EpilepsyRx

Phenytoin / fosphenytoin

Dilantin · Cerebyx

Seizure aggravation / coverage
May aggravate absence or myoclonic seizures; review syndrome before use (NICE NG217, UK guidance).

DailyMed-verified antiseizure indications

Indication / use

Label / evidence summary
Dilantin oral formulations: tonic-clonic and psychomotor (temporal-lobe) seizures. Dilantin extended-release capsules also list peri-neurosurgical seizure prevention and treatment. Cerebyx (fosphenytoin): status epilepticus with generalized tonic-clonic seizures, peri-neurosurgical seizure prevention and treatment, and short-term oral-phenytoin replacement when oral administration is not possible.
Role
Rescue / acute treatment; Maintenance
Class
Phenytoin: use-dependent sodium-channel inhibition; fosphenytoin is its prodrug

Indications checked 26 September 2026. Product, route, age, and treatment-role limits apply. A DailyMed listing alone does not establish FDA approval.

Formulations & strengths

U.S. products unless another country is named. Strengths are per unit or stated volume.

Brand & formulation labels

Each link names the product and formulation it covers. Archived labels do not establish current availability.

Dosing & administration

Adult / product-specific schedule
Common maintenance 300 mg/day; individualize by concentrations.
Pediatric
Oral phenytoin and IV fosphenytoin are not interchangeable dose schedules. Oral dosing requires its specific label. Cerebyx maintenance: initial 2–4 mg PE/kg 12 hours after loading, then 4–8 mg PE/kg/day in divided doses every 12 hours. Loading and infusion-rate limits are separate; see the linked Cerebyx dosing section.
Titration / repeat dosing
Maintenance commonly begins at 100 mg three times daily, then adjusts no more often than every 7–10 days because of nonlinear kinetics. Loading for status epilepticus follows a separate monitored IV protocol.

Dose adjustment & concentrations

Renal impairment
Interpret free level in renal dysfunction.
Hepatic impairment
Reduce/monitor free concentration.
Serum reference information
Mayo reference intervals: total 10–20 mcg/mL and free 1–2 mcg/mL. Altered albumin binding, renal/hepatic disease or interacting medicines can make total levels misleading; interpret free concentrations when indicated.

Safety

Boxed warning
Fosphenytoin boxed warning—rapid IV administration can cause severe hypotension and arrhythmias; incidence varies by rate and illness and is not reliably quantifiable. Oral phenytoin has no boxed warning.
Contraindications
Cerebyx: hydantoin hypersensitivity; sinus bradycardia, sinoatrial block, second/third-degree AV block or Adams–Stokes syndrome; prior attributable acute hepatotoxicity; delavirdine.
Serious precautions & monitoring
IV fosphenytoin requires ECG, blood-pressure and respiratory monitoring during and after infusion because of hypotension/arrhythmias. Serious rash, DRESS, hepatotoxicity, blood dyscrasias and local injury can occur. Saturable metabolism means small dose increases may cause toxicity; use unbound concentrations when binding is altered.

Common / selected adverse effects

  • Nystagmus, ataxia and confusion are concentration-related.
  • Gingival hyperplasia with chronic oral treatment.

Drug interactions: toxicity & clinical action

Partner / combinationClinical effectClinical action
ValproateProtein displacement/metabolic effects make total levels misleading; free phenytoin can rise and cause toxicity.Measure unbound phenytoin when appropriate; assess ataxia/nystagmus and do not dose to total level alone.
Cenobamate, sulthiame, felbamate, azoles or other CYP inhibitorsMay substantially raise phenytoin; saturable metabolism magnifies dose changes.Check levels and toxicity after additions/removals; use small, individualized dose adjustments.
Carbamazepine / other enzyme inducers; many partner medicinesBidirectional variable ASM effects; phenytoin lowers many substrate/contraceptive concentrations.Review the exact pair and monitor partner effectiveness/concentrations.
Enteral feeds / antacidsCan reduce oral absorption and seizure control.Use a consistent product-specific feed/administration plan and monitor concentrations.

Pregnancy & contraception

Fetal / neonatal risk
Prenatal phenytoin exposure, including exposure after fosphenytoin, is associated with major malformations and fetal hydantoin syndrome, including growth and neurodevelopmental abnormalities.
Contraception
Enzyme induction may reduce oral contraceptive effectiveness; use an effective alternative or backup method.
Pregnancy / postpartum monitoring
Pregnancy can alter phenytoin clearance and binding. Base concentration monitoring on the unbound fraction and reassess postpartum to avoid toxicity after dose increases.

Clinical evidence

Research summaries describe studied populations and outcomes; they do not add indications or constitute treatment recommendations.

Extrapolation Guideline-supported off-label use

Trial summary

Study design / duration
Introduced before contemporary Phase 3 standards; evidence derives from controlled comparisons and extensive clinical use rather than one pivotal placebo-controlled registration trial.
Primary endpoint
No single pivotal endpoint is identified in the cited source.
Results
Use predates modern Phase 3 programs. Controlled and active-comparator trials established efficacy for focal and generalized tonic-clonic seizures; efficacy is concentration- and adherence-dependent.

Trial publications

Mechanism of action

  • Phenytoin inhibits voltage-gated sodium-channel activity and limits sustained high-frequency firing. Experimental findings support preferential interaction with inactivated channels; the precise clinical mechanism is not fully established.
  • Fosphenytoin is a water-soluble phosphate prodrug converted to phenytoin after administration. It is not a second independent receptor-targeting mechanism.

Pharmacology

Adult values unless specified. Vd/F denotes apparent oral distribution volume.

Pharmacokinetics

Bioavailability
Oral absorption is formulation-dependent. IV phenytoin: 100%. Fosphenytoin is completely converted to phenytoin after IV or IM administration.
Elimination half-life
Phenytoin has concentration-dependent, nonlinear elimination; oral mean approximately 22 hours (range 7–42). After IV fosphenytoin, mean phenytoin values were 12–28.9 hours across studied doses. Fosphenytoin conversion half-life: approximately 15 minutes.
Volume of distribution
Phenytoin: approximately 0.52–1.19 L/kg (UK SmPC). Fosphenytoin: 4.3–10.8 L, dependent on dose and infusion rate (Cerebyx label).
Active metabolite(s)
Phenytoin has no clinically important active metabolite. Fosphenytoin is a prodrug whose active product is phenytoin.
Active-metabolite half-life
Phenytoin formed from fosphenytoin: 12–28.9 hours in the cited IV studies, increasing with concentration. The ~15-minute value describes prodrug conversion, not active phenytoin elimination.
Protein binding
~90%
Metabolism / elimination
CYP2C9/2C19; saturable kinetics

Distinguish mg phenytoin equivalents, prodrug conversion, free/total phenytoin and saturable clearance.

Molecular structure

Molecular structure of Phenytoin — active drug
Phenytoin is shown; fosphenytoin has an additional phosphate-containing prodrug group.
NIH PubChem structure and record ↗

Product history

Initial U.S. approval
1953 (Dilantin record; earlier clinical use)
Market / formulation history
1938 historically; later FDA records by formulation
Brands
Dilantin · Cerebyx
Manufacturer / marketer
Pfizer (Dilantin); Pfizer (Cerebyx legacy brand)
Generic availability
Yes
Related drugs
Fosphenytoin is a water-soluble prodrug converted to phenytoin.

Sources & review status

Representative sources are selected product labels, not an exhaustive list of generic manufacturers. Consult the exact product and formulation prescribed. Brand-name package inserts are linked separately.

Brand references: Dilantin capsules ↗ · Dilantin Infatabs ↗ · Dilantin-125 suspension ↗ · Cerebyx ↗

Indications and DailyMed PDFs checked: 2026-09-26. Other profile sources reviewed: 2026-09-15 · label revision noted at that review: 8/2024. This is a draft reference; final review is pending.

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