What are the recommended dosing, infusion rates, therapeutic serum concentrations, and safety monitoring guidelines for intravenous and oral phenytoin in adults, including loading dose, maintenance dose, and special precautions for elderly patients, those with cardiac disease, hepatic impairment, or pregnancy?

Phenytoin Use Guidelines

Intravenous Phenytoin/Fosphenytoin Dosing

For status epilepticus, administer fosphenytoin 20 mg PE/kg IV at a maximum rate of 150 mg PE/min in adults (or 50 mg/min for standard phenytoin), with continuous cardiac and blood pressure monitoring required due to a 12% risk of hypotension. 1, 2

Loading Dose Protocol

• Adults: Fosphenytoin 15–20 mg PE/kg IV at 100–150 mg PE/min (maximum 150 mg PE/min), or standard phenytoin 15–20 mg/kg IV at ≤50 mg/min 1, 2, 3
• Pediatric patients (birth to <17 years): Fosphenytoin 15–20 mg PE/kg IV at 2 mg PE/kg/min or 150 mg PE/min, whichever is slower 2
• Non-emergent loading: Adults receive 10–20 mg PE/kg IV; pediatric patients receive 10–15 mg PE/kg IV at 1–2 mg PE/kg/min or 150 mg PE/min, whichever is slower 2

Maintenance Dosing

• Adults: Initial maintenance of 4–6 mg PE/kg/day in divided doses, not exceeding 150 mg PE/min infusion rate 2
• Pediatric patients: Initial maintenance dose of 2–4 mg PE/kg given 12 hours after loading, then 4–8 mg PE/kg/day in divided doses every 12 hours at 1–2 mg PE/kg/min or 100 mg PE/min, whichever is slower 2

Oral Phenytoin Dosing

• Oral loading: 18 mg/kg as a single dose of phenytoin capsules or suspension for patients with undetectable serum levels who can tolerate oral intake 4
• Maintenance: Phenytoin sodium capsules are approximately 90% bioavailable; when substituting for IV therapy, use the same total daily phenytoin sodium equivalents 2

Therapeutic Serum Concentrations

Target therapeutic serum total phenytoin concentrations of 10–20 mcg/mL (unbound phenytoin concentrations of 1–2 mcg/mL) for optimal seizure control without toxicity. 2

Monitoring Timing

• After IV fosphenytoin: Do not monitor phenytoin levels until conversion is complete—approximately 2 hours after IV infusion ends 2
• After IM fosphenytoin: Wait 4 hours after injection before checking levels 2
• Steady-state: Plasma phenytoin concentration normally reaches steady-state within 1–2 weeks 5
• Trough levels: Obtain just prior to the next scheduled dose to assess therapeutic range 2
• Peak levels: Obtain at time of expected peak concentration (10–20 minutes after end of fosphenytoin infusion) to identify threshold for dose-related toxicity 2

Special Population Monitoring

• Renal or hepatic disease, hypoalbuminemia: Monitor unbound (free) phenytoin concentrations, as these are more clinically relevant than total levels 2
• Use EDTA-containing tubes for blood samples before complete fosphenytoin conversion to minimize ex vivo conversion 2

Safety Monitoring and Precautions

Cardiovascular Monitoring

Continuous ECG and blood pressure monitoring is mandatory during IV phenytoin/fosphenytoin administration due to risks of hypotension (12%), cardiac arrhythmias, and rare fatal cardiovascular collapse. 1, 2, 3

• Hypotension and cardiac arrhythmias are the primary cardiovascular risks, particularly with rapid infusion 2, 3
• Infusion rates >50 mg/min of standard phenytoin are associated with increased mortality in case reports 3
• Observe patients throughout the period of maximal serum concentrations (approximately 10–20 minutes after infusion ends) 2

Respiratory Monitoring

• Continuous respiratory function monitoring is essential during administration 2
• Have airway equipment immediately available, though phenytoin causes less respiratory depression than benzodiazepines or barbiturates 1

Injection Site Complications

• Standard IV phenytoin carries risk of serious injection site reactions including skin necrosis and amputation of extremities 6
• Fosphenytoin eliminates injection site complications and can be administered faster than standard phenytoin, making it the preferred formulation 6

Special Populations

Elderly Patients

• Use slower infusion rates (≤50 mg/min for standard phenytoin) with careful cardiac and blood pressure monitoring 3
• Phenytoin half-life is prolonged in elderly patients 5
• Levetiracetam 30 mg/kg IV may be preferable in elderly patients due to minimal cardiovascular effects and no requirement for cardiac monitoring 1

Cardiac Disease

• Patients with cardiovascular comorbidity require slower infusion rates and meticulous monitoring of heart rhythm and blood pressure 3
• Consider alternative second-line agents: valproate (0% hypotension risk) or levetiracetam (minimal cardiovascular effects) 1

Hepatic Impairment

• Phenytoin is almost completely metabolized in the liver; dose adjustments and monitoring of unbound phenytoin concentrations are necessary 2, 5
• Individual differences in phenytoin metabolism can lead to phenytoin encephalopathy with cognitive impairment and cerebellar syndrome 5

Pregnancy

• Activate emergency medical services immediately for any seizure during pregnancy 1
• Valproate is absolutely contraindicated in women of childbearing potential due to fetal teratogenic risk; levetiracetam is preferred 1

Pediatric Considerations

• IM fosphenytoin should ordinarily not be used in pediatric patients 2
• Pediatric infusion rates must not exceed 2 mg PE/kg/min or 150 mg PE/min, whichever is slower, for loading doses 2
• Maintenance infusion rates must not exceed 1–2 mg PE/kg/min or 100 mg PE/min, whichever is slower 2

Treatment Algorithm Context

Position in Status Epilepticus Management

• Phenytoin/fosphenytoin is a second-line agent after benzodiazepines fail to terminate seizures 1, 2
• Administer after adequate first-line benzodiazepine therapy (typically lorazepam 4 mg IV at 2 mg/min) 1
• Phenytoin has 84% efficacy as a second-line agent, with 95% of neurologists recommending it for benzodiazepine-refractory seizures 1

Alternative Second-Line Agents

• Valproate 20–30 mg/kg IV: 88% efficacy with 0% hypotension risk—superior safety profile 1
• Levetiracetam 30 mg/kg IV: 68–73% efficacy with minimal cardiovascular effects 1, 7
• Phenobarbital 20 mg/kg IV: 58.2% efficacy but higher risk of respiratory depression 1

High-Dose Phenytoin

• The Epilepsy Foundation of America recommends up to 30 mg/kg phenytoin before using another antiepileptic drug for refractory status epilepticus 4
• In one case series, high-dose phenytoin (mean 24 mg/kg) prevented need for pentobarbital in 38% of status epilepticus patients 4

Critical Pitfalls to Avoid

• Never use IM phenytoin for status epilepticus—therapeutic concentrations are not reached quickly enough; IM fosphenytoin is acceptable only when IV access is impossible 2
• Do not exceed recommended infusion rates: >50 mg/min for standard phenytoin or >150 mg PE/min for fosphenytoin in adults increases risk of fatal cardiovascular complications 2, 3
• Avoid phenytoin in patients with intellectual disability, balance disturbances, or cerebellar disease due to risk of phenytoin encephalopathy with cognitive impairment and cerebellar syndrome 5
• Do not monitor phenytoin levels too early after fosphenytoin administration—immunoanalytical techniques significantly overestimate levels due to cross-reactivity before conversion is complete 2
• Oral phenytoin has no role in acute seizure termination—it is not mentioned in status epilepticus treatment guidelines 1
• Phenytoin half-life is shortened when given with enzyme-inducing drugs (phenobarbital, carbamazepine), requiring dose adjustments 5