Fosphenytoin sodium: new drug to replace intravenous phenytoin sodium

Pediatric Nursing, Sept-Oct, 1997 by Sarah Mills Voytko, Elizabeth Farrington

Safety of Fosphenytoin: Clinical Trials

Several pharmacokinetic trials comparing fosphenytoin and phenytoin also provided adequate safety data. Jamerson and colleagues (1994) looked at the frequency, severity, and the course of venous irritation after the administration of a single IV dose of undiluted phenytoin and after a dose of fosphenytoin. In this crossover study, 12 volunteers received a 30 minute infusion of phenytoin sodium (250 mg) or an equimolar equivalent dose of fosphenytoin sodium (375 mg). The subjects then received the other treatment 14-21 days later. The subjects assessed venous irritation by evaluating the severity of pain, burning, and itching, while the investigators evaluated phlebitis, induration, exodation, and cording. All 12 patients had some degree of venous irritation associated with the phenytoin administration, with 8 of the 12 subjects having phlebitis. In contrast, 2 of the 12 subjects in the fosphenytoin group admitted to discomfort associated with fosphenytoin administration, while one subject had documented phlebitis.

In a study by Donn, Drissel, and Quon (1987), the safety of IM fosphenytoin was to compared to IV phenytoin. Intramuscular doses of fosphenytoin (375 mg/5 ml) and equimolar doses of undiluted IV phenytoin (250 mg/5 ml) were administered to 12 volunteers in a randomized, cross over study. Fosphenytoin sodium given as an intramuscular injection did not cause irritation at the site beyond 1 hour after administration in any of the 12 subjects. Intravenous phenytoin sodium produced moderate pain and burning at the infusion site, and phlebitis was still present in 7 of the 12 volunteers 5 days after the infusion.

Boucher and colleagues (1996) also evaluated the safety and tolerableness of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. In the open-labeled intramuscular arm of the study, 118 patients received fosphenytoin loading doses ranging from 4801500 mg phenytoin equivalents (PE) and daily maintenance doses ranging from 130-1250 mg PE for 3-14 days. In the double-blind intravenous arm of the study, 88 patients received fosphenytoin and 28 received phenytoin sodium for 3- 14 days. All intravenous doses were diluted with equal volumes of 0.9% sodium chloride and were administered at rates not exceeding 50 mg PE/min and 50 mg/min for fosphenytoin and phenytoin, respectively. Intramuscular administration of fosphenytoin was safe and well tolerated with no irritation found for 99% of injection sites. For intravenous administration, the frequency of mild irritation at the infusion site was significantly lower in the fosphenytoin group than in the phenytoin group (6% versus 25%, p [is less than] 0.05). Reductions in infusion rates occurred in 17% of the patients in the fosphenytoin group compared to 36% of the patients in the phenytoin group.

Leppik and investigators (1990), in an open-label study of patients with well-controlled seizures, administered maintenance doses of fosphenytoin sodium (dose range 150-450 mg phenytoin equivalents) by the intramuscular route (n= 32 subjects) or intravenously (n = 37). When fosphenytoin was administered intravenously, the rate of the IV infusion was 75 mg/min. No significant changes in the heart rate, respirations, or in diastolic blood pressure were noted, regardless of the route of administration. However, significant systolic hypotension was apparent 15 minutes to 2 hours following IV administration and 30 minutes to 4 hours after IM administration of fosphenytoin. Nystagmus occurred in 44% of the patients receiving IV fosphenytoin and 25% of the patients receiving IM fosphenytoin on at least one occasion following drug administration. Paresthesia associated with IV infusion was the most frequent side effect reported in 20.9% of the patients receiving IV fosphenytoin.