The safety and efficacy of fosphenytoin for the treatment of status epilepticus

Abstract

Fosphenytoin, a water-soluble prodrug of the antiepileptic drug phenytoin, is entirely and rapidly converted to this antiepileptic drug. The mechanism of action of fosphenytoin is related to the blockade of voltage-operated sodium channels. It was developed in order to obtain a phenytoin-like drug with improved water solubility. Its maximal plasma concentration is achieved within 90–190 min following intramuscular administration with bioavailability being complete after intravenous injection. The main indications for fosphenytoin are the treatment of convulsive status epilepticus and the prevention/management of seizures during neurosurgery. Adverse effects of fosphenytoin may include: cardiovascular events (hypotension, arrhythmias), paresthesias or pruritus or some central events – somnolence, headache, dizziness, nystagmus and ataxia. The incidence of purple glove syndrome (edema, discoloration and pain distal to the site of intravenous administration) is less frequent than after phenytoin. Generally, the development of fosphenytoin aimed at avoiding complications associated with parenteral use of phenytoin.

Keywords:

• antiepileptic drugs
• epilepsy
• fosphenytoin
• phenytoin
• seizures

Financial & competing interests disclosure

SJ Czuczwar has been a speaker for GlaxoSmithKline, UCB, Sanofi-Aventis and Janssen and received an unrestrictive grant from GlaxoSmithKline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Fosphenytoin sodium was approved as an antiepileptic drug in the United States in 1996 and later on, in many other countries.

• As a water soluble prodrug of phenytoin, fosphenytoin is rapidly converted to this antiepileptic drug. Its mechanism of action is associated with a blockade of voltage-operated sodium channels.

• Fosphenytoin is superior to intravenous phenytoin as regards fluid incompatibilities, vein irritation and tissue damage.

• Pharmacokinetics of fosphenytoin does not differ in terms of age, gender or race.

• Main indications for the use of fosphenytoin are convulsive status epilepticus and prevention or management of seizures related to neurosurgery.

• The clinical efficacy of fosphenytoin in young patients (5–18 years of age) and adults (aged in the range of 40 years) is comparable. However, data on its efficacy in infants and newborns is scarce.

• Cardiovascular adverse effects (hypotension or arrhythmias) may be observed and they are associated with the rate of drug infusion. Other adverse events may include paresthesias or pruritus, somnolence, dizziness, headache and ataxia.

• Generally, fosphenytoin was developed to avoid complications resulting from parenteral administration of phenytoin. For a short period of time, it may be substituted for oral phenytoin.