Fosphenytoin Sodium Injection, USP is a prodrug intended for parenteral administration; its active metabolite is phenytoin. 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE). The amount and concentration of fosphenytoin is always expressed in terms of mg PE.
The pharmacological class of the fosphenytoin sodium is hydantoin derivative, and the therapeutic class is anticonvulsant.
Fosphenytoin sodium injection, USP is marketed as a 2 mL fill in 5 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE, for intravenous or intramuscular administration. The concentration of each vial is 50 mg PE/mL. Fosphenytoin Sodium Injection, USP is supplied in vials as a sterile solution in Water for Injection, USP, and Tromethamine, USP (TRIS), buffer adjusted to pH 8.6 to 9.0 with either Hydrochloric Acid, NF, or Sodium Hydroxide, NF. Fosphenytoin Sodium Injection, USP 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:
The molecular weight of fosphenytoin is 406.24.
Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.
Intravenous: When fosphenytoin sodium injection is administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion.
Intramuscular: Fosphenytoin is completely bioavailable following IM administration of fosphenytoin sodium injection. Peak concentrations occur at approximately 30 minutes postdose. Plasma fosphenytoin concentrations following IM administration are lower but more sustained than those following IV administration due to the time required for absorption of fosphenytoin from the injection site.
Fosphenytoin is extensively bound (95% to 99%) to human plasma proteins, primarily albumin. Binding to plasma proteins is saturable with the result that the percent bound decreases as total fosphenytoin concentrations increase. Fosphenytoin displaces phenytoin from protein binding sites. The volume of distribution of fosphenytoin increases with fosphenytoin sodium injection dose and rate, and ranges from 4.3 to 10.8 liters.
The conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes.
Following parenteral administration of fosphenytoin sodium injection, fosphenytoin is converted to the anticonvulsant phenytoin. The mechanism of fosphenytoin conversion has not been determined, but phosphatases probably play a major role. Fosphenytoin is metabolized to phenytoin, phosphate, and formate. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. 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.
Fosphenytoin is not excreted in urine.
Phenytoin (after fosphenytoin sodium injection administration)
In general, IM administration of fosphenytoin sodium generates systemic phenytoin concentrations that are similar enough to oral phenytoin sodium to allow essentially interchangeable use. The pharmacokinetics of fosphenytoin following IV administration of fosphenytoin sodium, however, are complex, and when used in an emergency setting (e.g., status epilepticus), differences in rate of availability of phenytoin could be critical. Studies have therefore empirically determined an infusion rate for fosphenytoin sodium that gives a rate and extent of phenytoin systemic availability similar to that of a 50 mg/min phenytoin sodium infusion. A dose of 15 to 20 mg PE/kg of fosphenytoin sodium infused at 100 to 150 mg PE/min yields plasma free phenytoin concentrations over time that approximate those achieved when an equivalent dose of phenytoin sodium (e.g., parenteral phenytoin sodium) is administered at 50 mg/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].
FIGURE 1. Mean plasma unbound phenytoin concentrations following IV administration of 1,200 mg PE fosphenytoin sodium infused at 100 mg PE/min (triangles) or 150 mg PE/min (squares) and 1,200 mg phenytoin sodium infused at 50 mg/min (diamonds) to healthy subjects (N = 12). Inset shows time course for the entire 96-hour sampling period.
Following administration of single IV fosphenytoin sodium injection doses of 400 to 1,200 mg PE, mean maximum total phenytoin concentrations increase in proportion to dose, but do not change appreciably with changes in infusion rate. In contrast, mean maximum unbound phenytoin concentrations increase with both dose and rate.
Fosphenytoin is completely converted to phenytoin following IV administration, with a half-life of approximately 15 minutes. Fosphenytoin is also completely converted to phenytoin following IM administration and plasma total phenytoin concentrations peak in approximately 3 hours.
Phenytoin is highly bound to plasma proteins, primarily albumin, although to a lesser extent than fosphenytoin. In the absence of fosphenytoin, approximately 12% of total plasma phenytoin is unbound over the clinically relevant concentration range. However, fosphenytoin displaces phenytoin from plasma protein binding sites. This increases the fraction of phenytoin unbound (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin (approximately 0.5 to 1 hour postinfusion).
Mean total phenytoin half-life values (12.0 to 28.9 hr) following fosphenytoin sodium injection administration at these doses are similar to those after equal doses of parenteral phenytoin sodium and tend to be greater at higher plasma phenytoin concentrations.
Phenytoin derived from administration of fosphenytoin sodium injection is extensively metabolized in the liver by the cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Phenytoin hepatic metabolism is saturable, and following administration of single IV fosphenytoin sodium doses of 400 to 1,200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose.
Phenytoin derived from administration of fosphenytoin sodium injection is excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1% to 5% of the fosphenytoin sodium dose) is recovered in urine.
Age: Geriatric Population:
The effect of age on the pharmacokinetics of fosphenytoin was evaluated in patients 5 to 98 years of age. Patient age had no significant impact on fosphenytoin pharmacokinetics. Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age).
Gender and race have no significant impact on fosphenytoin or phenytoin pharmacokinetics.
Renal or Hepatic Impairment:
Increased fraction of unbound phenytoin (the active metabolite of fosphenytoin sodium injection) in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported.
It has been reported in the literature that the plasma clearance of phenytoin (the active metabolite of fosphenytoin sodium injection) generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery [see Dosage and Administration (2.9)].
Drug Interaction Studies
Phenytoin derived from administration of fosphenytoin sodium injection is extensively metabolized in the liver by the cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19 [see Drug Interactions (7.1, 7.2)]. No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. Conversion could be affected by alterations in the level of phosphatase activity, but given the abundance and wide distribution of phosphatases in the body it is unlikely that drugs would affect this activity enough to affect conversion of fosphenytoin to phenytoin.
The pharmacokinetics and protein binding of fosphenytoin, phenytoin, and diazepam were not altered when diazepam and fosphenytoin sodium injection were concurrently administered in single submaximal doses.
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