Phenytoin (after CEREBYX administration)
In general, IM administration of CEREBYX 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 CEREBYX, 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 CEREBYX 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 CEREBYX 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 DILANTIN) 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 1200 mg PE CEREBYX infused at 100 mg PE/min (triangles) or 150 mg PE/min (squares) and 1200 mg Dilantin 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 CEREBYX doses of 400 to 1200 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.
Absorption:
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.
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 postinfusion).
Elimination:
Mean total phenytoin half-life values (12.0 to 28.9 hr) following CEREBYX administration at these doses are similar to those after equal doses of parenteral Dilantin and tend to be greater at higher plasma phenytoin concentrations.
Metabolism
Phenytoin derived from administration of CEREBYX 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 CEREBYX doses of 400 to 1200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose.
Excretion
Phenytoin derived from administration of CEREBYX is excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1% to 5% of the CEREBYX dose) is recovered in urine.
Specific Populations
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).
Sex/Race:
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 CEREBYX) in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported.
Pregnancy:
It has been reported in the literature that the plasma clearance of phenytoin (the active metabolite of CEREBYX) 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 CEREBYX 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 CEREBYX were concurrently administered in single submaximal doses.