Finally, cost data were used with effectiveness data from a questionnaire (covering drug administration, frequency of adverse events and their management) used with 33 nurses to determine cost-effectiveness with fosphenytoin (Armstrong et al. 1999). The study showed that the average expected cost of phenytoin alone ($US58) was less than when 50% of patients were treated with fosphenytoin and 50% with phenytoin ($US94), or when fosphenytoin was used alone ($US130). However, the cost-effectiveness ratio is a more useful measure, as it reflects the cost to achieve the loading dose of the drug without complication. Thus, the average cost-effectiveness ratios were $US225 for phenytoin alone, $US149 for the 50 : 50 option and $US130 for fosphenytoin alone. The incremental cost- effectiveness ratio was approximately $US97 to replace phenytoin loading doses with fosphenytoin, which was accepted as a reasonable increase in cost to achieve a reduction in adverse events (Armstrong et al. 1999). Resource utilization Rapid control of seizures in SE is necessary to limit the potentially damaging neurologic morbidity and the resulting costs in treating complications that can occur if treatment is delayed. The advantages of fosphenytoin compared with phenytoin include a faster rate of administration and a reduced potential for adverse events, particularly venous irritation and cardiac toxicity. Monitoring potential adverse events is essential when using intravenous phenytoin, and typically blood pressure, respiration, and continuous electrocardiogram (ECG) are observed. As the risk of hypotension exists with intravenous fosphenytoin administration at the recommended rate of administration (≤150 mg phenytoin equivalent per minute) continuous monitoring of these parameters is also essential. Therefore cost implications associated with the use of monitoring equipment are present irrespective of the choice between intravenous phenytoin or fosphenytoin for treating SE. Since the infusion rate for fosphenytoin can be up to three times faster than that with phenytoin this may save time in the ED and reduce resource use. There is also a potential saving of resource use through the avoidance of adverse events, and it has been estimated that the use of intravenous fosphenytoin results in an incremental cost-effectiveness of $US97 per adverse event avoided (Armstrong et al. 1999). Although there has been a focus on the large difference in cost between the two drugs this must be weighed against the medical costs and resources necessary to treat complications resulting from intravenous phenytoin or sequelae of inadequately controlled prolonged SE. Patient group/population Most patients with SE are eligible for treatment with intravenous fosphenytoin. There is limited evidence that fosphenytoin may be a more appropriate choice in selective populations. First, large vein access for the administration of intravenous phenytoin can be problematic in children, the elderly, or other SE patients with restricted venous access. In addition, the formulation can be painful and there is a risk of extravasation. Therefore, the use of intravenous fosphenytoin via peripheral vein access may offer advantages over phenytoin, although there is currently no Core Evidence 2005;1(1) Fosphenytoin | clinical impact review published evidence in these specific groups. Second, in resource- poor countries fosphenytoin may offer both clinical and practical advantages compared with intravenous phenytoin. For example, intravenous phenytoin must be infused slowly when treating SE, but this is not always possible in some basic health facilities (Ogutu et al. 2003). Therefore, fosphenytoin may be a useful option in these circumstances, although this must be weighed against the impact of its higher acquisition cost in countries with limited healthcare resources. There is limited evidence from case studies (level 4 evidence) indicating that parenteral fosphenytoin may be useful in seizure management in premature or extremely low-birthweight infants (Kriel & Cifuentes 2001). However, close monitoring of free phenytoin levels is advised, as there may be some variability in therapeutic phenytoin plasma concentrations. For example, unexpected subtherapeutic levels of phenytoin following intravenous fosphenytoin were observed in a 3-year-old boy (Koul & Deleu 2002) and one infant aged ≤1 year (Takeoka et al. 1998). The elimination half-life of intravenous fosphenytoin was not significantly different between neonates (<29 days), infants (2 days to <2 years), children (2 to <12 years), and adolescents (12 to <17 years). In addition, the elimination half-life in children (7.1 min; 5–10 years) is not significantly different to that in adults (7.9 min; 16–75 years) (Fischer et al. 2003). Therefore, as the rate of conversion of fosphenytoin to phenytoin remains consistent with age it would appear that the subtherapeutic levels of phenytoin seen in some neonates and infants (Takeoka et al. 1998; Koul & Deleu 2002) may be attributable to high clearance of phenytoin (reviewed in Fischer et al. 2003). Thus, it may be prudent to monitor therapeutic blood levels of phenytoin carefully following fosphenytoin administration in these groups. Dosage, administration, and formulations Fosphenytoin (5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4- imidazolidinedione disodium salt; Cerebyx®; fosphenytoin sodium injection) is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. It is supplied in vials containing 75 mg/mL fosphenytoin sodium equivalent to 50 mg/mL phenytoin sodium after administration. This formulation is supplied as a ready-mixed solution in water for injection and Tromethamine (tris) buffer adjusted to pH 8.6–9 with either hydrochloric acid or sodium hydroxide. The loading dose of fosphenytoin for treating SE is 15–20 mg phenytoin equivalent per kilogram administered at 100–150 mg phenytoin equivalent per minute. Fosphenytoin administered intramuscularly should not be used in the treatment of SE because therapeutic phenytoin concentrations may not be reached as quickly as with intravenous administration. Fosphenytoin is indicated for short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate, or deemed less advantageous. The safety and effectiveness of fosphenytoin in this use has not been systematically evaluated for more than 5 days. Fosphenytoin can be used for the control of GCSE and the prevention and treatment of seizures occurring during neurosurgery. It can also be substituted, short term, for oral phenytoin (Cerebyx 2002). 73