parenteral formulation, specifically excipients and high alkalinity, limits its rate of administration and influences its tolerability. Fosphenytoin is a water-soluble prodrug of phenytoin and is converted to the active compound by nonspecific phosphatases in the blood (reviewed in Browne 1997). The dose of fosphenytoin is expressed as phenytoin equivalence (75 mg fosphenytoin is labelled as 50 mg phenytoin equivalent). Unlike phenytoin, fosphenytoin is not formulated with propylene glycol and its pH of 8.6–9 means that it may be infused more rapidly, up to 150 mg phenytoin equivalent per minute. Thus, a starting dose of 20 mg/kg intravenous phenytoin equivalent may be given to a 70-kg patient in just under 10 min. Potential practical benefits with fosphenytoin include more rapid achievement of therapeutic blood levels and decreased risk and incidence of serious adverse effects compared with phenytoin. In addition, fosphenytoin may be preferable for patients with difficult vascular access (e.g. children, the elderly, and intravenous drug abusers). Although intramuscular administration of fosphenytoin may be used as a loading dose strategy, this route is not recommended for treating SE because of the delay in achieving therapeutic plasma concentrations of phenytoin (Fierro et al. 1996). Clinical evidence for the role of fosphenytoin in the treatment of SE Short-term outcomes are commonly examined in SE clinical trials. This is due to their importance in the longer-term prognosis following an episode of SE and treatment with antiepileptic drugs. Examples of short-term outcomes include achievement of therapeutic drug levels, time to seizure recurrence, failure of first- line therapy, and time to discharge from the ED. There are few studies of patients with new-onset seizures in the ED and most reports use abnormal laboratory or diagnostic tests (e.g. EEG) as the outcome measure (ACEP 2004). The long-term prognosis for SE is improved if seizures are controlled within 30 min of onset. Thus, rapid drug control of seizures is an advantage and a component of this is the timely achievement of therapeutic drug levels. Fosphenytoin should have an advantage over phenytoin in this respect, as it can be infused more rapidly. Clinical evidence is available that compares the achievement of therapeutic drug levels, seizure control, and tolerability (particularly vascular reactions) with fosphenytoin and phenytoin. Fosphenytoin | clinical impact review Achievement of therapeutic drug levels There is some good evidence supporting the achievement of therapeutic levels of phenytoin with intravenous fosphenytoin (Table 4). Most studies evaluating the pharmacokinetics of fosphenytoin and phenytoin use ‘achievement of a therapeutic serum concentration of phenytoin’ as the primary outcome measure. However, ‘therapeutic’ phenytoin serum level may be a misleading term, as some patients can be seizure-free at phenytoin levels <10 mg/L and yet others require serum levels >20 mg/L for seizure control (ACEP 2004). Studies evaluated here have included both SE and non-SE patient populations, as the achievement of therapeutic drug levels is independent of the presence of SE. In a study in children with malaria and SE (in endemic tropical regions falciparum malaria is a common cause of convulsions in children), maximum peak plasma phenytoin concentrations were achieved more rapidly with intravenous fosphenytoin compared with intravenous phenytoin (0.08 vs 0.37 h) (Ogutu et al. 2003). Two abstracts have reported the achievement of therapeutic levels of phenytoin with fosphenytoin administration in single-arm, open- label studies in patients with SE. Total phenytoin concentrations of ≥10 mg/L and free phenytoin concentrations of ≥1 mg/L were achieved within 10–20 min of commencing the infusion of fosphenytoin in 40 patients with SE; mean infusion duration 11 min (Allen et al. 1995). In another study of 39 patients (22 with SE and 17 non-SE patients), treated with intravenous fosphenytoin (10–20 mg/kg phenytoin equivalent), pharmacokinetic data were collected from 20 patients (Runge et al. 1995). Therapeutic levels of free phenytoin (0.9–1.8 mg/mL [sic]) were achieved within 10 min in all 20 patients. However, it should be noted that the target infusion rate for fosphenytoin was 50–100 mg/min for non-SE patients and 100–150 mg/min for SE patients and it is unclear what proportion of participants from these two groups provided the pharmacokinetic data. Although the maximal rate of intravenous administration is three times faster with fosphenytoin than with phenytoin, there is only limited evidence that phenytoin levels are actually achieved faster with fosphenytoin. For example, in a small, randomized controlled study, phenytoin (n=14) and fosphenytoin (n=15) were administered Table 4 | Summary of outcome evidence for intravenous fosphenytoin: achievement of therapeutic drug levels Level of evidence Outcomes Comparators Study population 2 3 3 3 Mean times to achieve therapeutic drug concentrations were 0.24 h (iv PT) and 0.21 h (iv FOS). Both iv groups were significantly shorter compared with oral PT (5.62 h, P<0.001) FOS (iv) vs. PT (iv or oral) n=45 patients with subtherapeutic PT levels within 48 h of a seizure (oral PT n=16; iv PT n=14; iv FOS n=15) Mean time to peak PT concentrations following loading dose were 0.08 h (iv FOS), 0.37 h (iv PT), and 0.38 h (im FOS) FOS (iv or im) vs PT (iv) n=38 children with SE and severe falciparum Ogutu et al. malaria (iv PT n=11; iv FOS n=16; im FOS n=11) 2003 Total and free phenytoin concentrations of ≥10 mg/L and ≥1 mg/L FOS (iv) respectively, achieved within 10–20 min of starting infusion Therapeutic PT levels achieved within 10 min of FOS infusion of all (n=20) patients with PK data n=40 patients with SE FOS (iv) n=39 patients following benzodiazepine therapy FOS, fosphenytoin; im, intramuscular; iv, intravenous; PK, pharmacokinetic; PT, phenytoin. Core Evidence 2005;1(1) Study reference Swadron et al. 2004 Allen et al. 1995 Runge et al. 1995 69