Fosphenytoin / Phenytoin (Cerebyx / Dilantin) | Medication Reference

Bedside Snapshot

Key Distinction: Fosphenytoin is a water-soluble IV/IM prodrug of phenytoin, dosed in phenytoin equivalents (PE); phenytoin is the active drug with more solvent-related toxicity and IV complications
Primary Uses: Classic sodium channel–blocking antiseizure meds used for status epilepticus and seizure prophylaxis, especially where levetiracetam is not first choice or as add-on therapy
Loading Preference: Fosphenytoin is preferred for IV loading—fewer infusion reactions, can be given IM, and can be infused faster than IV phenytoin
Typical Adult Loading: 20 mg PE/kg IV (max 1,500–2,000 mg PE) for status epilepticus, followed by maintenance 4–6 mg PE/kg/day (usually as 100 mg phenytoin PO/IV q8h)
Nonlinear Kinetics: Michaelis–Menten kinetics mean small dose changes can cause big swings in drug level; therapeutic range narrow (total phenytoin 10–20 mcg/mL)
Major Acute Risks: Hypotension and bradyarrhythmias with rapid IV infusion (worse with phenytoin than fosphenytoin), local tissue injury with IV phenytoin ("purple glove" syndrome), and CNS toxicity (nystagmus, ataxia, confusion)
Chronic Risks: Gingival hyperplasia, bone disease, folate deficiency, rash (including SJS/TEN), strong CYP induction → lots of drug–drug interactions

Brand & Generic Names

Generic Names: Fosphenytoin sodium, Phenytoin sodium
Brand Names: Cerebyx (fosphenytoin), Dilantin/Phenytek (phenytoin), generics

Important: Always confirm whether orders and pharmacy labels are expressed in mg PE (fosphenytoin) versus mg phenytoin to avoid dosing errors.

Medication Class

Hydantoin antiseizure medications; voltage-gated sodium channel blockers

Pharmacology

Mechanism of Action:

Phenytoin stabilizes neuronal membranes by blocking voltage-gated sodium channels in a use-dependent manner, reducing high-frequency repetitive firing of action potentials
Fosphenytoin is a water-soluble prodrug rapidly converted to phenytoin by plasma phosphatases after IV/IM administration; its antiseizure effect is entirely via released phenytoin
By limiting repetitive firing, phenytoin decreases seizure spread and propagation, particularly in focal and generalized tonic–clonic seizures

Pharmacokinetics:

Conversion: Fosphenytoin → phenytoin conversion half-life ≈15 minutes; peak phenytoin levels typically achieved within 1–3 hours after IV load
Distribution: Phenytoin is highly protein bound (~90% to albumin); only unbound fraction is pharmacologically active. Hypoalbuminemia or uremia ↑ free fraction → toxicity at lower total levels
Metabolism: Hepatic, capacity-limited (Michaelis–Menten) via CYP2C9/2C19; small dose changes can disproportionately change serum levels once enzymes are saturated
Elimination: Half-life often quoted ~22 hours, but highly variable; prolonged with hepatic dysfunction or enzyme saturation
Therapeutic Monitoring: Total phenytoin 10–20 mcg/mL (or adjusted/free levels in hypoalbuminemia/uremia)

Indications

Second-line treatment of convulsive status epilepticus after benzodiazepines (alternatively to levetiracetam or valproate depending on protocol)
Treatment and prevention of focal and generalized tonic–clonic seizures when phenytoin is chosen as long-term ASM
Seizure prophylaxis in select neurosurgical and neurotrauma patients (less favored vs levetiracetam in many centers but still used)
Bridging patients already on chronic phenytoin therapy when oral route is unavailable (IV fosphenytoin or IV phenytoin)

Dosing & Administration

Available Forms:

Fosphenytoin injection: typically 75 mg/mL (equivalent to 50 mg PE/mL) in vials (e.g., 2 mL, 10 mL). Dosed in mg PE, not mg of fosphenytoin
Phenytoin injection: 50 mg/mL in propylene glycol/ethanol vehicle; alkaline (pH ~12) and irritating to veins
Phenytoin oral: capsules (30 mg, 100 mg), chewable tablets, and suspension (e.g., 125 mg/5 mL); extended-release forms for outpatient maintenance

Adult Dosing (IV/IM/PO):

Indication / Scenario	Dose	Route / Rate	Notes
Status epilepticus loading – fosphenytoin	20 mg PE/kg (max 1,500–2,000 mg PE)	IV at up to 150 mg PE/min	Common range 15–20 mg PE/kg; slower rate in elderly/cardiac disease
Additional fosphenytoin loading (if needed)	5–10 mg PE/kg	IV at up to 150 mg PE/min	For subtherapeutic levels or ongoing seizures after initial load
Status epilepticus loading – IV phenytoin (less preferred)	15–20 mg/kg	IV at ≤50 mg/min	Requires cardiac monitoring and BP checks; central line preferred
Initial maintenance dose (phenytoin)	4–6 mg/kg/day	Divided (e.g., 100 mg IV/PO q8h)	Start 8–12 hours after loading; adjust to levels and clinical response
ICU common maintenance (adult)	100 mg	IV/PO q8h	Titrate up or down based on levels (total and/or free)
Obese patients	Use adjusted body weight for loading	—	Various formulas; follow institutional guidance
Renal or hepatic dysfunction	Consider lower maintenance dose	IV/PO	Hypoalbuminemia/uremia ↑ free phenytoin; monitor free or adjusted levels
IM fosphenytoin (when IV not available)	10–20 mg PE/kg	IM divided at multiple sites	Slower onset than IV but feasible in some settings
Status prophylaxis (neurotrauma/SAH)	Commonly 100 mg	IV/PO q8h	Practice is shifting toward levetiracetam; follow neurosurgery protocol

Contraindications

Contraindications:

Known hypersensitivity to phenytoin, fosphenytoin, or other hydantoins
History of phenytoin-induced hepatotoxicity, serious rash (e.g., SJS/TEN), or DRESS
Sinoatrial block, second- or third-degree AV block, or Adams–Stokes syndrome (for IV formulations)

Major Precautions:

Rapid IV administration, particularly of phenytoin, can cause severe hypotension and life-threatening arrhythmias; continuous ECG and BP monitoring required
Phenytoin IV is a vesicant; risk of purple glove syndrome and tissue necrosis with extravasation—prefer central line or very good peripheral access; fosphenytoin is much safer for peripheral use
Hypoalbuminemia (sepsis, liver disease, malnutrition) and uremia increase free phenytoin; a "therapeutic" total level may still be toxic—check free levels or use correction formulas
Strong CYP450 inducer (CYP3A4, 2C9, etc.) → numerous interactions: can lower levels of many drugs (e.g., DOACs, steroids, some antipsychotics, many others)
Genetic predisposition (e.g., HLA-B*1502 in certain Asian populations) is associated with higher risk of SJS/TEN; avoid phenytoin in known high-risk alleles
Chronic use can cause osteopenia/osteoporosis, folate deficiency, and neuropathy; more relevant for long-term management than ICU stay

Cardiac Risk: Rapid IV administration can cause severe hypotension and life-threatening arrhythmias. Continuous ECG and BP monitoring required during loading.

Purple Glove Syndrome: IV phenytoin is a vesicant with risk of tissue necrosis and "purple glove syndrome" with extravasation. Prefer fosphenytoin or ensure central line access for phenytoin.

SJS/TEN/DRESS Risk: Serious dermatologic reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome. Stop immediately if rash with systemic symptoms develops.

Adverse Effects

Common (dose-related):

Nystagmus (often first sign of toxicity)
Ataxia, dysarthria, dizziness
Sedation, confusion
Nausea, vomiting

Serious:

Severe hypotension and bradyarrhythmias or AV block during or shortly after IV infusion
Purple glove syndrome and tissue necrosis with IV phenytoin extravasation
Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS syndrome
Acute hepatic failure or severe hepatotoxicity
Agranulocytosis, leukopenia, thrombocytopenia (rare)

Long-term (chronic use):

Gingival hyperplasia
Coarsening of facial features
Peripheral neuropathy
Bone disease (osteopenia/osteoporosis)
Folate deficiency

Drug Interactions

Major CYP450 Inducer:

Phenytoin is a strong inducer of CYP3A4, 2C9, 2C19, and other enzymes
Can significantly reduce levels of: warfarin, DOACs, corticosteroids, many antipsychotics, immunosuppressants, antiretrovirals, hormonal contraceptives, and numerous other medications
Review all concurrent medications for potential interactions
May require dose adjustments of other medications when phenytoin is started or stopped

Drugs That Increase Phenytoin Levels:

Fluconazole, amiodarone, isoniazid, sulfonamides, cimetidine

Drugs That Decrease Phenytoin Levels:

Carbamazepine, rifampin, chronic alcohol use

Special Populations

Elderly Patients:

Use slower infusion rates (consider 100 mg PE/min instead of 150)
Higher risk of cardiovascular complications
May require lower maintenance doses

Renal Impairment:

Uremia increases free phenytoin fraction
Monitor free or adjusted phenytoin levels
May require lower maintenance doses

Hepatic Impairment:

Reduced metabolism and clearance
Lower maintenance doses required
More frequent level monitoring

Hypoalbuminemia:

Increases free phenytoin fraction significantly
Use corrected phenytoin levels or measure free levels
"Therapeutic" total levels may be toxic

Pregnancy:

Category D: Known teratogen (fetal hydantoin syndrome)
Use only if seizure control benefit outweighs fetal risk
Requires high-risk obstetric monitoring

Lactation:

Excreted in breast milk; concentrations variable
Monitor infant for sedation, poor feeding

Monitoring

Clinical Monitoring:

Continuous ECG and blood pressure monitoring during IV loading (especially IV phenytoin)
Serum total phenytoin levels after loading and periodically during maintenance; check free phenytoin or use corrected levels in hypoalbuminemia/uremia
Clinical signs of toxicity: nystagmus, ataxia, slurred speech, confusion, and new gait instability
CBC and liver function tests with ongoing therapy, especially if fever, rash, or systemic symptoms develop
Rash screening: any concerning rash with systemic symptoms → stop drug and evaluate for SJS/TEN/DRESS
Assess concomitant meds for interactions, especially other ASMs, anticoagulants, antiretrovirals, and immunosuppressants

Clinical Pearls

Prefer Fosphenytoin: If you have the choice in the ED/ICU, use fosphenytoin for loading—it's safer for the heart and veins and can be infused faster.

PE vs mg Clarity: Always clarify orders in mg PE for fosphenytoin to avoid under- or overdosing; double-check order sets and pharmacy labels.

Low Albumin Alert: In sick ICU patients with low albumin or renal failure, a "normal" total phenytoin level can still be toxic—look at the patient and consider free levels.

Levetiracetam Shift: Levetiracetam is often first-line now due to fewer side effects and interactions, but fosphenytoin/phenytoin still matter for status pathways and for patients already maintained on phenytoin.

Toxicity Recognition: If you see new nystagmus, unsteady gait, or confusion in a patient on phenytoin, think toxicity and check a level before piling on more.

Nonlinear Kinetics: Small dose increases can cause disproportionate rises in serum levels once metabolism is saturated—titrate cautiously and monitor levels frequently.

References

1. Lexicomp. (2024). Fosphenytoin and Phenytoin: Drug information. Wolters Kluwer.
2. Brophy, G. M., Bell, R., Claassen, J., et al. (2012). Guidelines for the evaluation and management of status epilepticus. Neurocritical Care, 17(1), 3–23. https://doi.org/10.1007/s12028-012-9695-z
3. Glauser, T., Shinnar, S., Gloss, D., et al. (2016). Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults. Epilepsy Currents, 16(1), 48–61. https://doi.org/10.5698/1535-7597-16.1.48
4. Garnett, W. R. (2000). Clinical pharmacokinetics of phenytoin. Clinical Pharmacokinetics, 4(4), 259–269. https://doi.org/10.2165/00003088-197904040-00002
5. Boucher, B. A., Feler, C. A., Dean, J. C., et al. (1996). The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy, 16(4), 638–645.