A critical review of fosphenytoin sodium injection for the treatment of status epilepticus in adults and children

ABSTRACT

Introduction

Status epilepticus (SE) is a neurological emergency that can occur in patients with or without epilepsy. Rapid treatment is paramount to mitigate risks of neuronal injury, morbidity/mortality, and healthcare-cost burdens associated with SE. Fosphenytoin is the prodrug of phenytoin designed to enable faster administration and improved tolerability as compared to intravenous (IV) phenytoin in the treatment of SE.

Areas covered

This review evaluates the chemistry, pharmacokinetics, pharmacodynamics, safety, and tolerability of fosphenytoin. Efficacy data for fosphenytoin in the treatment of SE in adults and children are analyzed from initial phase I trials in 1988 through current phase III trials, including the Established Status Epilepticus Treatment Trial (ESETT).

Expert opinion

IV phenytoin is an established treatment of SE, but its alkaline aqueous vehicle is associated with dermatologic irritation and systemic complications when rapidly infused. The water-soluble nature of its prodrug, fosphenytoin, allows for rapid infusion, and it is rapidly converted to phenytoin when administered intravenously or intramuscularly. In the ESETT, IV fosphenytoin demonstrated similar efficacy in treatment of established SE when compared to IV levetiracetam and IV valproate in adults and children, making it a reasonable choice in the treatment of SE that is unresponsive to benzodiazepines.

KEYWORDS:

• Status epilepticus
• seizure
• epilepsy
• fosphenytoin
• phenytoin
• prodrug

Article highlights

• Status epilepticus (SE) is a neurological emergency that requires rapid intervention to mitigate morbidity and decrease and risk of irreversible neuronal injury.

• Benzodiazepines (BZDs) are the first-line therapy for SE. If BZDs fail, it is deemed established SE (ESE), and there had been lack of evidence to which second-line anticonvulsant is most efficacious in ESE.

• Conventional phenytoin (PHT) is water insoluble and requires an alkaline aqueous vehicle to be administered intravenously (IV), which can lead to skin necrosis if extravasation occurs or cardiac arrhythmias/hypotension if it is infused too rapidly.

• Fosphenytoin (fPHT) is a water soluble PHT prodrug that avoids the risks associated with parenteral PHT administration and can be administered IV or intramuscularly (IM).

• IV fPHT can be infused at a rate of 150 mg phenytoin equivalents (PE) per minute (compared to 50 mg/min with IV PHT) and is rapidly and completely converted to PHT (T_1/2=8–21 min).

• Therapeutic plasma concentrations of PHT can be reached in 7 min following the start of IV fPHT administration and 30 minfollowing IM fPHT administration.

• fPHT is associated with less soft-tissue adverse effects and less cardiac arrhythmias as compared to PHT. Central nervous system (CNS) adverse effects including ataxia, nystagmus, and dizziness are dose related and attributable to PHT.

• Phase III trials, including the recent ESETT, have demonstrated that IV fPHT has similar efficacy as a second-line agent in treatment of ESE when compared to IV levetiracetam and IV valproate, and is well tolerated in adults and children.

Declaration of interests

N B Fountain has received clinical trial grants to the University of Virginia from UCB, GW Pharmaceuticals, SK LifeSciences, Xenon, Neurelis, Medtronic, and InSightec and is an independent director at Acumen Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Information resources

Home page of the Neurological Emergencies Treatment Trials (NETT) website [82].

Clinical guidance/resources information page of the American Epilepsy Society website [83].

Resource library page of the Epilepsy Foundation website [84].

Additional information

Funding

This paper was not funded.