Fosphenytoin Sodium

FOSPHENYTOIN SODIUM- fosphenytoin sodium injection, solution
Baxter Healthcare Corporation

DESCRIPTION

Fosphenytoin Sodium Injection, USP is a prodrug intended for parenteral administration; its active metabolite is phenytoin. Each fosphenytoin sodium injection vial contains 75 mg/mL fosphenytoin sodium (hereafter referred to as fosphenytoin) equivalent to 50 mg/mL phenytoin sodium after administration. Fosphenytoin sodium injection is supplied in vials as a ready-mixed solution in Water for Injection, and Tromethamine (TRIS), buffer adjusted to pH 8.6 to 9.0 with either Hydrochloric Acid, or Sodium Hydroxide. Fosphenytoin sodium injection is a clear, colorless to pale yellow, sterile solution.

The chemical name of fosphenytoin is 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4 imidazolidinedione disodium salt. The molecular structure of fosphenytoin is:

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The molecular weight of fosphenytoin is 406.24.

IMPORTANT NOTE: Throughout all fosphenytoin sodium injection product labeling, the amount and concentration of fosphenytoin is expressed in terms of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin sodium injection should always be prescribed and dispensed in phenytoin sodium equivalent units (PE) (see DOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY

Introduction

Following parenteral administration of fosphenytoin sodium injection, fosphenytoin is converted to the anticonvulsant phenytoin. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin include those of phenytoin.

However, the hydrolysis of fosphenytoin to phenytoin yields two metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which is in turn metabolized via a folate dependent mechanism. Although phosphate and formaldehyde (formate) have potentially important biological effects, these effects typically occur at concentrations considerably in excess of those obtained when fosphenytoin sodium injection is administered under conditions of use recommended in this labeling.

Mechanism of Action

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin.

After IV administration to mice, fosphenytoin blocked the tonic phase of maximal electroshock seizures at doses equivalent to those effective for phenytoin. In addition to its ability to suppress maximal electroshock seizures in mice and rats, phenytoin exhibits anticonvulsant activity against kindled seizures in rats, audiogenic seizures in mice, and seizures produced by electrical stimulation of the brainstem in rats. The cellular mechanisms of phenytoin thought to be responsible for its anticonvulsant actions include modulation of voltage-dependent sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and enhancement of the sodium-potassium ATPase activity of neurons and glial cells. The modulation of sodium channels may be a primary anticonvulsant mechanism because this property is shared with several other anticonvulsants in addition to phenytoin.

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