All Pharmacy Pearls

Introduction

  • Status epilepticus is a neurological emeregnecy

    • that required urgent assessment and treatment with

    pharmacologic agents

  • Lorazepam and diazepam are short-acting drugs

    • that can produce immediate effects.

  • Treatment with another long-acting anticonvulsant

    • drug is necessary to prevent recurrent convulsions.

  • Use of IV phenytoin (PHT) in the treatment of status

    • epilepticus dates back to the 50s with fosphenytoin

    (FPHT) being the primary agent in some institutions.

Clinical Detail

PropertiesPhenytoin / FosphenytoinLevetiracetam (Keppra)
Dose20 mg/kg PE (max 1500 mg)40–60 mg/kg
Administration / Max IV infusionPHT 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)
FormulationIV / POIV / PO
PK / PDOnset: ~30 min***
Half-life: 12–28 hr
Excreted: >90% in urine		Onset: 30–45 min
Half-life: 6–8 hr
Excreted: 66% renal
Adverse EffectPhlebitis, hypotension, bradycardia & dysrhythmiasAbnormal behavior, dizziness, irritability
Drug Interactions & WarningsMajor CYP3A4 inducer (↓ drug levels)—
CompatibilityPHT – only D5W
FPHT – D5W or NS		D5W or NS

PE = phenytoin equivalents. ** Fosphenytoin takes ~15 min to be metabolized to active metabolite in addition to the infusion time. *** Onset reflects time to therapeutic levels. Doses transcribed from the source handout (Micromedex, 2018); verify against current local protocol.

Evidence

Is phenytoin more effective in seizure control than levetiracetam? Comparative trials and analyses:

Author, YearDesign / Sample SizeDosing RegimenOutcome
ESETTRCTVPA 30 mg/kg (max 3000 mg) vs LEV 60 mg/kg (max 4500 mg) vs PHT 20 mg/kg (max 1500 mg)Result expected 2020
Nakamura, 2017Retrospective analysis, n=63LEV 1000 mg vs FPHT 22.5 mg/kgNo difference in control of seizure (81 vs 85.1%, p=0.69), adverse effects, or transition to PO antiepileptic drug
Gujjar et al, 2017Prospective, open-label trial, n=52LEV 30 mg/kg vs PHT 20 mg/kgLEV displayed no statistically significant difference than PHT in SE. Sequential use of these controlled 92–97% of cases without anesthetic agents.
Chakravarthi, 2017RCT, n=44LEV 20 mg/kg vs PHT 20 mg/kgBoth LEV and PHT were equally effective at termination of seizure activity within 30 min and recurrence of seizures within 24 hours
Mundlamuri, 2015RCT, n=150VPA 30 mg/kg vs LEV 25 mg/kg vs PHT 20 mg/kgNo statistically significant difference in control of SE between VPA (68%), PHT (68%), and LEV (78%)
Alvarez et al, 2011Retrospective analysis, n=466VPA 20 mg/kg vs LEV 20 mg/kg vs PHT 20 mg/kgVPA controlled SE in 74.6%, PHT in 58.6%, and LEV in 51.7% of episodes. LEV failed more often than VPA [odds ratio (OR) 2.69]

Answer: We don’t know. The few published studies do not show a difference; however, these trials have significant methodological flaws that would bias toward finding no difference if one exists. The ESETT trial should provide more answers.

* Did not reach power according to sample-size analysis, or power was not mentioned in the methods.

Conclusions

  • After a benzodiazepine fails to control status epilepticus, a longer-acting anticonvulsant is needed to prevent recurrent convulsions; fosphenytoin/phenytoin and levetiracetam (Keppra) are both established second-line options.
  • Across the published comparative studies summarized here (Nakamura 2017, Gujjar 2017, Chakravarthi 2017, Mundlamuri 2015, Alvarez 2011), levetiracetam and phenytoin showed no statistically significant difference in seizure control.
  • These trials carry methodologic limitations that would bias toward finding no difference, so a true superiority cannot be excluded from the data shown; the ESETT trial was awaited to provide clearer answers.
  • The two agents differ in practical profile rather than proven efficacy: phenytoin/fosphenytoin carries cardiovascular and infusion-related risks and CYP3A4 induction, while levetiracetam’s main concerns are behavioral and neuropsychiatric. Always verify doses against current local protocol.

References

Phenytoin. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved November 12, 2018, from http://www.micromedexsolutions.com/

Levetiracetam. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved November 12, 2018, from http://www.micromedexsolutions.com/

Alvarez V. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia. 2011 Jul;52(7):1292-

Chakravarthi S. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci. 2015 Jun;22(6):959-63.

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-

Gujjar AR. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study. Seizure. 2017 Jul;49:8-12.

Nakamura K. Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus. Medicine (Baltimore). 2017 Jun;96(25):e7206

Bleck T. The established status epilepticus trial 2013. Epilepsia. 2013 Sep;54 Suppl 6:89-92.

Kapur J, et al. “Randomized trial of three anticonvulsant medications for status epilepticus”. The New England Journal of Medicine. 2019. 381(22):2103-2113.

Dalziel SR, Borland ML, Furyk J, et al. (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019 May 25;393(10186):2135-2145.

Appleton RE, Rainford NE, Gamble Cet al. Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT. Health Technol Assess. 2020 Nov;24(58):1-96.

Tags:fosphenytoin levetiracetam status epilepticus ESETT

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fosphenytoin-keppra-status.pdf