Safety, Tolerability, and Pharmacokinetics of Fosphenytoin Loading in Patients With Subarachnoid Hemorrhage.

Abstract

Fosphenytoin is frequently used for the rapid delivery of phenytoin in subarachnoid hemorrhage (SAH) patients. The present study was performed to investigate the safety, tolerability, and pharmacokinetic profiles of rapid intravenous loading of fosphenytoin in SAH patients. Fosphenytoin was administered intravenously as a single loading dose of 20 mg phenytoin-equivalent/kg at an infusion rate of 150 mg PE/min to 30 adult patients with SAH, who experienced seizures or had a clinical suspicion of nonconvulsive seizures. Serum concentrations of free phenytoin were determined, and adverse events were assessed at 0, 10, 20 minutes, and 24 hours after the infusion of fosphenytoin. Four patients experienced transient lowering of blood pressure, but other adverse events were not observed. All patients achieved the therapeutic level of free phenytoin (1-2 mg/L) at the end of infusion, but most patients (28/30) entered the markedly supratherapeutic range and the mean serum concentration was 17.7 ± 8.13 mg/L; higher serum concentration was maintained up to 20 minutes after infusion (mean concentration; 3.46 ± 3.75 mg/L). At 24 hours after loading, a majority of the patients (25/30) maintained their levels within the therapeutic range of free phenytoin. Rapid intravenous loading of fosphenytoin was well tolerated and effective in promptly achieving the therapeutic level of free phenytoin, but most patients experienced overshoot of free phenytoin at the end of infusion. Because increased serum concentrations may increase the risk of cardiovascular complications, additional studies are needed to determine the optimal dose and infusion rate of fosphenytoin in SAH patients.