Fosphenytoin: Complete Drug Monograph

Quick Facts

Pharmacokinetic Profile

Conversion Half-Life

~15 min (to phenytoin)

Phenytoin Half-Life

12.0–28.9 h (dose-dependent)

Metabolism

Phosphatases → phenytoin; CYP2C9 (major), CYP2C19 (minor)

Protein Binding

Fosphenytoin 95–99%; phenytoin ~88% (free fraction ~12%)

Bioavailability

100% IV and IM

Volume of Distribution

4.3–10.8 L (fosphenytoin)

Clinical Information

Drug Class

Hydantoin (phenytoin prodrug)

Available Strength

50 mg PE/mL — 2 mL (100 mg PE) & 10 mL (500 mg PE) single-dose vials

Route

IV (preferred); IM

Renal Adjustment

Monitor unbound phenytoin

Hepatic Adjustment

Monitor unbound phenytoin; lower or less frequent dosing

Pregnancy

Fetal harm — congenital malformations & fetal hydantoin syndrome

Lactation

Phenytoin secreted in human milk; weigh benefits vs risk

Schedule / Legal

Rx only — non-scheduled

Generic Available

Yes

Boxed Warning

Cardiovascular risk — rapid infusion rates

Indications

Indication	Approved Population	Therapy Type	Status
Generalized tonic-clonic status epilepticus	Adults and pediatric patients (all ages)	Acute control	FDA Approved
Prevention & treatment of seizures during neurosurgery	Adults	Acute / perioperative	FDA Approved
Short-term substitute for oral phenytoin	Adults and pediatric patients	Substitution when oral administration is not possible	FDA Approved

Fosphenytoin is a water-soluble phosphate-ester prodrug of phenytoin developed to overcome the parenteral limitations of intravenous phenytoin sodium — namely the propylene glycol diluent, the strongly alkaline pH, and the resulting risk of tissue injury at the infusion site. After IV or IM administration, plasma and tissue phosphatases convert fosphenytoin to phenytoin with a conversion half-life of approximately 15 minutes, yielding the same therapeutic moiety with markedly better infusion-site tolerability. All doses, concentrations, and infusion rates are expressed in phenytoin sodium equivalents (PE): 1.5 mg fosphenytoin sodium = 1 mg phenytoin sodium = 1 mg PE.

Off-Label Uses

Early seizure prophylaxis after moderate–severe traumatic brain injury (≤7 days): Supported by Brain Trauma Foundation guideline (Level IIA recommendation for early post-traumatic seizure prophylaxis). Evidence: moderate quality.

Status epilepticus in pregnancy / eclampsia-related seizures refractory to magnesium and benzodiazepines: Magnesium sulfate remains first-line for eclampsia; fosphenytoin may be used when seizures persist despite first-line therapy. Evidence: low quality (case series, expert consensus).

Trigeminal neuralgia (acute exacerbation requiring parenteral therapy): Considered when oral therapy is not feasible. Evidence: low quality.

Dose

Dosing

All fosphenytoin doses are prescribed and dispensed in phenytoin sodium equivalents (PE). The 50 mg PE/mL vial concentration must not be confused with the total vial content (100 mg PE in the 2 mL vial; 500 mg PE in the 10 mL vial) — this misreading has caused fatal overdoses. The tables below organize dosing by clinical scenario rather than by vial strength to support bedside decision-making during emergencies.

Adult Dosing

Clinical Scenario	Starting Dose	Maintenance Dose	Maximum Dose / Rate	Notes
Status epilepticus (generalized tonic-clonic) — adults	15–20 mg PE/kg IV	4–6 mg PE/kg/day IV in divided doses	Infuse at 100–150 mg PE/min (do not exceed 150 mg PE/min)	IM should ordinarily not be used in status epilepticus Concomitant IV benzodiazepine usually required for seizure control
Non-emergent loading dose — adults	10–20 mg PE/kg IV or IM	4–6 mg PE/kg/day in divided doses	IV: not to exceed 150 mg PE/min	Administer more slowly than in status epilepticus to reduce cardiac risk Oral phenytoin should be used whenever possible
Short-term substitute for oral phenytoin (when oral not possible)	Same total daily PE dose as prior oral phenytoin	Same total daily PE dose, given IV or IM	IV: not to exceed 150 mg PE/min	1 mg PE = 1 mg phenytoin sodium; no molecular weight adjustment Phenytoin from fosphenytoin is 100% bioavailable; oral Dilantin is ~90%
Neurosurgical seizure prophylaxis (perioperative)	10–20 mg PE/kg IV	4–6 mg PE/kg/day in divided doses	≤150 mg PE/min IV	Long-term prophylaxis without seizure not routinely supported Reassess need beyond 7 days post-op

Pediatric Dosing (birth to less than 17 years)

Clinical Scenario	Starting Dose	Maintenance Dose	Maximum Dose / Rate	Notes
Status epilepticus — pediatric	15–20 mg PE/kg IV	See initial maintenance below	2 mg PE/kg/min, or 150 mg PE/min, whichever is slower	Continuous cardiac, BP, and respiratory monitoring required IM should ordinarily not be used in pediatric patients
Non-emergent loading dose — pediatric	10–15 mg PE/kg IV	See initial maintenance below	1–2 mg PE/kg/min, or 150 mg PE/min, whichever is slower	Therapeutic total phenytoin range 10–20 mcg/mL (unbound 1–2 mcg/mL)
Initial maintenance dose — pediatric	2–4 mg PE/kg given 12 hours after the loading dose		1–2 mg PE/kg/min, or 100 mg PE/min, whichever is slower	Note the lower maintenance rate ceiling (100 mg PE/min) versus loading (150 mg PE/min)
Ongoing maintenance dose — pediatric	4–8 mg PE/kg/day in divided doses every 12 hours		1–2 mg PE/kg/min, or 100 mg PE/min, whichever is slower	Adjust based on serum phenytoin concentrations

Dose Adjustment in Special Populations

Population	Starting Dose	Maintenance Dose	Maximum Dose / Rate	Notes
Renal impairment, hepatic impairment, or hypoalbuminemia	Standard loading dose	Adjust to unbound phenytoin concentration	Standard infusion limits	Fosphenytoin clearance to phenytoin may be increased without a corresponding increase in phenytoin clearance, raising adverse-event risk Total phenytoin levels misleading — measure unbound
Geriatric (≥65 years)	Standard loading dose	Lower or less frequent dosing	Standard limits, but consider slower infusion in cardiac comorbidity	Phenytoin clearance ~20% lower in patients >70 versus 20–30 y Severe complications more common in elderly
CYP2C9 intermediate or poor metabolizers (e.g., 1/3, 2/2, 3/3)	Start at low end of dosage range	Lower maintenance to keep total phenytoin 10–20 mcg/mL	Standard infusion limits	If early CNS toxicity develops, check serum levels immediately CYP2C9*3 also linked to increased SCAR risk
Pregnancy	Standard loading dose	Adjust based on serum levels (unbound)	Standard limits	Phenytoin clearance generally rises in pregnancy and peaks in T3 Postpartum dose reduction usually needed

Clinical Pearl — Infusion Rate Math & Dosing-Error Prevention

For an 80 kg adult in status epilepticus receiving 20 mg PE/kg = 1,600 mg PE total. At the maximum rate of 150 mg PE/min, the load takes about 11 minutes; the same dose of IV phenytoin sodium (max 50 mg/min) would take about 32 minutes. This time advantage is the principal clinical reason fosphenytoin is selected when speed is critical.

Fatal overdoses have occurred when the vial concentration (50 mg PE/mL) was misread as the total vial content. Always express orders, labels, and pump displays in mg PE, and verify total vial content (100 mg PE in 2 mL; 500 mg PE in 10 mL) before drawing up.

For IV infusion, dilute fosphenytoin in 5% dextrose injection or 0.9% sodium chloride injection to a final concentration of 1.5–25 mg PE/mL.

Pharmacology

Mechanism of Action

Fosphenytoin is an inactive phosphate-ester prodrug; its anticonvulsant effect is attributable entirely to phenytoin, its active metabolite. After parenteral administration, phosphatases hydrolyze fosphenytoin to phenytoin, phosphate, and formaldehyde (the latter further metabolized to formate). Phenytoin acts through voltage-dependent blockade of neuronal sodium channels, preferentially affecting channels in their inactivated state. This stabilization prolongs the refractory period of rapidly firing cortical neurons and limits the sustained, high-frequency action-potential propagation that underlies focal and secondarily generalized seizures, while leaving normal background neuronal activity largely undisturbed at therapeutic concentrations.

Phenytoin’s saturable (Michaelis–Menten) hepatic metabolism explains much of its clinical complexity: small dose changes near saturation can produce large concentration shifts. Its narrow therapeutic window and extensive protein binding further demand careful titration and level monitoring.

ADME Profile

Parameter	Value	Clinical Implication
Absorption	IV: maximum fosphenytoin concentrations at end of infusion. IM: fosphenytoin completely bioavailable; fosphenytoin Cmax at ~30 min and total phenytoin Cmax at ~3 h post-dose	IV preferred when therapeutic phenytoin concentrations are needed quickly; IM reserved for situations where IV access is impossible (and not used in status epilepticus or in pediatric patients)
Distribution	Fosphenytoin Vd 4.3–10.8 L; fosphenytoin protein binding 95–99% (saturable, primarily albumin); phenytoin highly protein-bound but to a lesser extent (~12% unbound, rising up to ~30% during the conversion period as fosphenytoin displaces phenytoin)	Free fraction rises further in renal disease, hepatic disease, hypoalbuminemia, and pregnancy — measure unbound phenytoin in these populations
Metabolism	Phosphatases convert fosphenytoin to phenytoin (conversion t½ ~15 min); phenytoin metabolized by CYP2C9 (major) and CYP2C19 (minor); metabolism is saturable	Disproportionate increases in total and unbound phenytoin AUC with rising dose; CYP2C9 polymorphisms (e.g., 2, 3 alleles) reduce clearance
Elimination	Fosphenytoin not excreted in urine; phenytoin metabolites excreted renally (primarily as the p-hydroxyphenyl glucuronide); only 1–5% of the dose recovered as unchanged phenytoin in urine; phenytoin t½ 12.0–28.9 h, increasing at higher concentrations	Apparent half-life lengthens at supratherapeutic levels; toxicity may persist longer than expected

Therapeutic plasma concentrations: total phenytoin 10–20 mcg/mL; unbound phenytoin 1–2 mcg/mL. Lateral gaze nystagmus typically appears at total levels ≥20 mcg/mL, ataxia at ≥30 mcg/mL, and dysarthria/lethargy at ≥40 mcg/mL — though there is wide interindividual variability.

Side Effects

Adverse effects fall into three groups: dose- and rate-related events occurring during or shortly after IV infusion, dose-dependent CNS effects related to phenytoin concentration, and idiosyncratic hypersensitivity and hematologic reactions. The incidence figures below are drawn from the controlled adult IV trial in the Cerebyx prescribing information (maximum dose and rate; n = 90), with pediatric figures from the open-label fosphenytoin study (n = 96).

≥10% Very Common (Adult IV, max dose & rate)

Adverse Effect	Incidence	Clinical Note
Pruritus (especially groin and perineum)	49%	Distinctive infusion-related itching/burning; transient, generally resolves within ~10 min after infusion ends; slowing or briefly stopping the infusion lessens it
Nystagmus	44%	Dose-related; first sign of supratherapeutic levels — recheck phenytoin concentration if new
Dizziness	31%	Concentration-dependent; correlates with peak unbound phenytoin
Somnolence	20%	More pronounced when administered with benzodiazepines for status epilepticus
Ataxia	11%	Indicates levels at or above the upper therapeutic range
Vomiting (pediatric IV)	21%	Most frequent adverse event in the pediatric open-label study
Nystagmus (pediatric IV)	18%	Same significance as in adults
Ataxia (pediatric IV)	10%	Suggests level at upper end of range

1–10% Common

Adverse Effect	Incidence	Clinical Note
Nausea	9%	Particularly with IM administration
Tinnitus	9%	Resolves with rate reduction or completion of infusion
Hypotension	8%	Dose- and rate-dependent; slow or pause infusion; supportive fluids if symptomatic
Stupor	8%	Distinguish from postictal state; recheck level if prolonged
Hypotension (pediatric)	5%	Continuous cardiac and BP monitoring during loading is mandatory
Vasodilatation	6%	Often coincident with hypotension during infusion
Pruritus (pediatric IV)	6%	Lower incidence than in adults; same management — slow the infusion
Somnolence (pediatric IV)	6%	Often coincident with ataxia and nystagmus
Rash (pediatric IV)	5%	Discontinue at first sign of rash unless clearly not drug-related
Pelvic pain, asthenia, back pain	2–4% each	Generally self-limited
Paresthesia	4%	Often coincident with pruritus; settles after infusion ends
Headache	2%	Usually self-limited
Dysarthria, vertigo, diplopia, taste perversion, tachycardia	2–3% each	Reversible; assess phenytoin level if persistent
Injection-site reaction (IM CEREBYX vs oral phenytoin study)	~3%	Markedly less than with IV phenytoin sodium; rotate sites if repeated IM dosing required

Serious Serious — Regardless of Frequency

Adverse Effect	Estimated Frequency	Typical Onset	Required Action
Severe hypotension; cardiac arrhythmias (bradycardia, heart block, QT prolongation, ventricular tachycardia/fibrillation, asystole, cardiac arrest)	Rare; risk ↑ with rapid infusion, cardiac comorbidity, elderly, but reported at recommended rates	During or shortly after infusion	Reduce rate or stop infusion; supportive care; do not resume if event is severe — consider alternative anticonvulsant
Severe cutaneous adverse reactions (SJS, TEN, DRESS, AGEP)	Rare	Usually within 28 days of starting therapy, but may occur later	Discontinue at first sign of rash; do not resume; consider non-hydantoin alternative; HLA-B1502 carriers (Asian ancestry) and CYP2C93 carriers face increased SCAR risk
DRESS / multi-organ hypersensitivity (fever, rash, lymphadenopathy, facial swelling, hepatitis, nephritis, hematologic abnormalities, eosinophilia)	Rare; some fatal	Usually within weeks of starting	Permanent discontinuation; evaluate hepatic, renal, hematologic systems; supportive care; corticosteroids in severe cases
Acute hepatotoxicity, including acute hepatic failure	Infrequent	First weeks; may accompany DRESS	Permanent discontinuation; supportive care; future use is contraindicated
Hematopoietic complications (thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia, megaloblastic anemia, pure red cell aplasia)	Occasional; some fatal	Variable	Discontinue and consider alternative anticonvulsant; folate supplementation if megaloblastic
Angioedema (facial, perioral, upper-airway swelling)	Postmarketing reports; frequency not established	Minutes to hours	Discontinue immediately; emergency airway and circulatory support; permanent discontinuation if no alternative cause
Anaphylaxis	Postmarketing reports; frequency not established	Minutes after exposure	Emergency supportive care; epinephrine; permanent discontinuation
Purple glove syndrome (edema, discoloration, pain distal to injection site)	Reported with fosphenytoin but markedly less common than with IV phenytoin sodium	Hours to several days after injection	Discontinue; elevate limb; vascular surgery review if severe
Suicidal ideation and behaviour (antiepileptic-drug class effect)	~0.43% (FDA pooled meta-analysis of antiepileptic drugs)	As early as 1 week into therapy	Counsel patients/caregivers; assess mood at each clinical contact
Withdrawal-precipitated seizure / status epilepticus	Variable	After abrupt discontinuation	Withdraw gradually unless rapid substitution required (e.g., hypersensitivity); alternative AED should not be a hydantoin
Cerebellar dysfunction / atrophy (chronic supratherapeutic exposure)	Rare	Months to years; described after overdosage	Avoid sustained supratherapeutic levels; prompt dose reduction at first signs of toxicity
Hyperglycemia (inhibition of insulin release)	Reported	During therapy	Monitor glucose, especially in diabetes

Discontinuation Discontinuation Rates (Premarketing Trials, n = 859)

All-cause discontinuation

~2%

Most common reasons: pruritus, hypotension, bradycardia.

Pediatric data

Limited

Specific pediatric discontinuation rates are not reported in the Cerebyx label; the overall pediatric adverse-reaction profile is similar to adults.

Reason for Discontinuation	Incidence	Context
Pruritus	0.5%	Most common single reason; usually managed with rate reduction rather than stopping
Hypotension	0.3%	Generally rate-related; many patients tolerate slower infusion
Bradycardia	0.2%	Continuous cardiac monitoring is required during loading

Management Pearl — Infusion-Related Pruritus & Paresthesia

The transient itching, burning, and warmth — frequently in the groin or perineum — is the single most distressing experience for awake patients receiving fosphenytoin. It is not an allergic reaction; it reflects a direct effect of the phosphate moiety and resolves within minutes of infusion completion. Slowing or briefly pausing the infusion usually relieves symptoms, and counselling patients before starting prevents premature discontinuation. Most alert patients receiving ≥15 mg PE/kg at 150 mg PE/min experience some degree of discomfort.

Int

Drug Interactions

Once converted to phenytoin, fosphenytoin inherits phenytoin’s extensive interaction profile. Phenytoin is a substrate of CYP2C9 (major) and CYP2C19 (minor), is highly protein-bound (creating displacement interactions), and is a potent inducer of hepatic drug-metabolizing enzymes including CYP3A4. The cards below highlight the most clinically important pairings; the full medication list should be reviewed before any loading dose. The Cerebyx label notes that this list is not exhaustive — individual product information for any concurrent agent should be consulted.

Contraindicated Delavirdine

MechanismPhenytoin substantially reduces delavirdine concentrations via CYP3A4 induction

EffectLoss of virologic response; possible NNRTI-class resistance

ManagementCoadministration is contraindicated — switch to alternative AED or alternative antiretroviral

FDA PI

Major Warfarin

MechanismBidirectional — both increased and decreased PT/INR responses reported

EffectUnpredictable INR; bleeding or thrombotic risk

ManagementFrequent INR checks (e.g., every few days for the first 2 weeks); also monitor phenytoin levels

FDA PI · Lexicomp

Major Combined hormonal contraceptives

MechanismPhenytoin reduces the efficacy of estrogens and oral contraceptives via enzyme induction

EffectContraceptive failure

ManagementUse a non-hormonal or progestin-only injectable/implant method, or copper/levonorgestrel IUD

FDA PI

Major Direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban)

MechanismPhenytoin decreases DOAC concentrations via enzyme/transporter induction

EffectSubtherapeutic anticoagulation; thrombotic risk

ManagementAvoid combination — switch to LMWH or warfarin (with INR monitoring) if anticoagulation is required

FDA PI · DOAC product labels

Major Azole antifungals (fluconazole, voriconazole, ketoconazole, itraconazole, posaconazole, miconazole)

MechanismAzoles inhibit phenytoin metabolism (CYP2C9); phenytoin in turn induces voriconazole/posaconazole metabolism

EffectPhenytoin toxicity; potentially subtherapeutic azole levels

ManagementMonitor phenytoin level; for voriconazole, dose adjustment per its label is required if combination is unavoidable

FDA PI · Lexicomp

Major Rifampin

MechanismStrong enzyme induction lowers phenytoin levels

EffectLoss of seizure control

ManagementMonitor phenytoin level and adjust dose; consider a non-inducer AED in TB regimens

FDA PI

Major Isoniazid, chloramphenicol, disulfiram, ticlopidine, amiodarone

MechanismInhibition of CYP2C9/2C19 raises phenytoin levels

EffectPhenytoin toxicity

ManagementCheck phenytoin level early after addition; reduce dose to maintain <20 mcg/mL

FDA PI · Lexicomp

Major Valproate / valproic acid

MechanismProtein-binding displacement plus partial CYP2C9 inhibition; total phenytoin may fall while unbound rises. Concomitant use also raises risk of valproate-associated hyperammonemia.

EffectPhenytoin toxicity at apparently normal total levels; symptomatic hyperammonemia

ManagementUse unbound phenytoin to guide therapy; monitor for hyperammonemia signs/symptoms; check ammonia if unexplained encephalopathy

FDA PI

Moderate SSRIs (fluoxetine, fluvoxamine, sertraline)

MechanismCYP2C9/2C19 inhibition raises phenytoin concentrations

EffectPhenytoin toxicity

ManagementCheck phenytoin level after starting any of these SSRIs; note that all three are listed in the Cerebyx label as agents that may raise phenytoin levels

FDA PI · Lexicomp

Moderate Carbamazepine, phenobarbital, valproate (level direction is variable)

MechanismBidirectional effects on phenytoin levels are reported with these AEDs

EffectVariable changes in seizure control

ManagementCheck both drug levels after any change; titrate to clinical effect and target ranges

FDA PI

Moderate Corticosteroids (prednisone, dexamethasone)

MechanismPhenytoin enzyme induction lowers steroid exposure

EffectReduced anti-inflammatory or anti-edema efficacy (relevant in neuro-oncology)

ManagementIncrease steroid dose or switch AED to a non-inducer (e.g., levetiracetam)

FDA PI · NCCN

Moderate Calcineurin / mTOR inhibitors (cyclosporine; also nifedipine, nimodipine, verapamil for CCBs)

MechanismPhenytoin reduces concentrations of cyclosporine and the calcium channel blockers nifedipine, nimodipine, nisoldipine, verapamil through induction

EffectPossible graft rejection; loss of antihypertensive control

ManagementUse a non-inducing AED if possible; otherwise monitor relevant drug level/blood pressure

FDA PI

Moderate Non-depolarizing neuromuscular blockers (cisatracurium, pancuronium, rocuronium, vecuronium)

MechanismResistance to neuromuscular blockade in patients chronically receiving phenytoin

EffectFaster recovery from blockade; higher infusion-rate requirements

ManagementMonitor train-of-four; anticipate higher dose requirements

FDA PI

Moderate Statins (atorvastatin, fluvastatin, simvastatin)

MechanismPhenytoin lowers atorvastatin, fluvastatin, simvastatin concentrations

EffectReduced lipid-lowering effect

ManagementMonitor lipid response; consider a non-CYP-metabolized statin (pravastatin, rosuvastatin)

FDA PI

Moderate St. John’s wort, folic acid, chronic alcohol

MechanismAll may decrease phenytoin serum levels; folic acid supplementation accelerates phenytoin clearance

EffectLoss of seizure control

ManagementCounsel against St. John’s wort; if folate is required (e.g., pregnancy planning), recheck phenytoin level after starting

FDA PI

Minor Antacids (Al/Mg-containing) — relevant after switch to oral phenytoin

MechanismReduced GI absorption (not relevant to IV/IM fosphenytoin itself)

EffectLower oral phenytoin bioavailability

ManagementSeparate doses by ≥2 hours when transitioning to oral therapy

Lexicomp

Mon

Monitoring

The monitoring schedule blends mandatory infusion-period observations with longer-term safety surveillance for patients continuing phenytoin therapy after the parenteral course.

Continuous ECG During infusion + 10–20 min after (peak phenytoin)
Routine Watch for bradycardia, heart block, QT changes, ventricular ectopy. Reduce rate or stop infusion for any new arrhythmia or marked rhythm disturbance.
Blood Pressure Frequent (every few minutes) during infusion
Routine Reduce rate or pause infusion for clinically significant hypotension; supportive fluids if symptomatic.
Respiratory rate, SpO₂ Continuous during infusion
Routine Particular vigilance with concurrent benzodiazepines; have airway support available.
Total phenytoin level ≥2 h after IV completion or ≥4 h after IM (after conversion is complete)
Routine Target 10–20 mcg/mL. Sampling earlier than these intervals causes immunoassay overestimation due to fosphenytoin cross-reactivity.
Unbound phenytoin When indicated
Trigger-based Target 1–2 mcg/mL. Indicated in renal impairment, hepatic impairment, hypoalbuminemia, pregnancy, valproate co-therapy, or unexplained toxicity at apparently normal total levels.
Liver function tests Baseline; with rash, fever, or systemic symptoms
Trigger-based Hepatocellular pattern with rash or eosinophilia suggests DRESS — immediate evaluation and discontinuation if no alternative cause.
Complete blood count Baseline; with rash, fever, or unexplained bruising
Trigger-based Watch for eosinophilia (DRESS), neutropenia, thrombocytopenia, megaloblastic changes, lymphadenopathy.
Renal function Baseline
Routine Informs interpretation of unbound fraction and phosphate load; important in severe renal impairment given the phosphate component of fosphenytoin.
Skin examination Daily during inpatient course
Routine Document any new rash. Mucosal involvement, blistering, fever, lymphadenopathy, or facial swelling warrants immediate discontinuation and dermatology review.
HLA-B*1502 / CYP2C9 genotyping Before first phenytoin exposure in selected patients
Trigger-based The Cerebyx label recommends considering avoidance in HLA-B*1502 carriers (most prevalent in patients of Asian, particularly Chinese, ancestry) and in CYP2C9*3 carriers, both of whom carry increased SCAR risk. Genotyping does not replace clinical vigilance.
Mood & suicidality At each clinical contact during chronic therapy
Routine FDA AED class effect — ask about new or worsening depression and intrusive thoughts.
Glucose Baseline and during therapy in patients with diabetes
Trigger-based Phenytoin can inhibit insulin release and elevate serum glucose.

Sampling Caveat — Immunoassay Cross-Reactivity

Common immunoassays for phenytoin (such as fluorescence polarization and enzyme multiplied methods) cross-react with unconverted fosphenytoin and may significantly overestimate phenytoin concentrations before conversion is complete. Draw samples at least 2 hours after IV completion or 4 hours after IM injection. If an earlier level is essential, alert the laboratory and request a chromatographic method, and collect the sample in an EDTA tube to minimize ex vivo conversion of fosphenytoin to phenytoin.

Contraindications & Cautions

FDA Boxed Warning Cardiovascular Risk Associated With Rapid Infusion Rates

The rate of intravenous fosphenytoin administration must not exceed 150 mg PE/min in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients, because of the risk of severe hypotension and cardiac arrhythmias.

Careful cardiac monitoring is required during and after administration. Although cardiovascular toxicity is more likely with rapid infusion, these events have also been reported at or below the recommended infusion rate. Reduce the rate of administration or discontinue dosing as needed.

Absolute Contraindications

Hypersensitivity to fosphenytoin, its inactive ingredients, phenytoin, or other hydantoins (including prior angioedema).
Sinus bradycardia, sino-atrial block, second- or third-degree A-V block, or Adams–Stokes syndrome (because of the effect of parenteral phenytoin or fosphenytoin on ventricular automaticity).
Prior history of acute hepatotoxicity attributable to fosphenytoin or phenytoin.
Coadministration with delavirdine — risk of antiretroviral failure and NNRTI-class resistance.

Relative Contraindications — Specialist Input Recommended

Pregnancy — phenytoin exposure in utero may increase the risks of major congenital malformations (including orofacial clefts and cardiac defects), fetal hydantoin syndrome (dysmorphic skull/facial features, nail and digit hypoplasia, growth abnormalities including microcephaly, cognitive deficits), and a vitamin K-dependent neonatal bleeding disorder. Use only when seizure control benefits outweigh these risks; coordinate with obstetrics and neurology; consider enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
HLA-B*1502 carriers (highest prevalence in patients of Asian, particularly Chinese, ancestry) — increased risk of SJS/TEN; the Cerebyx label recommends considering avoidance unless no alternative exists.
CYP2C9*3 carriers — increased risk of severe cutaneous adverse reactions and decreased phenytoin clearance; consider avoidance, or start at the low end of the dosage range with close serum-level monitoring.
Severe hepatic impairment — reduce dose or use less frequent dosing; monitor unbound phenytoin; consider non-inducing AED.
Hypoalbuminemia or end-stage renal disease — total phenytoin levels are misleading; monitor unbound levels.
Severe renal impairment requiring phosphate restriction — fosphenytoin delivers a phosphate load (0.0037 mmol phosphate per mg PE).
Diabetes mellitus — phenytoin may inhibit insulin release and worsen hyperglycemia; monitor glucose.
Acute intermittent porphyria — caution because phenytoin has been associated with exacerbations.

Use With Caution

Elderly patients — heightened risk of hypotension, sedation, and CNS toxicity; phenytoin clearance is reduced and lower or less frequent dosing may be required.
Cardiac disease (heart failure, structural disease, recent MI) — slow infusion and consider continuous cardiology input; severe complications are more frequent in this group.
Critically ill patients — early phenytoin toxicity may occur due to altered pharmacokinetics and protein binding; monitor unbound phenytoin.
Patients on multiple CYP-affecting drugs — verify the entire medication list before any loading dose; phenytoin both is metabolized by and induces CYP enzymes.
Patients receiving enteral feeds — relevant after switching to oral phenytoin; feeds reduce oral phenytoin bioavailability, so feeds should be held around oral doses per institutional protocol.

Patient Counselling

Purpose of Therapy

Explain that fosphenytoin is being given to stop or prevent seizures during the hospital stay and that it is converted by the body into phenytoin — the same medicine that some patients may know in oral form (Dilantin). Most patients receiving fosphenytoin are either acutely unwell (status epilepticus, post-neurosurgery) or temporarily unable to swallow oral phenytoin. The plan is usually to switch back to oral phenytoin once tolerated, or to transition to a different long-term anticonvulsant before discharge.

How It Will Be Given

Fosphenytoin is given through an IV line over 10–30 minutes (depending on the dose) or, less commonly, as an injection into a muscle. Patients will be on continuous heart monitoring with frequent blood-pressure checks during the infusion. A blood test is drawn afterwards (at least 2 hours after the IV finishes, or 4 hours after an IM injection) to confirm the level is in the right range.

Tingling, Itching, or Burning During Infusion

Tell patient It is common to feel tingling, itching, or warmth — often in the groin or face — during the infusion. This is a known reaction, not an allergy, and almost always settles within minutes after the infusion ends. Slowing or briefly pausing the drip usually relieves it.

Call prescriber For sudden swelling of the lips, face, mouth, or throat, difficulty breathing, hives, or wheezing — these are different reactions that need urgent assessment.

Drowsiness, Dizziness & Unsteadiness

Tell patient Drowsiness, mild double vision, and unsteadiness are common in the first day or two and usually mean the level is at the upper end of the target range. The team will adjust the dose based on blood tests.

Call prescriber If walking becomes very unsteady, speech becomes slurred, or thinking is markedly clouded — these can indicate too much drug.

Skin Rash

Tell patient A small minority of people develop a rash — usually within the first 28 days. Most rashes are mild, but some serious skin reactions need immediate care. Report any new rash promptly, even one that seems trivial.

Call prescriber For any rash with fever, painful skin or mouth sores, blistering, swollen face or glands, or feeling generally unwell. Stop the next dose and seek emergency evaluation.

Mood Changes & Suicidal Thoughts

Tell patient Antiepileptic medicines as a group carry a small increased risk of new or worsening depression and, rarely, thoughts of self-harm. Many people notice no change at all; we ask routinely so we don’t miss it.

Call prescriber For new or worsening depression, severe anxiety, agitation, or any thoughts of self-harm.

Drug Interactions & Other Medicines

Tell patient Phenytoin (the active drug fosphenytoin becomes) interacts with many medicines, including birth control pills, blood thinners, some antibiotics and antifungals, some antidepressants, and herbal products like St John’s wort. Bring an updated list of everything you take to every appointment.

Call prescriber Before starting any new medicine — including over-the-counter products, herbal remedies, and supplements — and after any antibiotic course or hospital admission elsewhere.

Pregnancy & Contraception

Tell patient Phenytoin can harm a developing baby, including risk of cleft lip and palate, heart defects, and neurodevelopmental issues. If pregnancy is possible, plan it with the neurology team. Hormonal contraception (the pill) can be less effective with phenytoin, so a non-hormonal method or a long-acting progestin method is generally preferred. Discuss folic acid supplementation with your team. If you become pregnant, please enroll in the North American AED Pregnancy Registry.

Call prescriber If pregnancy occurs or is being planned. Do not stop phenytoin abruptly — withdrawal can trigger seizures — but contact the team urgently for a tailored plan.

Don’t Stop Suddenly

Tell patient Stopping phenytoin abruptly can trigger seizures, including prolonged ones. Any change in dose or switch to another drug should be planned and gradual, unless your doctor stops it for safety (for example, an allergic reaction).

Call prescriber Before changing or stopping the medicine for any reason.

Ref

Sources

Regulatory (PI / SmPC)

Pfizer Laboratories. Cerebyx (fosphenytoin sodium injection) — full prescribing information. Revised August 2024. Available at: https://labeling.pfizer.com/ShowLabeling.aspx?id=749 Authoritative source for indications, dosing, infusion-rate limits, the Boxed Warning, contraindications, adverse-reaction tables, and CYP2C9/HLA-B*1502 guidance.
U.S. Food and Drug Administration. DailyMed: fosphenytoin sodium injection labels. Available at: https://dailymed.nlm.nih.gov/ Maintained repository of current FDA-approved labelling for branded and generic fosphenytoin products.

Key Clinical Trials

Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med. 1998;339(12):792–798. doi: 10.1056/NEJM199809173391202 Landmark VA Cooperative trial establishing phenytoin’s role in second-line status epilepticus management.
Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus (ESETT). N Engl J Med. 2019;381(22):2103–2113. doi: 10.1056/NEJMoa1905795 Pivotal head-to-head trial showing fosphenytoin, levetiracetam, and valproate had similar efficacy in benzodiazepine-refractory status epilepticus.
Boucher BA, Feler CA, Dean JC, et al. The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy. 1996;16(4):638–645. PMID: 8840370. Foundational pharmacokinetic and tolerability data in the neurosurgical population for which fosphenytoin was originally approved.

Guidelines

Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults — Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48–61. doi: 10.5698/1535-7597-16.1.48 Defines fosphenytoin (15–20 mg PE/kg) as a first-choice second-stage agent after benzodiazepine failure, alongside valproate and levetiracetam.
Carney N, Totten AM, O’Reilly C, et al. Brain Trauma Foundation: Guidelines for the Management of Severe Traumatic Brain Injury, 4th Edition. Neurosurgery. 2017;80(1):6–15. doi: 10.1227/NEU.0000000000001432 Supports phenytoin/fosphenytoin for early post-traumatic seizure prophylaxis (≤7 days) in moderate–severe TBI.
National Institute for Health and Care Excellence (NICE). Epilepsies in children, young people and adults (NG217). London: NICE; April 2022. Available at: https://www.nice.org.uk/guidance/ng217 UK guidance on AED selection, status epilepticus management, and pregnancy considerations.
Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus — Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515–1523. doi: 10.1111/epi.13121 ILAE consensus on operational definitions (t1, t2 timepoints) and treatment milestones in status epilepticus.

Mechanistic / Basic Science

Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5(7):553–564. doi: 10.1038/nrn1430 Mechanistic review of voltage-gated sodium-channel modulation by hydantoins and other AEDs.
Browne TR. Fosphenytoin (Cerebyx). Clin Neuropharmacol. 1997;20(1):1–12. PMID: 9037568. Early comprehensive review of fosphenytoin chemistry, conversion, and the rationale for the prodrug.

Pharmacokinetics / Special Populations

Fischer JH, Patel TV, Fischer PA. Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet. 2003;42(1):33–58. doi: 10.2165/00003088-200342010-00002 Comprehensive PK review covering adult, pediatric, geriatric, renal, and hepatic populations.
Aweeka FT, Gottwald MD, Gambertoglio JG, et al. Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease. Epilepsia. 1999;40(6):777–782. doi: 10.1111/j.1528-1157.1999.tb00778.x Demonstrates increased unbound phenytoin fraction and altered fosphenytoin clearance in renal/hepatic disease.
Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens–Johnson syndrome. Nature. 2004;428(6982):486. doi: 10.1038/428486a Original report linking HLA-B*1502 to severe cutaneous adverse reactions with aromatic antiepileptic drugs, supporting current pre-prescription screening recommendations.
Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs — best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239–1276. doi: 10.1111/j.1528-1167.2008.01561.x Practical guide to interpreting total versus unbound phenytoin levels and timing of post-load samples.
U.S. Food and Drug Administration. Statistical review and evaluation: antiepileptic drugs and suicidality. May 23, 2008. Available via FDA archives. Source for the AED-class suicidality risk estimate (~0.43% on AEDs versus ~0.22% on placebo).