Antiepileptic Drugs, 5th Edition

Phenytoin and Other Hydantoins

64

Fosphenytoin

Flavia M. Pryor MD*

Eugene R. Ramsay RN, BSN**

* Professor of Neurology and Psychiatry, Department of Neurology, University of Miami School of Medicine, Miami, Florida

** Nurse Researcher, Department of Neurology Service, Miami Veterans Affairs Medical Center, Miami, Florida

BACKGROUND

Fosphenytoin sodium (Cerebyx, Parke-Davis) is the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin (Figure 64.1). It was originally formulated in the early 1970s and was subsequently marketed as a replacement for parenteral phenytoin (PHT; Dilantin) (2).

Fosphenytoin is a phosphate ester prodrug of PHT. The phosphate moiety is rapidly and completely (conversion half-life of ~8 to 15 minutes) hydrolyzed by phosphatases found in blood and vascularized tissue such as muscle (Figure 64.2). There is little interindividual variability (2, 3, 4, 5, 6, 7, 8, 9, 10, 11), and it is not dependent on plasma fosphenytoin or PHT concentrations (2,4,9,12,13). The conversion of fosphenytoin to PHT is not influenced by age, race, or gender (14). Administration of fosphenytoin by the intravenous (i.v.) route appears to be better tolerated than PHT administered parenterally (15).

PHYSICAL AND CHEMICAL PROPERTIES

Fosphenytoin has a molecular weight of 406.24 and consists of an off-white congregated powder. Its water solubility at 37°C is 7.5 × 104 µg/mL (compared with 20.5 µg/mL for PHT) (2). Dosages of fosphenytoin are expressed as PHT equivalents (PE), a term that refers to the mg of active PHT delivered as fosphenytoin. Thus, 150 mg of fosphenytoin is equivalent to 100 mg PE, which is equivalent to 100 mg of parenteral PHT. Fosphenytoin is available as a ready-mixed solution of 50 mg PE/mL in water for injection USP, tromethamine USP (TRIS), buffer adjusted to pH 8.6 to 9.0 with either hydrochloric acid NF or sodium hydroxide NF (16). In contrast to fosphenytoin, parenteral PHT requires a chemical vehicle consisting of 40% propylene glycol and 10% ethanol in water adjusted to pH 12 with sodium hydroxide. Local and systemic adverse effects of parenteral PHT have been attributed to the relatively high pH of its chemical vehicle (14,15,17).

Fosphenytoin is a disodium phosphate ester of PHT. The attachment of a large phosphate ester to the central five-membered ring of PHT changes its physical chemical properties and renders it water soluble (18). It has a pH of 8.6 to 9.0 and does not require excipients such as propylene glycol or alcohol to remain in solution (18). The increased water solubility of fosphenytoin obviates the need for the propylene glycol and alcohol, which are required to make PHT water soluble. On entry into the vascular compartment, the phosphate molecule is removed by nonspecific tissue phosphatases, thus converting fosphenytoin into active PHT. The half-life of conversion is 8 to 15 minutes and is the same regardless of dose or fosphenytoin concentration range achieved (4,19). The plasma clearance of fosphenytoin is not dependent on dose administration and is 19.8±1.6 L/hr. The conversion is rapid after an i.v. infusion and is essentially completed within 30 to 45 minutes (4).

 

FIGURE 64.1. Structure of fosphenytoin (5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidinedione disodium salt.

P.612

 

FIGURE 64.2. Conversion of fosphenytoin to phenytoin.

CLINICAL PHARMACOLOGY

Bioavailability

The bioavailability of PHT from fosphenytoin as compared with i.v. PHT sodium was determined in healthy volunteers after i.v. and intramuscular (i.m.) administration of fosphenytoin (12). The mean absolute bioavailability of fosphenytoin was 0.992 after i.v. administration and 1.012 after i.m. injection, a finding demonstrating complete bioavailability irrespective of route of administration. Twelve healthy volunteers were randomized, in a double-blind, crossover fashion to receive PHT sodium and fosphenytoin i.v. in 30 minutes (15). The conversion half-life of fosphenytoin to PHT was 9.3±2.7 minutes. Greater than 99% of fosphenytoin was converted to PHT, and no fosphenytoin was detected in the urine. Fosphenytoin was shown to be bioequivalent to PHT and produced less irritation at the injection site than PHT.

Fosphenytoin is undetectable 4 hours after i.m. injection. Fosphenytoin bioavailability studies have demonstrated i.m. fosphenytoin to be 100% bioavailable (2). Two hours after administration, the plasma PHT level is essentially the same after equivalent doses of i.v. PHT and i.m. fosphenytoin. Levels >10 µg/mL can be achieved within 45 minutes of i.m. administration of a 20 mg/kg loading dose of fosphenytoin (Figure 64.3). Leppik et al compared the maximum concentration and time to maximum concentration of fosphenytoin administered i.m. on a single site versus two sites (4). For the single injection, the time to maximum concentration was 0.97±1.8 hours compared with 0.32±0.4 hours. The maximum concentration for a single site injection was 8.9 mg/L compared with 16.8 mg/L for two injection sites. Thus, faster and higher peaks are attained after injections at two sites. The tissue phosphatases responsible for the conversion of fosphenytoin to PHT are ubiquitous. Phosphatase activity is present at all ages and the activity is not altered by age, disease states, or medications. Thus, the conversion should be similar in all patients.

 

FIGURE 64.3. Plasma phenytoin levels after administration of 500 mg phenytoin (Dilantin) intravenously (filled boxes) or 500 mg fosphenytoin intramuscularly (filled wedges).

Protein Binding

The protein binding and pharmacokinetics of fosphenytoin, diazepam, and PHT were evaluated in nine healthy male volunteers (20). PHT free fraction increased significantly with rising fosphenytoin concentrations, a finding suggesting PHT displacement from its binding sites by fosphenytoin. Fosphenytoin is highly bound (95.7±0.48%) to serum proteins, predominantly albumin. Increased clearance of fosphenytoin may occur in hypoalbuminemia (21). Fosphenytoin competes with PHT for binding sites. Rapid infusion rates (50 to 150 mg/min) of fosphenytoin at relatively high doses (≥15 mg/kg) will result in increased PHT unbound fraction (22). However, PHT binding stabilizes as plasma fosphenytoin concentrations decline (30 to 60 minutes after infusion).

P.613

 

Distribution

The volume of distribution of fosphenytoin was evaluated in two pharmacokinetic studies. Fosphenytoin was administered by the i.v. route over 30 minutes using doses of 150, 300, 600, and 1,200 mg to four different groups of volunteers (3). The area under the curve (AUC) was 10, 19, 43, and 55 mg/hr/L respectively, and it was proportional to dose. Total clearance was 14 L/hr and was independent of dose. The volume of distribution was approximately 2.6 L, a finding suggesting the most of the dose remained in plasma. Ten patients (one female and nine male patients) received a single i.v. dose of 100 to 200 mg PE, and an equivalent i.m. dose was administered 1 week later (6). The volume of distribution for the i.v. dose was 0.040±0.0084 L/kg, with a conversion half-life of 8.0±2.9 minutes. Mean clearance overall was 0.24±0.080 L/kg/hr in the 10 patients. The volume of distribution was 2.8 L in this group of patients, similar to that previously reported in healthy volunteers.

Chemical Stability

Admixtures of fosphenytoin 1, 8, and 20 mg with sodium chloride 0.9% injection, dextrose 5%, and 11 other i.v. solutions were prepared and stored at -20°C in glass or polyvinyl chloride containers for 7 days (23). Additionally, 63 syringes were filled with fosphenytoin sodium 50 mg PE/mL (undiluted) and were stored at 25°, 4°, or -20°C. There were no discernible changes in color or clarity in any of the fosphenytoin solutions throughout the study. No visible precipitation was observed. Fosphenytoin concentrations remained stable at each sampling, regardless of container, concentration, i.v. solution, or storage temperature. Fosphenytoin remains stable for at least 30 days at room temperature, under refrigeration, or frozen. Furthermore, solutions of fosphenytoin in numerous different i.v. fluids were stable for at least 7 days at room temperature. Findings from a subsequent study indicate that fosphenytoin remains physically stable from at least 2 years at 25°C in pH ranging from 7.4 to 8.0 (24).

Intramuscular Clinical Trials

Of 882 patients and subjects involved in the clinical trials with fosphenytoin, 411 received i.m. injections. These include pharmacokinetics, dosage maintenance, and loading dose studies. In a double-blind parallel study, 240 patients were randomized to receive either oral PHT and i.m. placebo (n = 61) or oral placebo and i.m. fosphenytoin (n = 179) (25). This study was conducted in patients receiving oral PHT once a day for the treatment of epilepsy or seizure prophylaxis after neurosurgery. The dose given to each patient remained constant throughout the study. The fosphenytoin dose for each patient provided an equivalent amount of PHT as the dose of PHT taken during the baseline period. The trough plasma levels remained the same during open baseline and the double-blind treatment phase. The injection sites were evaluated for pain, burning, and itching after the loading and maintenance doses. The rating scale was none (score = 0), mild (score = 1), moderate (score = 2), and severe (score = 3). No severe reactions were reported. The average score 5 minutes after injection was less than 0.3 for all measures, except pain in the i.m. placebo group, which was 0.51. There was no difference in the scores for i.m. fosphenytoin and placebo for burning or itching. In a subset of 13 of the patients participating in this trial, serial timed plasma levels were drawn after oral PHT during baseline and on the last day of i.m. fosphenytoin administration during the blinded treatment period (11). The average plasma level as measured by the AUC of the plasma level versus time was higher with i.m. fosphenytoin (AUC = 418) than with oral PHT (AUC = 400), but this difference was not clinically significant. The trough plasma level at 24 hours was the same for both groups.

A prospective open-label study on the safety, tolerance, and pharmacokinetics was conducted in 118 patients (26). Neurosurgical patients ≥12 years old who were to be treated with PHT were included. Patients were given an i.m. loading dose of fosphenytoin (8 to 12 mg/kg), after which timed plasma samples were obtained for total and free fosphenytoin and PHT concentrations. The initial dose administered ranged from 480 to 1,500 mg (8 to 22 mg/kg). By the time the first PHT sample was drawn at 1 hour after administration, the total level was 11 µg/mL and the free PHT level was -1.5 µg/mL. Over the next 2 to 14 days, these patients were given maintenance doses of fosphenytoin that ranged from 130 to 1,250 mg/day (1.7 to 17.2 mg/kg/day). The duration of maintenance treatment varies: 98.8% (n = 116) of the patients received 2 days and 14.4% (n = 17) received 7 days of i.m. fosphenytoin. Trough plasma levels were obtained and remained stable. The injection sites were evaluated daily, with 96% of the patients reporting no discomfort or pain after the loading dose. At the end of the maintenance period, 98% of the patients reported no injection site discomfort. No adverse reactions were noted from the i.m. administration of fosphenytoin. These authors demonstrated the rapid and consistent attainment of therapeutic plasma total and free PHT after i.m. fosphenytoin.

The experiences derived from these studies indicate that dosage adjustments are not usually necessary when one converts from oral PHT to i.m. fosphenytoin for 1 to 2 weeks. The plasma total and free PHT concentrations were maintained in the therapeutic range after conversion from oral PHT to equimolar i.m. fosphenytoin. A 100-mg PHT (Dilantin) capsule actually contains 92 mg PHT, whereas the i.v. preparation actually contains 100 mg PHT per 1.0 mL of solution. Longer-term maintenance on fosphenytoin could result in some increase in the plasma level. The

P.614


plasma level should be checked after 2 or more weeks of i.m. or i.v. fosphenytoin therapy.

The safety and tolerance of i.m. fosphenytoin were tested in 60 patients (35 male and 25 female patients) requiring a loading dose of PHT (27). The mean age of patients was 43 years (range, 16 to 80 years); their mean weight was 79 kg (range, 40 to 146 kg). Reasons justifying the use of a loading dose included the following: noncompliance, 18%; first-time PHT treatment, 30%; decreased phenytoin serum levels, 37%; other factors, 15%. A dose of 20 mg/kg of PHT was given to patients with nondetectable plasma levels. Those with a plasma level <7.1 µg/mL were included in the study and were given a loading dose of 15 mg/kg. The mean loading dose administered was 17.7 mg/kg (range, 5.4 to 30.3 mg/kg) for a mean total dose of 1,359.8 mg (range, 525 to 2,250 mg). Most loading doses required 15 to 20 mL of fosphenytoin solution. Fosphenytoin was given as a single site injection in 29 cases, and multiple injection sites were used in the remaining 31 cases. Site of administration was the gluteus in 58 cases and the deltoid in two cases. Despite the relatively large volume of the i.m. injection, patients had no unusual discomfort or side effects with gluteal or deltoid injections. Local irritation at the site of injection occurred in 5% of patients and was considered mild in each case. No serious local adverse reactions were noted. The largest volume injected was 30 mL, which was given into a single muscle site. This patient reported no pain, burning, or discomfort, and this finding attests to how well i.m. fosphenytoin is tolerated. Forty patients reported experiencing some adverse events after the i.m. injection, with the most frequent being nystagmus (47%), dizziness (17%), and ataxia (13%). Eighty-two percent of the adverse events reported were considered mild. The nature and frequency of side effects reported after i.m. loading of fosphenytoin were similar to those experienced after i.v. PHT.

 

FIGURE 64.4. Intramuscular fosphenytoin total and free levels.

The rate and extent of absorption and the tolerability of i.m. fosphenytoin were evaluated in an open-label, doubleblind study (28). Twenty-four patients, 12 male and 12 female, were enrolled. Patients selected required a loading dose of PHT for the treatment of epilepsy or for seizure prophylaxis, or they volunteered to participate in the study. Each patient received 10 mg/kg of fosphenytoin i.m. and a saline injection to compare tolerability. Half of the patients received a volume of saline equal to that of the fosphenytoin, whereas the other half received only 2 mL of saline. The group ranged in age from 19 to 60 years (mean, 35±10 standard deviation years). Weight ranged from 49.1 to 97.3 kg (mean, 79.4±13.9 standard deviation kg). Doses of fosphenytoin ranged from 491 to 973 mg PE, which corresponded to injection volumes ranging from 9.8 to 19.5 mL. The accepted loading dose of fosphenytoin is 20 mg PE/kg, which corresponds to injection volumes ranging from 20 to 40 mL. Typically, this full loading dose is divided into two injection of 10 mg/kg each. Because study participants would be receiving saline injections on the opposite side for tolerability comparison, we used a loading dose of 10 mg/kg to abide by standard clinical practice and to avoid multiple injections of fosphenytoin. Therapeutic serum concentrations of PHT were achieved as early as 5 minutes after the i.m. administration of fosphenytoin in 14.3% of patients and in 26.3% after 10 minutes. By 20 minutes, 37% of the patients had achieved PHT serum concentrations

P.615


>10 µ/mL. More than half the patients had therapeutic serum concentrations at 30 minutes. Nearly 40% of patients had a free PHT level of 1.0 µg/mL by 40 minutes. At 50 minutes, 14 of 18 patients had achieved unbound PHT levels of ≥1.0 µg/mL (Figure 64.4). There was a statistically significant difference in pain between the fosphenytoin and saline sides immediately after injection and at 30 minutes (X2 = .0386 and X2 = .0386, respectively). However, there was no significant difference in pain at 60 minutes and thereafter. Fosphenytoin injections were slightly more uncomfortable than saline injections; however, volume did not appear to be the determining factor. These investigators demonstrated that i.m. administration of fosphenytoin produces therapeutic PHT serum concentrations very rapidly (as early as 5 to 20 minutes), and it is well tolerated by most patients irrespective of injection volume.

POTENTIAL CLINICAL USES FOR INTRAMUSCULAR FOSPHENYTOIN

Despite the efficacy of i.v. PHT in the treatment of status epilepticus and acute seizures, the potential side effects of the i.v. formulation have limited its use to situations in which adequate venous access is secured and appropriate monitoring systems are available. Fosphenytoin can be safely given i.m. by rescue squads in the field or at home by family members. It is rapidly absorbed and has a sustained serum half-life. The availability of fosphenytoin has the potential to revolutionize the way we treat serial seizures and tonic-clonic status epilepticus.

INTRAVENOUS CLINICAL TRIALS

The pharmacokinetics, safety, and tolerance of i.v. fosphenytoin were investigated in 17 clinical studies. Of 925 patients and subjects involved in fosphenytoin clinical trials, 514 received i.v. injections. Nine clinical trials involving 136 healthy subjects were completed using doses of 100 to 1,200 mg and infusion rates of 3.3 to 150 mg/min. Fosphenytoin, total PHT, and free PHT concentrations and pharmacokinetic parameters were similar in patients and in healthy subjects. Plasma fosphenytoin concentration increases with increasing dose and infusion rate, peaks at the end of infusion, and then declines with a half-life of -0.25 hour. The half-life is independent of dose and infusion rate (19). With the addition of the phosphate moiety to the PHT molecule, fosphenytoin weighs more than PHT. A dose of 150 mg of fosphenytoin is equivalent to 100 mg of PHT, and both are described as being equal in molar quantities of PHT. Dosing can be reported in actual weight of fosphenytoin or as PE, which refers on a one-toone basis to a dose of PHT.

A total of 378 patients received fosphenytoin in doses ranging from 205 to 2,280 mg (2.7 to 20.3 mg/kg) of PE and infusion rates of 3.3 to 167 mg PE/min. To investigate bioequivalence, 43 patients with chronic epilepsy were entered into an open-labeled, single-dose safety and pharmacokinetic study (4). These patients had been treated with PHT with documented stable levels. Mean trough PHT levels were the same after oral PHT, i.v. fosphenytoin, and i.m. fosphenytoin. Analysis of electrocardiograms revealed no significant change in RR, PR, QRS, and QT intervals and no disturbances of cardiac rhythms after i.v. administration of fosphenytoin. Minor and transient discomfort was reported with i.v. infusion (17%) and i.m. injection (14%).

To compare the safety and tolerance of i.v. fosphenytoin, a single-dose, double-blind study was conducted in patients requiring a loading dose of PHT (29). Fifty-two patients were randomized to receive either i.v. fosphenytoin (n = 39) or i.v. PHT (n = 13). Patients in the treatment group received similar doses of study drug (899 mg PE; 12.7 mg/kg) or PHT (879 mg; 11.3 mg/kg). However, the fosphenytoin was infused at nearly twice the rate of administration (82 mg PE/min; range, 40 to 103 mg PE/min) compared with patients in the PHT group (42.4 mg/min). Despite the higher rate of infusion, fosphenytoin was well tolerated and produced no significant cardiac arrhythmias or changes in heart rate, respiration, or diastolic blood pressure. A decline in systolic blood pressure occurred and was reported to be statistically but not clinically significant. A similar study was subsequently conducted, but patients were given maintenance doses of i.v. fosphenytoin or i.v. PHT for 3 to 14 days after receiving a loading dose (30). Patients were randomized to receive i.v. fosphenytoin (n = 88; mean dose, 1,088 mg PE or 15.3 mg PE/kg) or i.v. PHT (n = 28; mean dose, 1,082 mg or 15.0 mg/kg). Maintenance therapy was given for >4 days (fosphenytoin for 4.3 days; PHT for 4.7 days). Similar infusion rates were used (fosphenytoin, 37 mg PE/min; PHT, 33 mg/min). A significantly greater number of patients reported pain in the infusion site with PHT (17%) compared with fosphenytoin (2%). No electrocardiographic changes were found. Reduction in systolic and diastolic blood pressure was reported in five patients in both groups. However, symptomatic hypotension requiring reduction in infusion rates occurred four times more often with i.v. PHT (n = 4; 17.9%). A subset of 10 patients had serial timed total and free plasma fosphenytoin and PHT levels drawn after the loading dose. At the first sample drawn at 1 hour after infusion, all patients had total PHT levels >10 µg/mL, and the mean concentrations were essentially the same for the two groups.

PEDIATRIC POPULATIONS

In a retrospective study, 52 pediatric patients who received fosphenytoin i.v. therapy for seizures were evaluated (31). Age ranged from 4 days to 16 years of age. PHT serum levels

P.616


were maintained within the therapeutic range (10 to 20 µg/mL). No infusion site complications were reported in any of the patients. Only one patient experienced cardiac arrhythmia from an accidental overdose. Eight neonates (1 to 146 days old) received i.v. fosphenytoin for the treatment of status epilepticus (32). In six patients, treatment with phenobarbital had failed. Of these six patients, two had received lorazepam as well. Loading doses of fosphenytoin PE ranged from 14.5 to 24.3 mg/kg. Seven of the eight patients achieved therapeutic PHT levels. Complete seizure control was obtained in 50%. No side effects were observed in any of the patients.

CLINICAL EFFICACY

Status Epilepticus

PHT given by the i.v. route has been the mainstay of the treatment of status epilepticus. The previously described studies used fosphenytoin infusion rates of approximately 100 mg PE/min. At this rate, the free PHT levels reached were less than that those achieved with 50 mg/min of PHT, a rate commonly employed in the treatment of status epilepticus. Fosphenytoin must be given at 150 mg PE/min to produce a free PHT level bioequivalent to that produced by 50 mg/min of PHT. Thus, additional clinical experience was needed in the area of status epilepticus with faster rates of infusion.

The treatment of overt status epilepticus was evaluated in a Veterans Affairs Cooperative Study (33). The highest treatment success rate was obtained with parenteral lorazepam (64.9%), followed by phenobarbital (58.2%), diazepam/PHT (55.8%), and PHT alone (43.6%). Based on these findings, the recommended first-line treatment for generalized convulsive status epilepticus is i.v. lorazepam. Fosphenytoin or PHT is still recommended as a second-line agent if status epilepticus is not controlled within 5 to 7 minutes (34).

A double-blind parallel safety and tolerance study was conducted comparing i.v. fosphenytoin given at 150 mg PE/min versus PHT at 50 mg/min (27). Patients were randomized on a 4:1 basis to receive i.v. fosphenytoin (n = 90) or PHT (n = 22). The loading dose was either 20 mg/kg (patients with no detectable PHT in the plasma) or 15 mg/kg if the plasma PHT level was ≤7µg/mL. The most common reasons for patient inclusion were treatment of acute seizures, low PHT levels in patients with epilepsy, or seizure prophylaxis in neurosurgical patients. Patient demographics were similar between the fosphenytoin and PHT groups. Infusions had to be slowed or discontinued significantly more often with i.v. PHT than with fosphenytoin. Adverse events with the two drugs were different, with pruritus, at times very uncomfortable, more common with fosphenytoin (48.9%) and pain at the site of infusion more frequently reported with PHT (63.6%). The other side effects of dizziness, somnolence, and ataxia are typical of PHT and were the same for both drugs. The pruritus associated with fosphenytoin typically occurred in the trunk, especially in the groin region, or at the back of the head. Pruritus, when reported, presented soon after initiation of the infusion and abated rapidly when the infusion was discontinued. The occurrence and severity of the pruritus were rate-dependent phenomena because lowering the rate reduced or abolished the symptom. Changes in blood pressure were noted in both groups, with a mean decline in systolic pressure of 13.7 mm Hg with fosphenytoin and 5.9 mm Hg with PHT. By this one measure, the decrease was statistically more common with fosphenytoin, but it was not believed to be clinically significant. Direct cardiovascular effects in this study were difficult to compare because the duration of infusions were different (fosphenytoin, 13 minutes; PHT, 44 minutes). Blood pressure changes occurred 10 to 20 minutes after the initiation of the i.v. infusion. The decrease in systolic blood pressure was gradual and lasted for 10 to 15 minutes. Patients with preexisting hypertension and who were being treated with antihypertensives were at increased risk (13 of 16) of a systolic blood pressure decline of 20 mm Hg or more. There was no association between specific antihypertensive medication and a drop in systolic blood pressure. Patients with underlying ischemic heart disease also seemed to be at increased risk of a mild decline in blood pressure (9 of 13). In no case was the hypotension judged severe enough to justify discontinuation of treatment, although the i.v. infusion rate was reduced in a total of six patients (fosphenytoin, four patients or 4.7%; PHT, two patients or 9. 1%). Several clinically unstable ICU patients with neurosurgical, neurologic, or cardiac problems were included in the protocol. These patients tolerated the rapid infusions of i.v. fosphenytoin without clinically significant changes in blood pressure or cardiac arrhythmias.

An open-label, single-dose, safety, tolerance, and pharmacokinetic trial of fosphenytoin was completed in 85 patients in convulsive status epilepticus (35). Infusion rates of 100 mg/min were used in the first 10 patients, and rates of 150 mg/min were used in the remaining 75 patients. Patients ≥5 years old who had two or more generalized convulsions without regaining consciousness between seizures were included. The study included 10 patients <16 years of age (mean, 7.6 years) and 75 patients ranging from 18 to 82 years of age (mean, 43.7 years). Applying the same criteria used in the Veterans Affairs Cooperative Study 265 on status epilepticus (33), seizures were controlled in 79 (92.3%) patients with fosphenytoin. Only two patients experienced seizure recurrence within the next 24 hours. Three patients did not have their seizures controlled, and one was not evaluated because of the inadequate dose given (2 mg PE/kg). The mean dose administered was 967 mg PE (16.4 mg PE/kg) and ranged from 216 to 2,000 mg PE (8.2 to 26.1 mg PE/kg). The mean rate of infusion was 2.6 mg/kg/min in children and 135 mg

P.617


PE/min (36.4 to 218 mg PE/min) in adults. The mean duration of the i.v. infusion was 11 minutes. The infusion rate was not reduced in any patient. Hypotension, which has been a concern with high-dose high-rate infusion of i.v. PHT, was not encountered. Significantly higher free PHT levels were obtained in patients receiving fosphenytoin 20 mg/kg at 150 mg/min, with more than half having free levels ranging from 5 to 20 µg/mL. These levels are much higher than achieved using the same loading dose of parenteral PHT and may explain the better rate of control of status epilepticus. Blood samples were drawn at the conclusion of the infusion. Free levels >5 µg/mL were achieved in the majority of the patients, and this is likely the reason for the greater efficacy found in this study. No cardiac arrhythmias were observed, and no adjustments in infusion rates were required because of changes in vital signs. Some decline in blood pressure was observed during or after the infusion but was not judged to be clinically significant. At follow-up evaluation 24 hours later, only 3% of the patients reported tenderness at the infusion site, and no inflammation or phlebitis was found.

COST CONSIDERATIONS

The cost effectiveness of using parenteral fosphenytoin versus PHT for the treatment of acute seizures and status epilepticus remains a controversial issue. The cost per package for fosphenytoin is approximately 26 times greater than that for parenteral PHT (based on Parke-Davis catalog prices) (36). However, other factors must be considered in determining cost effectiveness of a prescription. Marchetti et al. (1996) conducted a multicenter, double-blind, parallel group study to evaluate costs of administering i.v. fosphenytoin versus i.v. PHT in emergency departments (37). Fifty-two patients were enrolled; 39 were randomized to the i.v. fosphenytoin group and 13 to the i.v. PHT group. The acquisition cost per loading dose was significantly higher for fosphenytoin ($90.00) compared with PHT ($6.72). The average wholesale price for PHT was $1.68 per package, and it was $45.00 per package for fosphenytoin (500-mg equivalent of phenytoin). Total adverse event monitoring costs were $536.86 for i.v. PHT versus $66.20 for i.v. fosphenytoin. The most common side effects reported with the use of PHT were significant neurologic toxicity (moderate to severe ataxia or vertigo), severe i.v. site reaction, and symptomatic decrease in blood pressure (>20 mm Hg systolic). Only the last side effect was reported with fosphenytoin. The adverse events resulted in higher use of resources. There was a significant cost savings of $386.89 (11%) with i.v. fosphenytoin compared with i.v. PHT, primarily based on the less favorable side effect profile of PHT.

Armstrong et al. (1999) developed a model of cost and clinical outcomes to compare the cost effectiveness of parenteral PHT versus fosphenytoin (38). The data were collected using a questionnaire. This model assumed that 50% of PHT would be replaced by fosphenytoin. They calculated mean cost-effectiveness ratios (defined as the cost to achieve the desired goal of administering a loading dose without complication) for PHT alone, for fosphenytoin plus PHT (50% fosphenytoin and 50% PHT), and for fosphenytoin alone. The average cost of a loading dose of PHT ($58) was less than the average cost of both 50%-50% fosphenytoin-PHT ($94) and fosphenytoin alone ($130). However, the average cost-effectiveness ratios were $225 for PHT, $149 for the 50%-50% option, and $130 for fosphenytoin alone. PHT-induced peripheral vascular failure (phlebitis-type effects) frequently required central line placement. In the PHT group, 62.3±43.4% of patients receiving loading doses and 74.0±32.9% receiving maintenance doses experienced venous irritation. In the fosphenytoin group, side effects were uncommon (0.3±1.0%). These investigators concluded that institutions with comparable drug costs should consider replacing PHT with fosphenytoin for loading and maintenance doses, primarily based on the reduction of side effects. Further pharmacoeconomic studies are needed to define more precisely the cost effectiveness of replacing parenteral PHT with fosphenytoin. However, present information indicates that fosphenytoin is most cost effective.

CONCLUSION

PHT is a very effective anticonvulsant, and despite significant problems with its parenteral formulation, it has been the mainstay of the treatment of various forms of acute seizures for many decades. In contrast to parenteral PHT, fosphenytoin does not need propylene glycol and alcohol vehicles for water solubility, so it is a much safer and better-tolerated preparation. PHT and fosphenytoin have identical therapeutic profiles. However, because much higher unbound PHT can be achieved when a loading dose of fosphenytoin is infused at the maximal approved rate, fosphenytoin appears to be more effective in status epilepticus. Given the risks associated with the use of parenteral PHT, fosphenytoin should entirely replace PHT in all its present i.v. indications. Moreover, the safety and tolerability of i.m. fosphenytoin extend its use to other clinical situations in which prompt administration of a nondepressing anticonvulsant is indicated but secure i.v. access and cardiac monitoring are not available such as in the following situations: (a) in the treatment of tonic-clonic status epilepticus by rescue workers in the field; (b) in the management of serial seizures in patients with intractable epilepsy; and (c) possibly in the treatment of acute ischemic stroke.

REFERENCES

  1. Stella VJ, Higuchi T. Esters of hydantoic acid as prodrugs of hydantoins. J Pharmacol Sci1973;62:962-962.

P.618

 

  1. Browne TR, Szabo GK, McGovern J. Bioavailability studies of drugs with nonlinear pharmacokinetics. II. Absolute bioavailability of intravenous phenytoin prodrug at therapeutic phenytoin serum concentration determined by double stable isotope technique. J Pharmacol Sci1993;33:89-94.
  2. Gerber N, Mays DC, Donn KH. Safety, tolerance, and pharmacokinetics of intravenous doses of phosphate ester of 3-hydroxymethyl-5-diphenyl hydantoin: a new prodrug of phenytoin. J Clin Pharmacol1988;28:1023-1032.
  3. Leppik IE, Boucher BA, Wilder BJ, et al. Pharmacokinetics and safety of a phenytoin prodrug given IV in patients. Neurology1990;40:456-460.
  4. Browne TR, Le Duc B. Phenytoin and fosphenytoin: biotransformation. In: Levy RY, Mattson R, Meldrum BS, eds. Antiepileptic drugs,4th ed. New York: Raven Press, 1995:283-300.
  5. Boucher BA, Bombassaro A, Rasmussen SN, et al. Phenytoin prodrug 3-phosphoryloxy-methyl phenytoin (ACC-9653): pharmacokinetics in patients following intravenous and intramuscular administration. J Pharmacol Sci1989;78:929-932.
  6. Eldon MA, Loewen GR, Voigtman RE, et al. Safety, tolerance, and pharmacokinetics of intravenous fosphenytoin. Clinical Pharmacological Therapy 1993;53:212-212.
  7. Aweeka F, Alldredge B, Boyer T, et al. Conversion of ACC-9653 to phenytoin in patients with renal or hepatic diseases. Clin Pharmacol Ther1989;45:152-152.
  8. Broumer K, Matier WL, Quon CY. Absolute bioavailability of phenytoin after IV 3-phosphoryloxymethyl phenytoin disodium. Clin Pharmacol Ther1988;43:178-178.
  9. Boucher BA, Kugler AR, Hess MM, et al. Pharmacokinetics of fosphenytoin, a phenytoin prodrug, following intramuscular administration in critically ill neurosurgery patients.Crit Care Med1995;23:A78-A78.
  10. Garnett WR, Kugler AR, O'Hara KA, et al. Pharmacokinetics of fosphenytoin following intramuscular administration of fosphenytoin substituted for oral phenytoin in epileptic patients. Neurology1995;45:A248.
  11. Browne TR, Davoudi H, Donn KH, et al. Bioavailability of ACC-9653 (phenytoin prodrug). Epilepsia1989;30:S27-S32.
  12. Eldon MA, Loewen GR, Voigtman RE, et al. Pharmacokinetics and tolerance of fosphenytoin and phenytoin administered intravenously to healthy subjects. Can J Neurol Sci1993;20: S180-S180.
  13. Kugler AR, Knapp LE, Eldon MA. Intravenous administration of fosphenytoin: pharmacokinetics and dosing considerations in special populations. Epilepsia1996;37:156.
  14. Jamerson B. Venous irritation related to intravenous administration of phenytoin versus fosphenytoin. Pharmacotherapy1994; 14:47-52.
  15. Parke-Davis. Cerebyx injection.Package insert. Parke-Davis, 1998.
  16. Hanna DR. Purple glove syndrome: a complication of intravenous phenytoin. J Neurosci Nurs1992;24:340-345.
  17. Smith RD, Brown BS, Maher RW, et al. Pharmacology of ACC-9653 (phenytoin prodrug)). Epilepsia1989;30[Suppl 2]: S15-S21.
  18. Besserer J, Cook J, Eldon M. A randomized, double blind, placebo controlled, rising single dose study of the pharmacokinetic and tolerance profiles of intravenous fosphenytoin sodium (CI-982) administered at five different infusion rates to healthy subjects. Unpublished data, 1994.
  19. Hussey EK, Dukes GE, Messenheimer JA, et al. Evaluation of the pharmacokinetic interaction between diasepam and ACC-9653 (a phenytoin prodrug) in healthy male volunteers. Pharm Res1990;7:1172-1176.
  20. Lai CM, Moore P, Quon CY. Binding of fosphenytoin, phosphate ester pro drug of phenytoin, to human serum proteins and competitive binding with carbamazepine, diazepam, phenobarbital, phenylbutazone, phenytoin, valproic acid or warfarin. Res Commun Mol Pathol Pharmacol1995;88:51-62.
  21. Dow M, Barry E, Bell W, et al. A double-blind, placebo-controlledstudy of vigabatrin 3 g/day in patients with uncontrolled complex partial seizures. Pfizer Inc. Data on file, 1995 and 2002.
  22. Fischer J, Cwik MJ, Luer MS, et al. Stability of fosphenytoin sodium with intravenous solutions in glass bottles, polyvinyl chloride bags, and polypropylene syringes. Ann Pharmacother1997;31:553-559.
  23. Narisawa S, Stella VJ. Increased shelf-life of fosphenytoin: solubilization of a degradant, phenytoin, through complexation with (SBE)7m-beta-CD. J Pharm Sci1998;87:926-930.
  24. Wilder BJ, Ramsay RE, Serrano EE, et al. A method for shifting from oral to intramuscular diphenylhydantoin administration. Clin Pharmacol Ther1974;16:507-513.
  25. Dean JC, Smith KR, Boucher BA, et al. Safety, tolerance and pharmacokinetics of intramuscular (IM) fosphenytoin, a phenytoin prodrug, in neurosurgery patients. Epilepsia1993;34:111.
  26. Ramsay RE, Philbrook B, Martinez OA, et al. A double-blinded, randomized safety comparison of rapidly infused intravenous loading doses of fosphenytoin vs. phenytoin.Epilepsia1995;36 [Suppl 4]:52.
  27. Pryor FM, Ramsay RE, Gidal BE, et al. Fosphenytoin: pharmacokinetics and tolerance of intramuscular loading doses. Epilepsia2001;42:245-250.
  28. Fischer J, Turnbull T, Uthman BM, et al. Safety, tolerance, pharmacokinetics of intravenous loading doses of fosphenytoin versus Dilantin. Neurology1995;45:A202.
  29. Baron BA, Hankin S, Knapp LE. Advantages of intravenous fosphenytoin (Cerebyx) compared with IV phenytoin (Dilantin). Neurology1995;45:248-249.
  30. Morton LD, O'Hara KA, Meloche NM, et al. Fosphenytoin experience in pediatric patients. Epilepsia1999;40:131-131.
  31. Gustafson MC, Ritter FJ, Minnesota Epilepsy Group PA. Fosphenytoin loading for status epilepticus in the neonate. Epilepsia1999;40:124-124.
  32. Treiman DM, Meyers PD, Walton NY, et al. Treatment of generalized convulsive status epilepticus: a randomized double-blind comparison of four intravenous regimens. N Engl J Med1998; 339:792-798.
  33. Bleck TP. Management approaches to prolonged seizures and status epilepticus. Epilepsia1999;40[Suppl 1]:S59-S63.
  34. Allen FH, Bunge JW, Legarda S, et al. Safety, tolerance and pharmacokinetics of intravenous fosphenytoin (Cerebyx) in status epilepticus. Epilepsia1995;36[Suppl 4]:90.
  35. Fierro L, Hudak J. Cost of fosphenytoin. Ann Emerg Med1998; 31:137-138.
  36. Marchetti A, Magar R, Fischer J, et al. A pharmacoeconomic evaluation of intravenous fosphenytoin (Cerebyx) versus intravenous phenytoin (Dilantin) in hospital emergency departments. Clin Ther1996;18:953-966.
  37. Armstrong EP, Sauer KA, Downey MJ. Phenytoin and fosphenytoin: a model of cost and clinical outcomes. Pharmacotherapy1999;19:844-853.