Fosphenytoin sodium: new drug to replace intravenous phenytoin sodium

Pediatric Nursing, Sept-Oct, 1997 by Sarah Mills Voytko, Elizabeth Farrington

Phenytoin sodium (Dilantin[R]) - Parke-Davis) is an agent used for the treatment of acute seizures and status epilepticus. When administered intravenously, phenytoin is effective in the management of seizures, especially when oral administration is not an option. Several complications are associated with the administration of IV phenytoin which are primarily due to its physiochemical properties.

Phenytoin is highly insoluble in aqueous solutions. To augment its solubility, parenteral phenytoin is formulated with 40% propylene glycol, 10% ethanol, and sodium hydroxide to an adjusted pH of 12. Parenteral phenytoin precipitates when diluted with common IV fluids and can only be diluted with 0.9% sodium chloride (Baumen, Siepler, & Fitzioff, 1977). Phenytoin is erratically absorbed and will crystallize in tissues after intramuscular administration. The intravenous route of administration of phenytoin is not without complications. Pain, burning, and phlebitis are common adverse events reported with undiluted phenytoin and are associated with the amount of propylene glycol, ethanol, and sodium hydroxide in the parenteral formulation (Earnest, Marx, & Drury, 1983). Propylene glycol in the formulation has also been implicated in causing hypotension and cardiac arrhythmias following rapid administration (Cranford, Leppik, Patrick, Anderson, & Kostrick, 1978). The incidence of these adverse events can be minimized by diluting the phenytoin with small volumes of normal saline and infusing slowly at a rate not to exceed 50 mg/min in adults or 1mg/kg/min in children (Earnest et al., 1983).

Fosphenytoin sodium (Cerebyx[R]) - Parke-Davis) is a new drug developed specifically to replace intravenous phenytoin sodium (Dilantin[R] - Parke-Davis). It is a water-soluble prodrug which undergoes conversion in the body to form phenytoin. Parenteral fosphenytoin is easier to administer and better tolerated than parenteral phenytoin.

Chemistry and Pharmacology

Fosphenytoin is the disodium phosphate ester of phenytoin and is highly soluble in aqueous solutions (Smith, Brown, Maher, & Matier, 1989). It is buffered with tromethamine USP to a more physiologic pH of 8.6 - 9.0. Because it is highly water soluble, propylene glycol and ethanol are absent from the fosphenytoin formulation.

As fosphenytoin enters the systemic system and tissues, it is converted completely by phosphatases present in the liver, erythrocytes, and other tissues (Browne, Kugler, & Eldon, 1996). The conversion process is rapid, with a conversion half-life of 8-15 minutes (Leppik et al., 1990). Each mmole of fosphenytoin sodium produces 1 mmole phenytoin (Cerebyx[R] Product Information, 1996). The hydrolysis of fosphenytoin to phenytoin also yields two metabolites, formate, and phosphate. The conversion of fosphenytoin to phenytoin is independent of the dose or the rate of administration of fosphenytoin (Eldon et al., 1993).

Fosphenytoin has no pharmacologic effects of its own. The anticonvulsant effects are due to its conversion to phenytoin. It is thought that phenytoin ceases seizure activity primarily by the modulation of voltage-dependent sodium neurons (McNamara, 1996). Other mechanisms by which phenytoin exerts its anticonvulsant effects include the inhibition of calcium ions across neuronal membranes, the modulation of voltage-dependent calcium channels of neurons, and the enhancement of sodium-potassium ATPase activity of neurons and glial cells (Cerebyx[R] Product Information, 1996).

Pharmacokinetics

The pharmacokinetics of intravenous fosphenytoin were studied in healthy volunteers, neurosurgical patients, and patients with epilepsy or status epilepticus (Fierro, Savulich, & Benezra, 1996). The pharmacokinetic variables for fosphenytoin and phenytoin were similar in patients and in healthy subjects (Ramsey & DeToledo, 1996). Fosphenytoin is rapidly and completely absorbed following intramuscular administration (Cerebyx[R] Product Information, 1996). Fosphenytoin is released slowly from the intramuscular site, therefore plasma fosphenytoin concentrations after IM administration tend to be lower, but are more sustained than those after IV administration. Following IM administration of fosphenytoin, therapeutic phenytoin concentrations are achieved approximately 30 minutes after administration and peak concentrations occur at approximately 3 hours (Leppik et al.,1990).

Much like phenytoin, fosphenytoin is highly bound to plasma proteins, specifically albumin (Cerebyx[R] Product Information, 1996). Fosphenytoin has a higher affinity for albumin than phenytoin, which causes phenytoin dissociation from plasma protein-binding sites. Phenytoin displacement leads to increased concentrations of free phenytoin (Eldon et al., 1993). Displacement of phenytoin is at its highest level when high loading doses of fosphenytoin are infused at high rates. Phenytoin displacement is transient and coincides with the conversion of fosphenytoin to phenytoin. However, due to the displacement of phenytoin from protein-binding sites, total phenytoin concentrations require careful interpretation as the concentration of unbound phenytoin is increased after fosphenytoin administration. Fosphenytoin, as with phenytoin, should be used with caution in patients with renal or hepatic diseases or with hypoalbuminemia because of increased concentrations of unbound phenytoin. In these patients, measuring free phenytoin plasma concentrations over total phenytoin concentrations is a more practical method for monitoring phenytoin plasma concentrations.