Fosphenytoin: A Novel Phenytoin Prodrug

Abstract

Fosphenytoin is a phenytoin prodrug that received an approvable letter from the Food and Drug Administration in February 1996. It was designed to overcome many of the shortcomings associated with parenteral phenytoin sodium. Specifically, fosphenytoin is a highly water‐soluble, phosphate ester of phenytoin that has no known pharmacologic activity before its conversion to phenytoin. Dosing of fosphenytoin uses phenytoin equivalents (PE) to minimize dosage errors when converting from the conventional formulation. Pharmacokinetic studies documented that the agent is rapidly and completely converted to phenytoin after intravenous and intramuscular dosing. Reported conversion half‐lives after intravenous administration range from 8–15 minutes. The absorption rate appears to be the rate‐limiting step in the conversion of fosphenytoin to phenytoin after intramuscular administration (half‐life range 22–41 min). Bioavailability of phenytoin derived from both intravenous and intramuscular fosphenytoin is essentially 100%. As a consequence of concentration‐dependent protein binding, fosphenytoin is bioequivalent to phenytoin sodium at intravenous infusion rates of 100–150 mg PE/minute and 50 mg/minute, respectively. In clinical studies to date, fosphenytoin is safe and significantly better tolerated than phenytoin sodium when administered intravenously. It is also well tolerated when given intramuscularly, and this is a valuable alternative route of administration when intravenous access or cardiographic monitoring is unavailable. Its pharmacoeconomic advantages over phenytoin have not been documented in formal studies to date, although the likelihood of savings based on cost‐effectiveness analyses is high. Hence, fosphenytoin has the potential as a safe, well‐tolerated, and effective means of delivering phenytoin parenterally in a variety of clinical settings.