportive care; consider activated charcoal within 1 hour of ingestion; monitor cardiac and respiratory function.
  • Toxicity: Chronic toxicity causing confusion, drowsiness, or coma · Stop or reduce dose; serum level monitoring; supportive care; consider dialysis only in severe cases.
  • Toxicity: Severe skin reactions (e.g., Stevens-Johnson syndrome) · Stop phenytoin immediately; emergency supportive care; seek specialist advice.
Clinical notes
Phenytoin has a narrow therapeutic index; serum concentrations should be monitored and the dose adjusted to maintain levels within the therapeutic range, typically 10 to 20 mg/L. It is used for focal and generalised tonic-clonic seizures and in status epilepticus given intravenously. Adverse effects include nystagmus, ataxia, sedation, gingival hypertrophy, hirsutism, and rare but serious skin reactions such as Stevens-Johnson syndrome. Phenytoin interacts with many drugs due to enzyme induction and displacement from protein-binding sites.

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BNF; local formulary