title: The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients.
abstract: OBJECTIVE
  To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water-soluble phenytoin prodrug, after intramuscular and intravenous administration.
  
  
  METHODS
  Open-label study of intramuscular administration, and double-blind, randomized study of intravenous administration.
  
  
  METHODS
  Six and ten hospitals throughout the United States for the intramuscular and intravenous multicenter studies, respectively.
  
  
  METHODS
  Neurosurgical patients who required anticonvulsant prophylaxis or treatment.
  
  
  METHODS
  In the intramuscular study, 118 patients received loading doses ranging from 480-1500 mg phenytoin equivalents (PE) and daily maintenance doses ranging from 130-1250 mg PE for 3-14 days. In the intravenous study, 88 patients received fosphenytoin and 28 received phenytoin sodium for 3-14 days. Mean +/- SD loading doses and maintenance doses of intravenous fosphenytoin and phenytoin were 1082 +/- 299 mg PE and 411 +/- 221 mg PE, and 1082 +/- 299 mg and 422 +/- 197 mg, respectively. Trough phenytoin concentrations were measured daily in all patients.
  
  
  RESULTS
  Intramuscular fosphenytoin was safe and well tolerated, with no irritation found for 99% of all injection site evaluations. Adverse events associated with the drug occurred in 9% of patients, commonly those typical of the parent drug. For intravenous treatment, the frequency of mild irritation at the infusion site was significantly lower in the fosphenytoin group (6%) than in the phenytoin group (25%, p < 0.05). Reductions in infusion rates were required in 17% and 36% of fosphenytoin and phenytoin recipients, respectively. No significant difference was observed relative to adverse events or seizure frequency between the groups. Trough plasma phenytoin concentrations were approximately 10 micrograms/ml or greater in patients receiving at least 3 days of intramuscular and intravenous fosphenytoin. Trough phenytoin concentrations were similar between patients receiving intravenous phenytoin and fosphenytoin on all study days.
  
  
  CONCLUSIONS
  Fosphenytoin can be administered intramuscularly and intravenously in neurosurgical patients to achieve and maintain therapeutic phenytoin concentrations for up to 14 days. Both routes are safe and well tolerated. Intravenous fosphenytoin is significantly better tolerated than intravenous phenytoin sodium in this patient subset.
authors.affiliation: Department of Clinical Pharmacy, University of Tennessee, Memphis, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Boucher
authors.forename: C A
authors.initials: CA
authors.lastname: Feler
authors.forename: J C
authors.initials: JC
authors.lastname: Dean
authors.forename: D D
authors.initials: DD
authors.lastname: Michie
authors.forename: B K
authors.initials: BK
authors.lastname: Tipton
authors.forename: K R
authors.initials: KR
authors.lastname: Smith
authors.forename: R E
authors.initials: RE
authors.lastname: Kramer
authors.forename: B
authors.initials: B
authors.lastname: Young
authors.forename: B R
authors.initials: BR
authors.lastname: Parks
authors.forename: A R
authors.initials: AR
authors.lastname: Kugler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D011355:Prodrugs; D010672:Phenytoin; C043114:fosphenytoin