Introduction

Status epilepticus is a neurological emergency that requires urgent assessment and treatment with pharmacologic agents. Lorazepam and diazepam are short-acting drugs that can produce immediate effects, but treatment with a long-acting anticonvulsant is necessary to prevent recurrent convulsions.

Key Clinical Context

  • IV phenytoin (PHT) use in status epilepticus dates back to the 1950s, with fosphenytoin (FPHT) being the primary agent at many institutions
  • Both PHT and FPHT can induce adverse reactions such as hypotension, arrhythmia, and allergic symptoms
  • Levetiracetam (Keppra) has emerged as a potential alternative with a more favorable safety profile
  • The ESETT trial and multiple smaller studies have evaluated these agents head-to-head

Comparative Pharmacology

Parameter Phenytoin / Fosphenytoin Levetiracetam (Keppra)
Dose

20 mg/kg PE

(max 1500 mg)

1–4.5 g IV

(40–60 mg/kg)*
Administration

Max IV Infusion Rate

PHT: 50 mg/min

FPHT: 150 mg/min

1 g IV push ~2 min**

1.5–2 g IV over 7 min

(2–5 mg/kg/min)
Formulation
IV / PO IV / PO
PK/PD

Onset: ~30 min***

Half-life: 12–28 hr

Excretion: >90% urine

Onset: 30–45 min

Half-life: 6–8 hr

Excretion: 66% renal
Adverse Effects
Phlebitis Hypotension Bradycardia Dysrhythmias
Abnormal behavior Dizziness Irritability
Drug Interactions
Major CYP3A4 Inducer

(decreases drug levels)

 Minimal interactions
Compatibility

PHT: D5W only

FPHT: D5W or NS

 D5W or NS

* GHS has utilized this administration based on clinical experience

** PE = Phenytoin equivalents

*** Fosphenytoin takes 15 min to be metabolized to active metabolite in addition to infusion time

Clinical Pearl

Levetiracetam offers a more favorable safety and drug interaction profile compared to phenytoin/fosphenytoin, with fewer hemodynamic concerns. However, both agents demonstrate similar efficacy in seizure control across available studies.

Overview of Key Evidence

Author / Year Design (n) Intervention Key Findings
Alvarez et al., 20113 Retrospective
n=466
Largest 		VPA 20 mg/kg vs LEV 20 mg/kg vs PHT 20 mg/kg
VPA 74.6% > PHT 58.6% > LEV 51.7%

LEV failed more often than VPA (OR 2.69)
Mundlamuri, 20155 RCT
n=150 		VPA 30 mg/kg vs LEV 25 mg/kg vs PHT 20 mg/kg
No significant difference

VPA 68% vs PHT 68% vs LEV 78% (p = NS)
Gujjar et al., 20176 Open-Label
n=52 		LEV 30 mg/kg vs PHT 20 mg/kg
No significant difference

Sequential use controlled 92–97% of cases without anesthetic agents
Chakravarthi, 20154 RCT
n=44 		LEV 20 mg/kg vs PHT 20 mg/kg
Equally effective

Equal seizure termination within 30 min and recurrence within 24 hr

* Several studies did not reach power according to sample size analysis or did not mention power in methods

Upcoming: ESETT Trial8

The Established Status Epilepticus Treatment Trial (ESETT) is a large multicenter RCT comparing VPA 30 mg/kg (max 3000 mg) vs LEV 60 mg/kg (max 4500 mg) vs PHT 20 mg/kg (max 1500 mg) for benzodiazepine-refractory status epilepticus. Results are expected to provide definitive guidance on second-line agent selection.

Clinical Conclusions

Bottom Line

Current evidence suggests levetiracetam and phenytoin/fosphenytoin are similarly effective for second-line treatment of status epilepticus. Levetiracetam offers a more favorable safety profile with fewer hemodynamic and drug interaction concerns.

Multiple studies demonstrate no statistically significant difference between LEV and PHT/FPHT in controlling status epilepticus.

Levetiracetam has a favorable safety profile — fewer cardiovascular effects, no CYP3A4 induction, and simpler IV compatibility.

The Alvarez 2011 retrospective analysis found LEV failed more often than VPA (OR 2.69), suggesting valproic acid may be an important alternative.

Sequential use of these agents can control 92–97% of cases without requiring anesthetic agents (Gujjar 2017).

Full Reference List

  1. Phenytoin. Micromedex [Electronic version]. Greenwood Village, CO: Truven Health Analytics. Retrieved November 12, 2018.
  2. Levetiracetam. Micromedex [Electronic version]. Greenwood Village, CO: Truven Health Analytics. Retrieved November 12, 2018.
  3. Alvarez V. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia. 2011 Jul;52(7):1292–6.
  4. Chakravarthi S. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci. 2015 Jun;22(6):959–63.
  5. Mundlamuri RC. Management of generalised convulsive status epilepticus (SE): A prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam — Pilot study. Epilepsy Res. 2015 Aug;114:52–8.
  6. Gujjar AR. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study. Seizure. 2017 Jul;49:8–12.
  7. Nakamura K. Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus. Medicine (Baltimore). 2017 Jun;96(25):e7206.
  8. Bleck T. The established status epilepticus trial 2013. Epilepsia. 2013 Sep;54 Suppl 6:89–92.
Tags: Neurology Status Epilepticus Fosphenytoin Levetiracetam Pharmacy Friday Pearls

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