Fosphenytoin more efficacious than Phenytoin in Treatment of Active Seizures during Emergency

A recently published research in Neurology India from scientists in Vellore, compared the efficacy of phenytoin and fosphenytoin for seizure abatement in emergency setting and found that the mean time for cessation of active seizure with fosphenytoin was less than half that of phenytoin.

Epilepsy is the fourth most frequent neurological illness and complaints related to seizure account for 1% of all emergency department (ED) visits. Anti-epileptic drugs (AEDs) are the basis of seizure care by achieving good control with medications alone in about 70% of patients. The goal of epilepsy treatment should be to stop seizure as soon as possible.

Phenytoin is a tested and proven drug used worldwide as the primary treatment of active seizures, but with worrying adverse effects. Rapid infusion is associated with drug extravasation, arrhythmia, skin necrosis, and hypotension. Fosphenytoin is a phosphate ester derivative of phenytoin that is more convenient to load for rapid intravenous administration, compatible intramuscular route, and lesser local reactions at the injection site. American epilepsy society guidelines (2016) states fosphenytoin as the preferred first-line for convulsive status epilepticus over phenytoin. However, its use is limited in developing countries due to the higher cost, scarce availability, and lack of definitive evidence of superiority, although suggested worthy by pharmaco-economic studies.

Madhiyazhagan et al conducted an observational study on patients with active seizure in the Emergency Department comparing phenytoin versus fosphenytoin protocol over one year. Their study showed a clear decrease in the average time taken for cessation of seizure, thus lowering recurrence rate and also progression to status epilepticus with the use of fosphenytoin. We observed a higher percentage of stable discharges from ED with fosphenytoin when compared to phenytoin. Thus, fosphenytoin can be beneficial in decreasing the time of seizure activity, thereby decreasing associated complications.

“Though the American Society has already preferred fosphenytoin over phenytoin, this study was conducted on the Indian population to analyze the effect of ethnic differences. Phenytoin is a widely used antiepileptic with documented complications and also with a prodrug designed to possibly reduce these complications. We, by doing this study, have statistically significant data to support the same, thus clinically improving seizure treatment”, said the authors.

Fosphenytoin is highly protein-bound and thus achieves higher plasma concentrations and clearance with increasing dose and infusion rate, thus reducing cardiac adverse effects such as arrythmia, as seen with rapid phenytoin infusion.

Owing to the advantage of faster infusion rates, there was a substantial cutback in drug administration time with fosphenytoin, thus significantly reducing the mean time taken for cessation of seizure. The usual loading dose of phenytoin is 15 mg/kg as intravenous route at a maximum rate of 50 mg/min, while that of fosphenytoin is 15–20 mg phenytoin equivalent/kg as intravenous infusion administered as quickly as 150 mg PE/min. The calculation for phenytoin equivalence could be weary and time-consuming, thus warranting a simple formula for quick dose calculation.

Intramuscular fosphenytoin is safe and readily absorbed; this would come in handy in patients with active seizures, where securing venous access is often a challenge. Another worrying fact about fosphenytoin is the cost: for a 50-kg man, loading dose would cost around ₹360 ($4.7) versus ₹80 ($1) for phenytoin, making it heavier on the pocket. Thus it was concluded, weighing the good outcomes and long-term benefits, fosphenytoin wins over phenytoin but benefits must be weighed carefully against its higher acquisition cost.

Reference

Comparison of Phenytoin and Fosphenytoin in Treatment of Active Seizures in the Emergency Department

Mamta Madhiyazhagan, Ramgopal Roshan, Sudhakar G Dhanapal, Joshua V Joseph, Priya Ganesan, Vivek Mathew, Paul P A Kundavaram

Neurology India, Vol. 71, No. 3, May-June 2023, pp. 447-452

DOI: 10.4103/0028-3886.378665