Fosphenytoin | clinical impact review Table 5 | Summary of outcome evidence for intravenous fosphenytoin: seizure control in status epilepticus patients Comparators Study population For nine patients with SE, seizures ceased after 31.8 min with PT vs 49.5 min with FOS (P=0.8) FOS (iv or im) vs PT (iv) n=9 with SE from 256 patients SE terminated within 30 min of FOS infusion in 85% of patients FOS (iv) n=40 patients with SE Seizures controlled in 97% of patients FOS (iv) n=39 patients following benzodiazepine therapy SE controlled in 36% (iv PT), 44% (iv FOS), and 64% (im FOS) of patients 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 Study reference Coplin et al. 2002 Allen et al. 1995 Runge et al. 1995 Level of evidence Outcomes 2 3 3 3 FOS, fosphenytoin; im, intramuscular; iv, intravenous; PT, phenytoin; SE, status epilepticus. at the recommended initial rates of 50 and 150 mg/min, respectively, and therapeutic phenytoin concentrations were reached at a mean of 0.24 and 0.21 h, respectively (Swadron et al. 2004). One possible reason for the difference is the delay (half-life 8–15 min) in the conversion of fosphenytoin to phenytoin by phosphatases in blood and other tissues (Browne 1997). Plasma phenytoin concentrations were measured using an immunoassay in this study (Swadron et al. 2004). This method may overestimate actual phenytoin plasma concentrations by 1.2–6-fold when fosphenytoin is present (Fischer et al. 2003). The other studies used more specific high-performance liquid chromatography assays where interference does not occur (Fischer et al. 2003). Seizure control in SE patients The evidence suggests that fosphenytoin is as effective as phenytoin in speed of seizure resolution and in the proportion of patients responding to treatment (Table 5). When considering the use of intravenous fosphenytoin specifically for the treatment of SE four studies categorized at level 3 evidence or higher were identified. Two of these were single-arm design (Allen et al. 1995; Runge et al. 1995), while the third was a study in children with SE plus the added complication of falciparum malaria (Ogutu et al. 2003). Finally, although the fourth study involved a large number of patients only nine were diagnosed with SE (Coplin et al. 2002). In the study in children with malaria plus SE, the defined clinical outcomes were abolition of seizures within 30 min of commencing drug therapy, or SE characterized by recurrent convulsions of short duration, which were considered controlled if there were no convulsions within 12 h of drug therapy (Ogutu et al. 2003). SE was controlled in seven of 16 children following intravenous fosphenytoin and in four of 11 following intravenous phenytoin. In an abstract of a single-arm, open-label study in SE patients, seizure control was achieved in 85% (37 of 40) patients within 30 min of receiving intravenous fosphenytoin (mean infusion duration 11 min) (Allen et al. 1995). In the second single-arm study 39 patients (SE n=22, epilepsy patients n=17) were treated with intravenous fosphenytoin. No seizures were noted in 38 (97%) of these patients after intravenous fosphenytoin. The mean dose in SE patients was 16.1 mg/kg (range 9.6–22 mg/kg) administered at a mean infusion rate of 134.4 mg/min (range 54–183 mg/min) (Runge et al. 1995). 70 In a large, open-label randomized study, 256 ED patients were prescribed 279 parenteral doses of phenytoin or fosphenytoin (phenytoin n=77, fosphenytoin n=202). Time to seizure cessation in the nine patients diagnosed with SE was not significantly different with fosphenytoin compared with phenytoin (Coplin et al. 2002) Tolerability and adverse events There is some good evidence supporting the improved tolerability of fosphenytoin compared with phenytoin (Table 6). Some studies with non-SE patient populations have been used in this evaluation, as tolerability of fosphenytoin does not depend on the presence of SE. In a study of 29 non-SE patients, phenytoin and fosphenytoin were administered intravenously at the recommended initial rates of 50 and 150 mg/min, respectively, and a total of 27 and 32 adverse events were recorded in the respective groups (P=0.55). However, pain and phlebitis were experienced more frequently following phenytoin compared with fosphenytoin (11 vs 3, P<0.001). The occurrence of perineal pruritus was exclusively associated with fosphenytoin (12 vs 0, P<0.0001), requiring a reduction in infusion rate in some patients (Swadron et al. 2004). Perineal pruritus is reversible and has previously been noted to occur with high infusion rates of fosphenytoin (Sirven & Waterhouse 2003). There is further evidence to support improved tolerability with fosphenytoin. In a randomized, double-blind, crossover study, 12 healthy volunteers received a 30-min infusion of 250 mg phenytoin, or fosphenytoin equivalent, to evaluate venous irritation. Phenytoin was associated with a significantly higher level of infusion site pain (all subjects, P<0.05) and phlebitis (eight subjects P<0.05); cording occurred in six subjects. Erythema and tenderness were prominent at the conclusion of the phenytoin infusion and again on examination 24 h later. In contrast, fosphenytoin was associated with mild pain in only two subjects, and phlebitis in one; no instances of erythema or cording were noted (Jamerson et al. 1994). In this early study, both drugs were infused at the same rate; however, it is now recognized that fosphenytoin may be administered at three times the rate of phenytoin. Venous-related adverse events were also noted more often with intravenous loading doses of phenytoin compared with fosphenytoin in a randomized, double-blind study in 23 non-SE © 2005 Core Medical Publishing Limited