Antiepileptic

Fosphenytoin (Cerebyx)

Also called Cerebyx

Reviewed by Alex G, BSN, RN, CEN, CCRN, CMC, NREMT-P · From the Reference tab of the app

Indications

Generalized convulsive status epilepticus after a benzodiazepine (ESETT 2019: 45% response)
Prevention and treatment of seizures during neurosurgery
Short-term IV or IM replacement for oral phenytoin
Early post-traumatic seizure prophylaxis for 7 days after severe TBI (off-label; Brain Trauma Foundation guidance names phenytoin)

Dosing

Where	Dose
Seizures and neuro	Fosphenytoin: 20 mg PE/kg (max 1,500 mg PE) at up to 150 mg PE/min; watch BP and rhythm

Mechanism of action

Fosphenytoin has no activity of its own: phosphatases in blood and tissues remove the phosphate and release phenytoin. Phenytoin binds voltage-gated sodium channels in their inactivated state and slows their recovery, so a neuron firing at high frequency runs out of available channels while normal low-frequency firing is spared (use-dependent block). This stops seizure activity spreading from its focus. The same block in cardiac conducting tissue slows conduction, the source of its cardiac toxicity.

Pharmacology

CNS: stops seizure spread with little sedation at therapeutic levels; nystagmus near 20 mcg/mL, ataxia near 30 and lethargy over 40
Cardiovascular: rate-related hypotension, bradycardia, heart block and ventricular arrhythmias (boxed warning); in ESETT, hypotension and intubation were numerically more frequent than with levetiracetam or valproate
Sensory: burning, itching or tingling, often in the groin, during fast infusions (7 of 16 volunteers at the maximum rate); transient
Metabolic: hyperglycemia from inhibited insulin release; phosphate load of 0.0037 mmol per mg PE
Other: phenytoin strongly induces CYP3A4 and other liver enzymes; teratogenic (fetal hydantoin syndrome)

Pharmacokinetics

Onset	Conversion half-life about 15 min; phenytoin peaks 10–20 min after the infusion ends, with free levels like phenytoin given at 50 mg/min
Half-life	Phenytoin 12–29 h after a load, lengthening at high levels as metabolism saturates
Distribution	Fosphenytoin Vd 4.3–10.8 L; phenytoin enters the brain readily and crosses the placenta
Protein binding	Fosphenytoin 95–99% to albumin; it displaces phenytoin, raising the free fraction to about 30% during conversion; otherwise about 12% of phenytoin is free
Metabolism	Each mmol yields 1 mmol of phenytoin plus phosphate and formaldehyde (to formate); CYP2C9, and less CYP2C19, hydroxylate phenytoin to inactive HPPH, which is glucuronidated
Elimination	Urine, mainly as HPPH glucuronide; little phenytoin is excreted unchanged
Nonlinear kinetics	Michaelis-Menten: near the therapeutic range metabolism saturates, so a small dose increase can raise the level steeply
Levels	Draw total phenytoin at least 2 h after IV or 4 h after IM, as unconverted prodrug falsely raises immunoassays; target total 10–20 mcg/mL, free 1–2 mcg/mL
Low albumin, organ failure	Kidney or liver disease and hypoalbuminemia speed conversion and raise free phenytoin without faster clearance; follow free levels, since a normal total can hide toxicity
Routes	IV or IM (fully bioavailable, peak about 30 min); IM is too slow for status epilepticus

Chemistry

Disodium phosphate ester prodrug: a phosphonooxymethyl group on N3 of phenytoin (5,5-diphenylhydantoin); both are achiral
Phenytoin is a weak acid (pKa 8.3) almost insoluble in water, so IV phenytoin needs pH 12 with 40% propylene glycol and 10% ethanol; fosphenytoin dissolves in water at pH 8.6–9.0 (tromethamine buffer), allowing IM use, faster infusion and less vein injury
Dosed in phenytoin sodium equivalents: 1.5 mg fosphenytoin sodium = 1 mg PE; vials hold 50 mg PE/mL (100 mg PE in 2 mL, 500 mg PE in 10 mL), and reading 50 mg/mL as the vial total has caused fatal overdoses
Refrigerate at 2–8 °C, no more than 48 h at room temperature; dilute in D5W or saline to 1.5–25 mg PE/mL

Adverse effects and cautions

Safety

Boxed warning: severe hypotension and arrhythmias with fast infusion; do not exceed 150 mg PE/min in adults, and monitor ECG, BP and breathing through the 10–20 min after the infusion
Contraindicated with sinus bradycardia, SA block, second- or third-degree AV block, Adams-Stokes syndrome, prior phenytoin hepatotoxicity, or delavirdine
Order, label and dispense only in mg PE
SJS/TEN (more likely with HLA-B*15:02 or CYP2C9*3), DRESS, liver injury and blood dyscrasias
Purple glove syndrome and infusion-site pain are less common than with IV phenytoin but still occur, sometimes days later; inspect the limb
Interactions: induces metabolism of warfarin, DOACs, steroids, contraceptives and many others; amiodarone, fluconazole and valproate raise phenytoin levels
Phosphate load in severe kidney impairment; hyperglycemia; no antidote for toxicity

In the one-pagers

Practice Neuro: ICP and Stroke questions free55 exam-style questions with rationales on the topic where Fosphenytoin comes up most. No account or download needed.

In the algorithms

Status Epilepticus

Practice free in your browser2,450+ exam-style questions with rationales. No account, no ads. Also free on the App Store and Google Play.

Sources

FDA label: Cerebyx (2025)
Kapur 2019, ESETT (NEJM)
PubChem: phenytoin

For education and exam preparation only. Follow your institution’s protocols. Typical adult values for study. Follow your local protocols and medical direction.