Bedside Snapshot

Use It For
Benzodiazepine-refractory convulsive status epilepticus; seizures during neurosurgery; short-term IV/IM replacement of oral phenytoin
Adult Dose
  • Fosphenytoin 20 mg PE/kg IV (max 1,500 mg PE) at ≤150 mg PE/min. Differs from FDA label (15–20 mg PE/kg, no cap).
  • Phenytoin (no fosphenytoin) 20 mg/kg IV (max 1,500 mg) at ≤50 mg/min. Differs from FDA label (10–15 mg/kg).
Pediatric Dose
Fosphenytoin 20 mg PE/kg IV at ≤2 mg PE/kg/min or 150 mg PE/min, whichever is slower (max 1,500 mg PE). Phenytoin (no fosphenytoin): 20 mg/kg at ≤1 mg/kg/min or 50 mg/min, whichever is slower. Label rate 1–3 mg/kg/min.
Onset / Duration
IV: onset during the infusion, peak 10–20 min after it ends / ≥12 hr; IM: peak about 3 hr; PO: peak 4–12 hr
Do Not Give / Hold If
IV only: sinus bradycardia, SA block, 2nd/3rd-degree AV block, Adams-Stokes. Any form: hydantoin allergy; prior phenytoin hepatotoxicity; delavirdine. Slow/stop for hypotension, bradycardia (adult HR <50) or arrhythmia
Watch For
Hypotension and bradyarrhythmia during and 10–20 min after the load (continuous ECG, BP); purple glove at the IV site; rash (SJS/TEN, DRESS); nystagmus and ataxia (toxic level)
Reversal / Rescue
No antidote: slow or stop the infusion; IV fluids for hypotension; treat bradycardia per ACLS; supportive care; hemodialysis can be considered in severe toxicity
Must Remember
Fosphenytoin is ordered in mg PE. Vials are 50 mg PE/mL, so a 10 mL vial holds 500 mg PE. Reading the concentration as the vial content has caused fatal 10-fold overdoses.

Indications

Emergency & Prehospital

  • Benzodiazepine-refractory convulsive status epilepticus: second line, once an adequate dose of lorazepam, midazolam or diazepam has failed. Fosphenytoin, levetiracetam and valproate are about equal here. Each one stops seizures in about half of patients (ESETT trial; ACEP 2024 Level A). The label covers generalized tonic-clonic status epilepticus.

ED / ICU / Transport

  • Seizures during neurosurgery: prevention and treatment (labeled)
  • Short-term parenteral replacement of oral phenytoin: intubated, NPO or vomiting patients on maintenance phenytoin, at the same total daily dose
  • Neonatal seizures not controlled by phenobarbital: a second-line option (with levetiracetam, midazolam or lidocaine) in the ILAE 2023 neonatal guideline. It is first-line only when a channelopathy is the likely cause
  • Early seizure prophylaxis after severe traumatic brain injury: per neurosurgical protocol (off-label)

Other Uses

  • Tonic-clonic and focal (temporal lobe) epilepsy: long-term oral phenytoin maintenance (labeled)
Wrong tool for these seizures: Eclampsia needs magnesium sulfate. It outperforms phenytoin. Toxin-induced and alcohol-withdrawal status epilepticus are the evidence gap: ACEP 2024 says fosphenytoin may not work there. Use benzodiazepines and treat the cause.

Dosing & Administration

The doses below follow the E3 status epilepticus ladder. Where they differ from the FDA label, the difference is noted.

Available Forms

  • Fosphenytoin sodium injection (Cerebyx, generics): 50 mg PE/mL in 2 mL (100 mg PE) and 10 mL (500 mg PE) single-dose vials. 1.5 mg fosphenytoin sodium = 1 mg PE (phenytoin sodium equivalent). This is the loading form for ED, ICU and transport. Keep it refrigerated.
  • Phenytoin sodium injection: 50 mg/mL in 2 mL (100 mg) and 5 mL (250 mg) single-dose vials, in propylene glycol and alcohol; pH 10–12.3.
  • Oral phenytoin sodium extended capsules: Dilantin and generics 30 mg and 100 mg; Phenytek 200 mg and 300 mg.
  • Oral phenytoin (free acid): 50 mg chewable tablets (Dilantin Infatabs) and 125 mg/5 mL suspension (Dilantin-125). The free acid holds about 8% more drug than the sodium salt. Check levels when you switch.
Dosing-error trap: Order, label and chart fosphenytoin only in mg PE. Reading the 50 mg PE/mL concentration as the vial content has caused 2- and 10-fold overdoses, some of them fatal. Name the total: 500 mg PE/10 mL. Then check the drawn-up volume.

Adult Dosing

IndicationDose & RouteRepeat / MaxNotes
Status epilepticus, benzodiazepine-refractory (fosphenytoin, preferred)
20 mg PE/kg IV at 100–150 mg PE/min (label range 15–20 mg PE/kg)
Max 1,500 mg PE (ESETT; ACEP 2024 Table 1); the FDA label sets no mg maximum. Rate ≤150 mg PE/min
Give after an adequate benzodiazepine dose. Differs from FDA label: the label gives 15-20 mg PE/kg with no mg cap; E3 uses 20 mg PE/kg with a 1,500 mg PE cap (ESETT, ACEP 2024). A 1,500 mg PE load at 150 mg PE/min takes 10 min. Above 75 kg the 1,500 mg PE cap gives less than 20 mg PE/kg: follow local protocol. If the load does not stop seizures, move to another antiseizure drug rather than repeating the load (Cerebyx label, section 2.3: "If administration of CEREBYX does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered"). If still seizing about 20 min after the load starts (40 min of seizure): give a different second-line drug (levetiracetam or valproate) or start an anesthetic infusion with continuous EEG.
Status epilepticus (phenytoin, if no fosphenytoin)
20 mg/kg IV, max 1,500 mg
Rate ≤50 mg/min (30 min for 1,500 mg); single load
Large vein, saline only, in-line filter. Expect a longer infusion and more site pain than fosphenytoin. Differs from FDA label: the label gives adults 10-15 mg/kg; E3 uses 20 mg/kg (the ESETT fosphenytoin-equivalent dose) with a 1,500 mg cap.
Non-emergent loading (fosphenytoin)
10–20 mg PE/kg IV or IM
IV ≤150 mg PE/min; infuse more slowly when not urgent
Adults: IV or IM (IM can also replace oral phenytoin when oral dosing is not possible). IM ordinarily not for status epilepticus (levels rise more slowly than IV); it has been used for loading when IV access is impossible. Ordinarily not IM in children.
Oral loading (phenytoin extended capsules, hospital only)
1 g PO divided as 400 mg, 300 mg, 300 mg every 2 hr
Total 1 g; start maintenance 24 hr later
Not for patients with renal or liver disease. Check levels.
Maintenance
Fosphenytoin 4–6 mg PE/kg/day IV in divided doses, or phenytoin 100 mg IV/PO every 6–8 hr
Titrate to level; oral max 200 mg three times daily
Total phenytoin 10–20 mcg/mL (free 1–2 mcg/mL). IV rate limits as above.
Replacing oral phenytoin (NPO)
Same total daily dose as fosphenytoin (mg PE) IV or IM, or phenytoin IV
Same daily total; no conversion factor
Levels may rise modestly: oral capsules are about 90% bioavailable, IV/IM 100%.

Dosing weight: The FDA label doses by weight, 15–20 mg PE/kg, and sets no mg maximum. The 1,500 mg PE cap comes from ESETT, where a 10-min infusion limited the dose. ACEP 2024 restates it (Table 1). At 20 mg PE/kg, the cap is reached at 75 kg. The ESETT authors note it may be submaximal in heavier patients: a 110 kg patient capped at 1,500 mg PE gets about 13.6 mg PE/kg, below the label minimum. Follow local protocol for patients over 75 kg and for obesity.

Pediatric Dosing

IndicationDose (per kg) & RouteMax Single / Max TotalNotes
Status epilepticus, birth to <17 yr (fosphenytoin, preferred)
20 mg PE/kg IV (label range 15–20 mg PE/kg)
Max 1,500 mg PE single load (ESETT protocol cap; the label sets no mg maximum); rate ≤2 mg PE/kg/min or 150 mg PE/min, whichever is slower
ESETT enrolled children aged 2 yr and older. TREKK 2025 uses 20 mg PE/kg, max 1,000 mg PE, over 10 min. In children, levetiracetam has similar efficacy with fewer adverse events.
Status epilepticus (phenytoin)
20 mg/kg IV
Rate up to 1 mg/kg/min or 50 mg/min, whichever is slower (EcLiPSE); label 1–3 mg/kg/min
Saline only, large vein, flush before and after.
Neonatal seizures not responding to phenobarbital
Fosphenytoin 15–20 mg PE/kg IV (labeled from birth)
Single load; rate ≤2 mg PE/kg/min
Second-line per the ILAE 2023 neonatal guideline. Levetiracetam may be preferred in neonates with cardiac disease.
Non-emergent loading (fosphenytoin)
10–15 mg PE/kg IV
Rate 1–2 mg PE/kg/min or 150 mg PE/min, whichever is slower
Avoid IM in children unless IV access is impossible.
Maintenance (fosphenytoin IV)
2–4 mg PE/kg 12 hr after the load, then 4–8 mg PE/kg/day divided every 12 hr
Rate 1–2 mg PE/kg/min or 100 mg PE/min, whichever is slower
Adjust to levels.
Maintenance (oral phenytoin)
5 mg/kg/day PO in 2–3 divided doses; usual 4–8 mg/kg/day
Max 300 mg/day
Children over 6 yr may need the adult minimum of 300 mg/day.

Weight-based dose checks: pediatric weight-based dosing.

Preparation & Administration

  • Fosphenytoin dilution: dilute in D5W or 0.9% sodium chloride to 1.5–25 mg PE/mL (never above 25 mg PE/mL).
  • Fosphenytoin rate: adults ≤150 mg PE/min; children ≤2 mg PE/kg/min or 150 mg PE/min, whichever is slower. Run it on an infusion pump. Expect burning or itching, often in the groin, at fast rates. Slow or pause the infusion.
  • Phenytoin diluent: 0.9% sodium chloride only. It precipitates in dextrose. For an infusion, keep the final concentration at least 5 mg/mL and start right after mixing. Finish within 1–4 hr. Do not refrigerate the mix. Use a 0.22–0.55 micron in-line filter.
  • Phenytoin line: large peripheral or central vein through a large-gauge catheter. Flush with saline before (to confirm patency) and after every dose.
  • IM route: in adults, fosphenytoin IM is an option for a non-emergent load, or to replace oral phenytoin when oral dosing is not possible. That is a single daily dose, into 1–2 sites. Ordinarily, don't use IM fosphenytoin for status epilepticus: therapeutic levels come more slowly than with IV. It has been used for a load when IV/IO access is impossible. Ordinarily not IM in children. Phenytoin should not be given IM. Absorption is erratic, and the injection can cause necrosis or abscess.
  • Inspect and discard: single-dose vials; do not use a vial with particulate matter; discard the unused portion.
Dosing Notes: Check phenytoin levels at least 2 hr after an IV fosphenytoin infusion ends, or 4 hr after IM. Earlier immunoassays overestimate the level. Renal, hepatic and low-albumin dosing are covered under Special Populations.

Contraindications & Precautions

Contraindications

  • Hypersensitivity: to fosphenytoin, phenytoin, other hydantoins or any ingredient (reactions have included angioedema)
  • Conduction disease (IV fosphenytoin and phenytoin only): sinus bradycardia, sinoatrial block, second- or third-degree AV block, or Adams-Stokes syndrome. Parenteral phenytoin affects ventricular automaticity, and that is the reason. Oral phenytoin is not contraindicated here. Don't stop chronic oral therapy abruptly, because of withdrawal seizures
  • Prior hepatotoxicity: acute liver injury attributed to phenytoin or fosphenytoin
  • Delavirdine: coadministration (loss of antiviral effect)
  • In status epilepticus: if any of these apply, levetiracetam is the usual alternative. Valproate is the other option, but only after checking its own contraindications (liver disease, POLG mitochondrial or urea-cycle disorders) and fetal risk

Precautions

  • Critically ill, elderly, hypotensive or severe heart failure patients: highest risk of hypotension and arrhythmia. Infuse at the slow end of the range. Events also happen at recommended rates in patients without heart disease.
  • Low albumin, renal or hepatic disease: more unbound, active drug. A normal total level can still be toxic.
  • Severe renal impairment: fosphenytoin adds 0.0037 mmol phosphate per mg PE (about 5.6 mmol in a 1,500 mg PE load).
  • HLA-B*1502 (mainly Asian ancestry) or CYP2C9*3 carriers: higher risk of severe skin reactions (SJS/TEN). Consider an alternative. Poor or intermediate CYP2C9 metabolizers need lower doses.
  • Hydantoin hypersensitivity: consider alternatives to structurally similar drugs, such as carbamazepine, barbiturates and succinimides. A personal or family history of reactions to those drugs is a reason to consider an alternative to phenytoin.
  • Porphyria and diabetes: may worsen porphyria. It raises glucose.
  • Toxicologic seizures: per TREKK 2025, avoid phenytoin and fosphenytoin. Benzodiazepines come first for seizures from local anesthetic systemic toxicity and organophosphate poisoning (2025 AHA Guidelines for CPR and ECC, Part 10).
  • Already on phenytoin at home: per TREKK 2025, choose another drug or consider a partial 10 mg PE/kg load.
  • Abrupt withdrawal: can trigger status epilepticus. Taper, unless a serious reaction forces a switch. Then use a non-hydantoin drug.

Hold / Reassess If

  • Hypotension (adults SBP <90 mmHg; children below the PALS threshold for age; or per protocol) or a falling BP during the infusion: slow or stop
  • Bradycardia (adults HR <50 bpm; children below the normal range for age), new AV block, QT prolongation or any ventricular arrhythmia: stop
  • Any rash: stop at the first sign unless clearly not drug-related
  • Facial, perioral or airway swelling: stop and do not restart
  • New nystagmus, ataxia or confusion during maintenance: hold and check a level
FDA Boxed Warning: Rapid IV infusion carries cardiovascular risk. Do not exceed 150 mg PE/min for fosphenytoin (children: 2 mg PE/kg/min or 150 mg PE/min, whichever is slower). For phenytoin, the limit is 50 mg/min (children: 1–3 mg/kg/min or 50 mg/min, whichever is slower). Severe hypotension and arrhythmias can happen even at these rates. Watch the heart during and after the infusion, and slow or stop as needed.

Adverse Effects & Toxicity

Common

  • Pruritus, burning or tingling (fosphenytoin): 49% at maximum dose and rate, often in the groin; resolves within about 10 min of the infusion ending
  • Nystagmus: 44% (fosphenytoin) to 59% (phenytoin) after an IV load
  • Dizziness, somnolence, ataxia: 11–31%
  • Hypotension: about 8–9% during IV loading
  • Infusion-site pain and burning (phenytoin): 90% in the label trial vs 9% with fosphenytoin
  • Children: vomiting, nystagmus and ataxia (10% or more)
  • Long-term oral use: gingival hyperplasia, coarse facial features, sensory peripheral neuropathy, low bone density and fractures, megaloblastic anemia

Serious / Life-Threatening

EffectRecognitionManagement
Hypotension, bradycardia, heart block, VT/VF, asystole
During or within minutes after IV loading; continuous ECG and BP
Slow or stop; IV fluids; treat bradycardia and arrhythmia per ACLS
Purple glove syndrome and tissue injury
Edema, purple discoloration and pain distal to the IV site; may appear days later. Mostly phenytoin; reported with fosphenytoin
Stop the infusion at that site; notify the provider; severe cases have needed fasciotomy or grafting
SJS/TEN, DRESS, AGEP
Rash, fever, lymph node swelling, facial edema, organ involvement; usually within 28 days
Stop and do not restart; switch to a non-hydantoin drug
Angioedema or anaphylaxis
Facial, lip or airway swelling; hypotension; wheeze
Stop permanently; treat as anaphylaxis with IM epinephrine
Acute hepatotoxicity
Jaundice, hepatomegaly, rising transaminases, often with DRESS
Stop and never re-challenge
Blood dyscrasias
Thrombocytopenia, leukopenia, agranulocytosis, pancytopenia
Stop; use another antiseizure medication

Overdose & Toxicity Management

  • Signs by level (total phenytoin): lateral-gaze nystagmus near 20 mcg/mL, ataxia near 30 mcg/mL, slurred speech and lethargy above 40 mcg/mL. Then comes coma, hypotension and respiratory depression. Individual variation is wide. The estimated lethal adult dose is 2–5 g.
  • Fosphenytoin-specific: formate can cause a severe anion-gap metabolic acidosis. A rapid phosphate load can cause hypocalcemia (paresthesia, spasms, seizures). Check ionized calcium.
  • Management: stop the drug. Support airway, breathing and circulation. Keep continuous ECG. Consider co-ingested sedatives or alcohol.
  • Antidote: none. Hemodialysis can be considered. Exchange transfusion has been used in children.

Monitoring
ParameterWhen / How OftenTarget / Act If
Clinical: ECG, BP, RR and SpO₂
Continuously during IV loading and for 10–20 min after the fosphenytoin infusion ends
Hypotension, bradycardia (adults HR <50 bpm; children low for age), AV block, QT prolongation or ventricular arrhythmia: slow or stop; treat per ACLS
Clinical: seizures and mental status
Continuously during and after the load
Still seizing 20 min after the load started: different second-line drug or anesthetic infusion with continuous EEG. Not waking up: evaluate for ongoing nonconvulsive seizures
Clinical: IV site and limb
Every check during the infusion and for several days after either drug (mostly phenytoin; also reported with fosphenytoin)
Distal swelling, purple discoloration or pain: stop at that site, notify the provider
Clinical: sensory symptoms (fosphenytoin)
During the infusion
Groin or perineal burning or itching: slow or pause the infusion
Drug Levels: total phenytoin
At least 2 hr after IV fosphenytoin ends (4 hr after IM); trough during maintenance
Target 10–20 mcg/mL. Above 20 mcg/mL with nystagmus or ataxia: hold and recheck
Drug Levels: free (unbound) phenytoin
With low albumin, renal or hepatic disease, or pregnancy
Target 1–2 mcg/mL. Dose by the free level, not the total
Laboratory: glucose
Baseline and during maintenance, especially in diabetes
Rising glucose: treat per protocol (phenytoin inhibits insulin release)
Laboratory: liver panel and CBC
Baseline on long-term therapy and with any fever, rash or lymph node swelling
Abnormal liver panel or CBC with these signs: stop, evaluate for DRESS
Laboratory: ionized calcium and phosphate
Fosphenytoin overdose or severe renal impairment
Low calcium: replace and recheck
Laboratory: ammonia
When given with valproate
Rising ammonia or new lethargy: evaluate for hyperammonemia

Interactions & Compatibility

Clinically Significant Interactions

Drug / ClassEffectWhat To Do
Valproate
Unpredictable phenytoin levels (protein-binding displacement); higher risk of hyperammonemia
Monitor free phenytoin and ammonia
Nondepolarizing neuromuscular blockers (rocuronium, vecuronium, cisatracurium)
Resistance and faster recovery in patients on long-term phenytoin
Expect higher doses or infusion rates; monitor train-of-four
Drugs that raise phenytoin (amiodarone, fluconazole and other azoles, trimethoprim-sulfamethoxazole, isoniazid, cimetidine, omeprazole, fluoxetine, acute alcohol)
Toxicity: saturable metabolism magnifies small increases
Check a level when one is started or stopped
Drugs that lower phenytoin (carbamazepine, rifampin, chronic alcohol use, St. John's wort, theophylline, some chemotherapy)
Subtherapeutic levels and breakthrough seizures
Check levels; adjust the dose
Enteral tube feeds, antacids, sucralfate
Lower absorption of oral or tube-given phenytoin: subtherapeutic levels
Do not give phenytoin with tube feeds; separate it from feeds and antacids per pharmacy protocol; check levels more often, especially when switching between IV and enteral dosing
DOACs (apixaban, rivaroxaban, dabigatran, edoxaban), ticagrelor
Levels lowered by enzyme induction: loss of protection
Avoid the combination where possible; involve pharmacy
Warfarin
INR may rise or fall
Monitor INR closely when phenytoin starts or stops
Other drugs weakened by induction (hormonal contraceptives, corticosteroids, cyclosporine, methadone, nifedipine, nimodipine, verapamil, quetiapine, clozapine, many antiretrovirals)
Reduced effect; delavirdine is contraindicated
Review the full medication list; adjust doses

IV Compatibility

  • Fosphenytoin: compatible with D5W and 0.9% sodium chloride (1.5–25 mg PE/mL).
  • Phenytoin: 0.9% sodium chloride only. It precipitates in dextrose-containing fluids. Flush the line with saline before and after each dose.
  • Verify with an institutional compatibility resource.

Special Populations
  • Pediatrics: fosphenytoin is labeled from birth, for status epilepticus and neurosurgical seizures. Its rate limits are weight-based. Ordinarily, don't use IM in children. Use it only when IV access is impossible. Pediatric trials show levetiracetam works as well, with fewer adverse events and recurrences. Find the doses in the Pediatric Dosing table.
  • Neonates: phenobarbital comes first per the ILAE 2023 neonatal guideline. Phenytoin or fosphenytoin is a second-line option. Levetiracetam may be preferred with cardiac disease.
  • Pregnancy: prenatal phenytoin exposure raises the risk of major malformations, such as orofacial clefts and cardiac defects. It can also cause fetal hydantoin syndrome: craniofacial, nail and digit changes, plus growth and cognitive deficits. Give vitamin K to the mother before delivery and to the newborn, to prevent neonatal bleeding. Clearance rises in pregnancy, so follow free levels. In status epilepticus, stop the seizure first. For eclampsia, use magnesium sulfate. Enroll patients in the North American Antiepileptic Drug Pregnancy Registry.
  • Lactation: phenytoin passes into breast milk. Weigh the benefits of breastfeeding against the mother's need for the drug and against any effect on the infant.
  • Older Adults: clearance is about 20% lower after age 70. Cardiovascular complications are more common too. Use slower infusions, and lower or less frequent maintenance doses. AGS Beers Criteria 2023: avoid trimethoprim-sulfamethoxazole with phenytoin (toxicity).
  • Renal Impairment: no fixed dose change. Uremia raises the free fraction, so dose by free levels. If phosphate is restricted, count the fosphenytoin phosphate load. Hemodialysis can be considered in overdose.
  • Hepatic Impairment: metabolism is hepatic and saturable, so toxicity shows up early. Dose by free levels. Use lower maintenance doses, and avoid oral loading.
  • Obesity / Dosing Weight: the label gives no obesity weight and no mg maximum. The 1,500 mg PE cap (ESETT; ACEP 2024) is reached at 75 kg with 20 mg PE/kg. Above that, it may be submaximal. Follow institutional policy and check a post-load level.
  • CYP2C9 and HLA-B*1502 carriers: CYP2C9*2 or *3 carriers clear phenytoin more slowly. Start low and follow levels. HLA-B*1502 raises the SJS/TEN risk.

Field & Transport Considerations
  • Scope: ED, ICU, critical-care and flight transport (RN, paramedic and CCT under protocol). Ground EMS rarely carries it. It varies by state and agency protocol.
  • Storage & Stability: fosphenytoin vials need refrigeration at 2–8°C (36–46°F). They should not sit at room temperature for more than 48 hr, which limits them in vehicle kits. Phenytoin vials are stored at 20–25°C (68–77°F). Cold can cause a precipitate, and it redissolves at room temperature.
  • Carried Concentration: both injections read 50 per mL. Fosphenytoin is 50 mg PE/mL, and phenytoin is 50 mg/mL. A 10 mL fosphenytoin vial holds 500 mg PE, not 50 mg PE.
  • Infusions in Transport: pump only, with continuous ECG, BP and SpO₂. At handoff, confirm which drug is running, fosphenytoin or phenytoin. Confirm the dose in mg PE, the rate and the volume left. A phenytoin infusion must finish within 1–4 hr of mixing.
  • Airway: about 1 in 4 patients in the ESETT fosphenytoin arm needed intubation (26%). Prepare for airway support after benzodiazepines and a second-line load.
  • Handoff Essentials: seizure onset time; benzodiazepine doses and times; load start and stop times, total mg PE and rate; any hypotension, bradycardia or arrhythmia; current seizure activity and mental status; when the post-load level is due (2 hr or more after the infusion ends).

Clinical Pearls
Status epilepticus timing: Stabilize for 0–5 min. At 5 min, give one benzodiazepine course: two doses at most, counting EMS and ED doses. Still seizing 5 min after an adequate dose? Start a second-line drug now, no later than the 20-minute mark. At 40 min of seizure, switch to a different second-line drug or an anesthetic infusion with continuous EEG.
Exam discriminator: fosphenytoin vs phenytoin:
  • Units: mg PE vs mg
  • Max adult rate: 150 mg PE/min vs 50 mg/min
  • Diluent: D5W or saline vs saline only
  • IM: possible (non-emergent, ordinarily not for status epilepticus) vs avoid
  • Storage: refrigerated vs room temperature
Faster to infuse, not faster to work: The rate cap for fosphenytoin was chosen to match free phenytoin levels from a 50 mg/min phenytoin infusion. The payoff is a shorter infusion (13 vs 44 min in the label trial), less site pain and an IM option.
A normal total level can be toxic: Low albumin, uremia or liver disease leaves more phenytoin unbound. Nystagmus, ataxia or confusion? Believe the patient and send a free level.
Groin burning is not an allergy: Burning or itching in the groin and perineum is common when fosphenytoin runs fast. Slow or pause it. It usually fades within minutes.
Second-line choice: In ESETT, each of fosphenytoin, levetiracetam and valproate stopped seizures in about half of patients. Fosphenytoin had numerically more life-threatening hypotension: 3.2% against 0.7% for levetiracetam. Patients were randomized even when already on maintenance antiseizure drugs, with no regard to their home medication.
Do not draw the level too early: Fosphenytoin needs time to convert, about 2 hr after IV. Until then, immunoassays cross-react and overestimate phenytoin. An early high number can lead to under-dosing.

Pharmacology

Mechanism of Action

  • Phenytoin blocks voltage-gated sodium channels in a voltage-dependent way. That means fewer sustained high-frequency neuronal discharges, and less seizure spread.
  • Fosphenytoin is an inactive, water-soluble prodrug. Phosphatases convert it to phenytoin, phosphate and formaldehyde, then formate.
  • Phenytoin's effects on cardiac conduction and automaticity explain the bradycardia, heart block and hypotension you see with fast IV loading.

Pharmacokinetics

RouteOnsetPeakDuration
IV fosphenytoin
Builds during the infusion (converted with a T½ of about 15 min)
10–20 min after the infusion ends
≥12 hr (phenytoin T½ 12–29 hr)
IM fosphenytoin
Slower than IV
Phenytoin about 3 hr
≥12 hr
IV phenytoin
Builds during the infusion
End of infusion
≥12 hr (T½ 10–15 hr)
PO phenytoin (extended capsules)
Slow, extended absorption
4–12 hr
≥24 hr (once-daily dosing possible)
  • Half-life: IV phenytoin 10–15 hr; 12–29 hr after fosphenytoin loads (longer at higher levels); oral average 22 hr (7–42 hr). Oral steady state takes 7–10 days.
  • Metabolism: hepatic, through CYP2C9 and to a lesser extent CYP2C19. Metabolism saturates (it is nonlinear), so a small dose increase near the top of the range causes a large rise in level.
  • Protein binding: phenytoin is about 88% bound to albumin, leaving 12% free. Fosphenytoin is 95–99% bound. During conversion it displaces phenytoin, which raises the free fraction to as much as 30%.
  • Elimination: mostly as inactive metabolites (HPPH and its glucuronide), in bile and urine. Only 1–5% leaves unchanged.

Names & Classification
Generic Name
Fosphenytoin sodium; phenytoin sodium (injection, extended capsules); phenytoin free acid (chewable tablets, suspension)
Brand Names
Cerebyx (fosphenytoin); Dilantin, Dilantin Infatabs, Dilantin-125, Phenytek (phenytoin); generics
Pharmacologic Class
Hydantoin; voltage-gated sodium channel blocker
Therapeutic Class
Antiseizure medication (anticonvulsant)
Controlled Substance
Not controlled
ISMP High-Alert
No
Look-Alike / Sound-Alike
Cerebyx / CeleBREX (celecoxib); Cerebyx / CeleXA (citalopram); fosphenytoin / phenytoin (mg PE vs mg)
Error-Prone Orders to Avoid
Fosphenytoin ordered in "mg" without "PE"; vial concentration (50 mg PE/mL) mistaken for vial content

Related

References
  1. Pfizer Laboratories. (2025). Cerebyx (fosphenytoin sodium) injection [prescribing information]. DailyMed, National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d4c36fad-0ba2-4cd4-9c5e-dcf843f38a5a
  2. Hikma Pharmaceuticals USA. (2024). Phenytoin sodium injection, USP [prescribing information]. DailyMed, National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=035a8d4e-2063-4240-83cb-d7eebcabe301
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