2 2 2 2 3 3 3 Fosphenytoin | clinical impact review Study reference Boucher et al. 1996 Swadron et al. 2004 Jamerson et al. 1994 Andrews et al. 1994 Baron et al. 1995 Armstrong et al. 1999 Table 6 | Summary of outcome evidence for intravenous fosphenytoin: adverse events Level of evidence Outcomes Lower incidence of infusion site irritation with iv FOS (6%) compared with iv PT (25%, P<0.05) Total of 17 (oral PT), 27 (iv PT), and 32 (iv FOS) AEs Significantly fewer AEs with oral PT vs both iv groups, P≤0.02 Venous irritation (pain) reported by 12 subjects receiving PT vs two subjects receiving FOS. Phlebitis, eight cases with PT vs one case with FOS (P<0.05); and six cases of cording vs 0 instances with FOS Infusion rate altered because of an AE with 6.5% PT patients vs 6.4% FOS patients (P=1.0) AE frequency 9.1% with PT vs 15.8% with FOS (P=0.3) Comparators Study population FOS (iv or im) vs PT (iv) FOS (iv) vs PT (iv or oral) FOS (iv) vs PT (iv) n=116 neurosurgical patients (n=88 iv FOS; n=28 iv PT) n=45 patients (oral PT n=16; iv PT n=14; iv FOS n=15) n=12 healthy volunteers (crossover study) FOS (iv or im) vs PT (iv) n=256 ED patients (279 parenteral doses of a PT equivalent; FOS n=202; PT n=77) Coplin et al. 2002 AEs arising from loading doses included adjustment of infusion rate in 67% PT vs 12% FOS recipients (P<0.05). Injection site pain occurred in 83% PT vs 0% FOS recipients FOS (iv) vs PT (iv) Initial iv site maintained in a higher proportion of FOS recipients (58%) FOS (iv) vs PT vs PT recipients (38%) (iv) Fewer site changes (due to irritation) with FOS (11%) vs PT (42%) n=17 FOS, n=6 PT n=208 (n=167 FOS; n=41 PT). Review of 3 studies Nurse-reported venous irritation in 62.3–74% of PT recipients vs 0% with FOS FOS (iv or im) vs PT (iv) n=33 nurses from critical care, ED and neurology services AE, adverse event; ED, emergency department; FOS, fosphenytoin; im, intramuscular; iv, intravenous; PT, phenytoin; SE, status epilepticus. patients (Andrews et al. 1994). Pain and phlebitis occurred in 83% of phenytoin recipients compared with none in those treated with fosphenytoin. Infusion rate adjustment, as a result of adverse events, was required in significantly more phenytoin recipients compared with those receiving fosphenytoin (67 vs 12%; P<0.05). Although there were complaints of transient, generalized itching and warmth in 53% of the fosphenytoin group, as noted above, infusion rate adjustment was only necessary in a minority of the group. In another double-blind, randomized study, 88 patients received intravenous fosphenytoin and 28 patients received intravenous phenytoin to achieve serum phenytoin concentrations of 10–20 mg/L. This was followed by maintenance doses for up to 14 days. The frequency of mild irritation was significantly lower following fosphenytoin compared with phenytoin (6 vs 25%, P<0.05) and reductions in infusion rates were required in 17 and 36% of recipients, respectively (Boucher et al. 1996). Infusion site changes were also highlighted in a review of 208 patients (with epilepsy, neurosurgical or with SE) participating in three studies. A larger proportion of fosphenytoin recipients maintained their original intravenous site (58 vs 38%), and change in infusion site was less common with fosphenytoin compared with phenytoin (11 vs 42%) (Baron et al. 1995). A questionnaire was used to capture effectiveness data from 33 nurses in critical care, emergency, and neurology services in a metropolitan area in the USA. In this study, venous irritation occurred in a mean of 62.3±43.4% of patients receiving phenytoin loading doses and 74±32.9% receiving maintenance doses. Each local reaction required 34.7±9.3 min of nursing time for management. In contrast, adverse events associated with fosphenytoin were uncommon (0.3±1%) and there were no nurse- reported local reactions following intravenous (or intramuscular) Core Evidence 2005;1(1) administration (Armstrong et al. 1999) (see also ‘Resource utilization’ below). One study, however, reported that fosphenytoin and phenytoin are associated with a similar incidence of adverse events. In this large, open-label randomized study of 256 ED patients who were prescribed 279 parenteral doses of phenytoin or fosphenytoin (phenytoin n=77, fosphenytoin n=202), the incidence of adverse events was similar between the two treatment groups (odds ratio 0.7, confidence interval 0.3–1.4; P=0.3). It is worth noting that, although the time taken to administer fosphenytoin (13 min, range 1–75 min) was significantly shorter than with phenytoin (45 min, range 15–165 min, P<0.001), the protocol specified the rate of phenytoin administration as 20 mg/min (vs maximum recommended rate of 50 mg/min). Thus, the reduced rate of administration with phenytoin is the most likely reason for the lower incidence of adverse events, since it would avoid serious adverse events, including drug extravasation and hypotension. In addition, fosphenytoin was also administered at a reduced rate of 100 mg phenytoin equivalent per minute (Coplin et al. 2002). Since only nine patients of the 256 patients had SE, rapid seizure resolution was not the prime objective of the study. Hence, the low rates of infusion are not necessarily appropriate for the treatment of SE. Economic evidence When compared strictly on acquisition cost, fosphenytoin is more expensive than phenytoin. It has been reported that the difference in cost with fosphenytoin is 10–20 times greater when compared with generic versions of intravenous phenytoin (Jobst & Holmes 2004). To get an overall evaluation of the economic impact of using fosphenytoin to treat SE, the costs associated with adverse events, rapid seizure control and discharge from ED, and long-term sequelae need to be considered. However, at present there is no published 71