PRO-EPANUTIN Concentrate for solution for infusion Ref.[9267] Active ingredients:

Fosphenytoin is a pro-drug of phenytoin and it is rapidly converted into phenytoin mole for mole.

Fosphenytoin Pharmacokinetics

Absorption/Bioavailability

When Pro-Epanutin is administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion. Fosphenytoin is completely bioavailable following IM administration of Pro-Epanutin. 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.

Distribution

Fosphenytoin is extensively bound (95% to 99%) to human plasma proteins, primarily albumin. Binding to plasma proteins is saturable with the result that the fraction unbound increases as total fosphenytoin concentrations increase. Fosphenytoin displaces phenytoin from protein binding sites. The volume of distribution of fosphenytoin increases with fosphenytoin sodium dose and rate and ranges from 4.3 to 10.8 L.

Metabolism and Excretion

The hydrolysis of fosphenytoin to phenytoin yields 2 metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which is in turn metabolised 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 Pro-Epanutin is administered under conditions of use recommended in this labelling.

The conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes. The mechanism of fosphenytoin conversion has not been determined but phosphatases probably play a major role. Each mmol of fosphenytoin is metabolised to 1 mmol of phenytoin, phosphate and formate.

Fosphenytoin is not excreted in urine.

Phenytoin Pharmacokinetics (after Pro-Epanutin administration)

The pharmacokinetics of phenytoin following IV administration of Pro-Epanutin, 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 Pro-Epanutin that gives a rate and extent of phenytoin systemic availability similar to that of a 50 mg/min phenytoin sodium infusion. Because Pro-Epanutin is completely absorbed and converted to phenytoin following IM administration, systemic phenytoin concentrations are generated that are similar enough to oral phenytoin to allow essentially interchangeable use and to allow reliable IM loading dose administration.

The following table displays pharmacokinetic parameters of fosphenytoin and phenytoin following IV and IM Pro-Epanutin administration.

Mean Pharmacokinetic Parameter Values by Route of Pro-Epanutin Administration:

Dose = Fosphenytoin dose (phenytoin sodium equivalents [mg PE] or phenytoin sodium equivalents/kg [mg PE/kg]).
Infusion Rate = Fosphenytoin infusion rate (mg phenytoin sodium equivalents/min [mg PE/min]).
C_max = Maximum plasma analyte concentration (µg/mL).
T_max = Time of C_max (hr).
t_½ = Terminal elimination half-life (min).

Absorption/Bioavailability

Fosphenytoin sodium is rapidly and completely converted to phenytoin following IV or IM Pro-Epanutin administration. Therefore, the bioavailability of phenytoin following administration of Pro-Epanutin is the same as that following parenteral administration of phenytoin.

Distribution

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 post infusion).

The volume of distribution for phenytoin ranges from 24.9 to 36.8 L.

Metabolism and Excretion

Phenytoin derived from administration of Pro-Epanutin is extensively metabolised in the liver and excreted in urine primarily as 5-(p-hydroxy-phenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1%-5% of the Pro-Epanutin dose) is recovered in urine. Phenytoin hepatic metabolism is saturable and, following administration of single IV Pro-Epanutin doses of 400 to 1,200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose. Mean total phenytoin half-life values (12.0 to 28.9 hr) following Pro-Epanutin administration at these doses are similar to those after equal doses of parenteral phenytoin and tend to be longer at higher plasma phenytoin concentrations.

Characteristics in Patients

Patients with renal or hepatic disease

Fosphenytoin conversion to phenytoin is more rapid in patients with renal or hepatic disease than with other patients because of decreased plasma protein binding, secondary to hypoalbuminaemia, occurring in these disease states. The extent of conversion to phenytoin is not affected. The fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminaemia. Unbound concentration of phenytoin may be elevated in patients with hyperbilirubinaemia. Phenytoin metabolism may be reduced in patients with hepatic impairment resulting in increased plasma phenytoin concentrations (see section 4.2).

Elderly patients

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 20-30 years of age) (see section 4.2).

Gender

Gender had no significant impact on fosphenytoin or phenytoin pharmacokinetics.

Paediatric population

Limited studies in children (age 5 to 10) receiving Pro-Epanutin have shown similar concentration-time profiles of fosphenytoin and phenytoin to those observed in adult patients receiving comparable mg PE/kg doses.

The systemic toxicity of fosphenytoin is qualitatively and quantitatively similar to that of phenytoin at comparable exposures.

Carcinogenicity studies with fosphenytoin are unavailable. Since fosphenytoin is a prodrug of phenytoin, the carcinogenicity results with phenytoin can be extrapolated. Carcinogenicity studies in mice have shown an increased incidence of hepatocellular tumours at phenytoin plasma concentrations approximating the therapeutic range. Similar studies in rats have shown an inconsistent increase in hepatocellular tumours. The clinical significance of these findings is unknown.

Genetic toxicity studies showed that fosphenytoin was not mutagenic in bacteria or in mammalian cells in vitro. It is clastogenic in vitro but not in vivo.

Fetal toxicity, developmental toxicity and teratogenicity occurred in offspring from rats given fosphenytoin prior to and during mating, gestation, and lactation. No developmental effects were observed in offspring of pregnant rabbits given fosphenytoin; malformations have been reported in offspring of pregnant rabbits given phenytoin. Perinatal/postnatal effects in rats include decreased growth of offspring and behavioural toxicity. Fosphenytoin had no effect on fertility in male rats. In females, altered oestrous cycles, prolonged gestation, and delayed mating were observed.

Local irritation following IV or IM dosing or inadvertent perivenous administration was less severe with fosphenytoin than with phenytoin and was generally comparable to that observed with vehicle injections. The potential of fosphenytoin to induce intra-arterial irritation was not assessed.