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Fosphenytoin (Cerebyx®, Parke-Davis; Prodilantin®, Pfizer Holding France) is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures. more...

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On 18 November 2004, Sicor Pharms received a tentative approval letter from the United States Food and Drug Administration for a generic version of fosphenytoin.



Fosphenytoin is approved in the United States for the short term (five days or less) treatment of epilepsy when more widely used means of phenytoin administration are not possible or are ill-advised, such as endotracheal intubation, status epilepticus or some other type of repeated seizures; vomiting, and/or the patient is unalert or not awake or both.


In April of 2003, Applebaum and colleagues at the Ben Gurion University of the Negev in Beersheva reported that even though anticonvulsants are often very effective in mania, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect even 60 minutes after administration of doses used in status epilepticus.

Fosphenytoin was more successfully used to relieve pain refractory to opiates in a 37-year-old woman with neuroma, according to Dr. Gary J. McCleane of the Rampark Pain Center in Lurgan, Northern Ireland. She was given 1,500 phenytoin equivalent units of fosphenytoin over a 24 hour period, producing pain relief that last three to fourteen weeks after each infusion, allowing her to use less opiates.


One mmol (millimole) of phenytoin is produced for every mmol of fosphenytoin administered; the hydrolysis of fosphenytoin also yields phosphate and formaldehyde, the latter of which is subsequently metabolized to formate, which is in turn metabolized by a folate dependent mechanism.

Side effects

Side effects are similar to phenytoin, except that fosphenytoin causes less hypotension and more paresthesia. Fosphenytoin can cause hyperphosphatemia in end-stage renal failure patients.


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Randomized evaluation of adverse events and length-of-stay with routine emergency department use of phenytoin or fosphenytoin
From Neurological Research, 12/1/02 by Coplin, William M

Intravenous phenytoin has come under increased scrutiny with the introduction of the prodrug, fosphenytoin. We evaluated adverse events and length-of-stay using parenteral the two drugs in routine emergency department use. Open-label randomization of phenytoin or fosphenytoin in 256 Emergency Department patients prescribed 279 parenteral doses of a phenytoin-equivalent. All phenytoin was administered intravenously, and fosphenytoin was given intravenously or intramuscularly (physician preference). Adverse events and Emergency Department length-of-stay were recorded; re-presentation to the Emergency Department within three months was reviewed for evidence of the purple glove syndrome. Nonparametric statistics were used to analyze the data. Seventy-seven patients received phenytoin and 202 fosphenytoin; 28 (10.0%) received intramuscular fosphenytoin. The mean phenytoin-equivalent dose was similar between the groups. Eighteen patients required reduction in infusion rates because of an adverse event (phenytoin = 6.5%, fosphenytoin = 6.4%; OR 0.9, 95% CI 0.4 2.6; p = 1.0). Adverse events occurred with similar frequency (phenytoin 9.1%, fosphenytoin 15.8%; OR 0.7, 95% CI 0.3 1.4; p = 0.3). The most common events were: pruritis, pain on infusion, and paresthesias. One patient developed hypotension (fosphenytoin); there were no other serious adverse events, including phlebitis. Median Emergency Department length-of-stay was 6.7 h for phenytoin and 5.7 h for fosphenytoin (p = 0.6). In routine Emergency Department use, our data do not support formulary conversion from phenytoin to fosphenytoin, based on the incidence of adverse events or Emergency Department length-of-stay. [Neurol Res 2002; 24: 842-848]

Keywords: Phenytoin; fosphenytoin; seizures; Emergency Department; adverse events; length of stay


Fosphenytoin sodium (FOS) (Cerebyx; Parke-Davis, Morris Plains, NJ, USA) is a water-soluble phosphate ester pro-drug of phenytoin (PHT) for parenteral administration1. The manufacturer marketed the drug to replace its brand of PHT (Dilantin; Parke-Davis) for parenteral administration. Serum and other phosphatases completely convert FOS to PHT in vivo following parenteral administration (conversion half-life of

Among the perceived disadvantages of intravenous (i.v.) PHT are: reports of vein irritation, slower maximum rate of infusion, alkalinity of the vehicle, hypotension, and the 'purple glove syndrome' (PGS), a condition characterized by distal limb edema, discoloration, and pain, resulting from drug extravasation15-18. Parenteral PHT contains propylene glycol as the vehicle; this potential renal and cardiovascular toxin induces such adverse events (AEs) as arterial hypotension and/or cardiac dysrhythmias and exhibits both rate and dose related toxicities19-23. While not necessarily the agent of first choice in the treatment of status epilepticus (SE), many consider i.v. PHT a mainstay of therapy for this condition24. Among the common reasons for emergency department (ED) prescription of a parenteral PHT-- equivalent (PE) drug are: ongoing or recent seizures, severe traumatic brain injury (TBI)25, or as a means of supplementing subtherapeutic serum PHT concentrations in patients with recent seizures.

We performed an open-label, block randomized ED drug evaluation of FOS and i.v. PHT at a large urban, university-based, Level-One trauma center. The evaluation was conducted to provide objective comparative data to be utilized in the decision-making process of whether to admit FOS to our hospital's open pharmacy formulary, and, if so, whether it should completely replace i.v. PHT. Based on reports of less-frequent AEs (including serious AEs such as hypotension and PGS) and faster administration time, we hypothesized that, in routine ED use, FOS would be associated with fewer AEs and a shorter ED LOS.


Study population

Two-hundred-fifty-six patients receiving a total of 279 doses of a parenteral PE compound in the ED were prospectively evaluated. The sample size was passively determined as a convenience cohort that continued until the manufacturers' available gift of FOS was completely dispensed. The local Human Investigation Committee approved reporting of the study results. The decision to administer anticonvulsants was left to the discretion of the ED attending staff. Patients were randomized to receive FOS on even-numbered days of the month and i.v. PHT on odd-numbered days. If the ED staff was unable to obtain i.v. access, i.m. FOS could be given on any day of the month. Patients were not necessarily told which drug they were receiving. The administering nurse was aware of drug group assignment, and when the ED physician prescribed a parenteral PHT-equivalent drug, the ED pharmacist dispensed the appropriate drug according to schedule. The patient's nurse was asked to complete a five-point Likard scale to evaluate ease of administration and patient tolerance. The ED pharmacist completed the case report form.

Study medications

Phenytoin was obtained according to pre-existing hospital contract (Elkins-Sinn, Cherry Hill, NJ, USA). Fosphenytoin for the study was supplied complementarily by the manufacturer. Patients and third-party payers were not charged for FOS. The manufacturer had no further involvement in the study protocol. The two drugs also were being compared for potential inclusion of FOS as a formulary item.

Drug administration

Patient doses of PHT and FOS were ordered by the ED staff physicians. All PHT was mixed in 50 ml normal (0.9%) saline (NS) and administered by pre-existing hospital policy using a 10 ml saline flush to test the i.v. site against extravenous infiltration. The pre-existing ED policy for i.v. PHT administration also calls for an in-line filter and infusion pump (Sigma 6000+; Smith & Nephew, Medina, NY, USA) rate of 20 mg min^sup -1^. After PHT administration, the i.v. was again flushed with 10 ml NS. The FOS was stored under refrigeration for reasons of stability12. For i.v. administration, FOS was prepared in 50 ml of NS and our institution's pre-existing protocol allowed a maximum pump rate of 100 mg PE min^sup -1^. Both PHT and FOS infusions could be decreased if patients experienced AEs. For i.m. administration, FOS was used directly from the vial as a 50 mg PE ml^sup -1^ solution, given in a large muscle mass (e.g., gluteus maximus).

Patient tolerance

Both minor and serious AEs were assessed by the nurse and pharmacist. Among the minor AEs defined were: pruritis, paresthesias, nausea, tinnitus, and subjective administration site irritation without evidence of phlebitis. Serious AEs included: hypotension (defined as systolic blood pressure


We reviewed the records of all prospectively identified patients to see who returned to the ED over a three-- month period after the index drug administration and whether they had phlebitis at the i.v. site. Our intent was to evaluate the incidence of delayed PGS development in our population and compare it to others' reported incidence of the complication.

Statistical tests

All data were collected on standardized forms and entered into a computerized database (SPSS for Macintosh 6.1; SPSS Inc., Chicago, IL, USA). Data were presented as means +/- standard deviation for continuous variables and medians and ranges for ordinal variables or data without a normal distribution. Main results were presented as an odds ratio (OR) and associated 95% confidence intervals (CI), where appropriate. Chi-square or Fisher's exact test (two-tailed) were used to assess relationships between categorical variables. We used nonparametric statistical methods (Wilcoxon rank-sum analysis) to compare both continuous and ordinal variables; statistical significance was set at p


Study population

There were a total of 279 doses of a parenteral PE compound (202 of FOS and 77 of PHT) administered to 256 individual patients during the 16-week study period. No patient received both drugs during the same ED visit. Patients ranged from 19 to 86 years of age (median of 44 years for PHT and 45 years for FOS). Other demographic and presenting clinical data are summarized in Table 1. Specifically, there were no significant differences between the groups regarding age, gender, seizure history, or presenting serum PHT concentration. The presenting median Glasgow Coma Scale (GCS) score26 of the whole population was 15 (range 3-15). The 1 Orth %ile GCS was 12, and the 25th was 14; GCS scores were similar between the groups (p= 1.0). The reasons for prescription of a parenteral PE compound are summarized in Table 2; 3.2% of patients were actively convulsing upon arrival to the ED (presumed SE). While there was a trend for more patients receiving FOS to be convulsing upon arrival to the ED (p=0.06), no diagnosis was significantly more common for either of the treatment groups (Table 2).

Drug delivery

The mean PE dose administered in the study was 819.3 +/- 226.2 mg (11.3 +/- 1 3.4 mg kg^sup -1^). While PE doses were similar between the groups, the administration rate of FOS was faster than that of PHT (89.0 +/- 25.9 versus 19.0 +/- 1 4.4 mg PE min^sup -1^, p

Seizure cessation

For the small number of patients presenting in SE (see Table 2), seizures did not appear to stop any faster with either medication (31.8 min for PHT and 49.5 min for FOS; p= 0.8). Only two patients had recurrent discrete seizures in the ED after drug administration. Both were taking PHT as outpatients, and both received FOS at a rate of 100 mg PE min^sup -1^ through peripheral veins. The first patient was a 64-year-old 70 kg male who presented in SE with a baseline serum PHT concentration of 4.0 (mu)g ml^sup -1^. He received i.v. lorazepam followed by 1000 mg PE of FOS (14 mg kg^sup -1^) over 10 min; he spent 94 min in the ED before being admitted to hospital. The second patient was a 32-year-old 45 kg male who presented to the ED after a seizure and had a preinfusion serum PHT concentration of 3.4 (mu)g ml^sup -1^. He received no medication other than 700 mg PE of FOS (16 mg kg^sup -1^) over 8 min and spent 343 min in the ED before being discharged home. Neither of these patients suffered any AE from FOS administration.

Adverse events

In the PHT group, seven patients suffered local irritation at the infusion site; this was the only recorded type of AE from PHT administration. In the FOS group, 28 patients experienced a total of 32 separately recorded AEs. The overall incidence of AEs was similar between the groups (OR 0.7, CI 0.3 1.4; p= 0.3), but showed a different profile as to the type of AE observed; this is summarized in Table 4. Cardiovascular AEs were not significantly different between the drug groups (p= 1.0) nor was the incidence of paresthesias (p=0.2); however, patients receiving FOS were more likely to have pruritis (p=0.01), and those receiving PHT were more likely to have vein burning (p=0.0006). There was a relation between the rate of infusion and the risk of having any AE for patients receiving PHT (p= 0.02) but not for those receiving FOS (p=0.3). There was only one serious adverse event recorded: hypotension in a patient receiving FOS.

Administration ease and patient tolerance

Only two patients were considered to have 'extremely poor' tolerance of drug administration. The first was the second patient with a recurrent seizure after FOS administration, as mentioned previously, and the second was the patient who developed hypotension during FOS administration. This 32-year-old, 55 kg female presented GCS 15 after TBI without any seizures. She had no history of epilepsy or PHT prescription and was prescribed FOS, 850 mg PE, administered at 100 mg PE min^sup -1^ through a peripheral i.v. catheter. Her hypotension abated after holding the infusion and restarting it at a lower rate. She suffered no sequelae from the event but was admitted to the hospital for observation. Results of patient tolerance of drug administration are shown in Figure 1; both drugs were generally well-tolerated, according to both patients and nurses. Both administration ease and patient tolerance were rated as better for FOS (both p


As shown in Figure 2, ED LOS, one of the main outcome measures, was similar between the groups (FOS = 449.7 +/- 323.1 min, PHT =452.8 +/- 303.0 min; p=0.6). Drug administration time did not determine ED LOS. The subset of 91 patients (32.7%) who were awake, and not actively seizing, having an aura, or postictal also experienced similar ED LOS with either drug (p=0.1). The two most common reasons for prolonged LOS were, respectively, ethanol intoxication and awaiting consultations) and disposition (e.g., bed availability in the hospital, discharge arrangements).

Follow-up and the Purple Glove Syndrome

In the three months after receiving the index dose of PHT or FOS, 155/256 patients (60.5%) returned to the ED for care. Only one patient had any cutaneous complaints related to the index drug administration at that second visit. This patient (PHT group) had a small ecchymosis noted at the site of central venous catheter insertion for drug administration. No patient presented with any features of PGS.

Intramuscular fosphenytoin

The subset of patients receiving i.m. FOS (n=28) received 598.1 +/- 236.8 mg PE via 2.8 +/- 1.5 injections per patient. The maximum volume administered per i.m. injection was 10 ml; therefore, patients receiving more than 500 mg PE total dose necessarily received more than one injection. The number of i.m. injections varied depending on the comfort level of the nurse. Patients received up to four injections to get the total prescribed dose. Two patients underwent uneventful cardiac monitoring around the time of i.m. drug administration. Patients receiving i.m. FOS had a mean ED LOS of 468.9 +/- 250.1 min which was similar to the ED LOS for i.v. administration of either drug. The only reported AE in the i.m. group was one patient with pruritis. No patient presenting in SE received i.m. FOS.

Adjunctive anticonvulsant use

Patients presenting in SE were more likely to receive adjunctive AED therapy in addition to the index PHT or FOS dose (p=0.00007). There was no difference between the drug groups regarding the administration of adjunctive AEDs for patients presenting in SE (p=1.0); however, of patients not presenting in SE, more patients receiving FOS were more likely to receive a second AED (p=0.01). Overall, there was more frequent use of lorazepam and phenobarbital in the FOS group, as shown in Table 3; however this difference was explained by use patterns associated with patients presenting in SE. The study design did not assess whether such use of other anticonvulsant medications occurred before or after PE drug administration, nor whether patients were still having seizures at the time of such other drug administration.


This randomized drug evaluation of parenteral FOS and PHT administration in a large university-based urban ED, found no significant differences between treatment groups regarding AE incidence or ED LOS. Patients' comorbidities and clinical presentations also were similar. As expected, owing to a faster allowable rate administration rate and hospital protocol, similar PE doses of FOS were administered more quickly than PHT. Factors other than drug administration (e.g., ethanol intoxication) often prolonged ED LOS. Receiving i.m. FOS did not shorten ED LOS. Occasionally, there was a need to reduce the FOS or PHT infusion rate because of minor AEs, and there was only one serious AE (FOS group.)

Importantly, with i.v. PHT, there were no incidents of hypotension, cardiac dysrhythmia, or PGS. Retrospectively assessing a three month period seven years prior to their evaluation, one group reported a 5.9% incidence of PGS with i.v. PHT administration18. 'Appropriate' use of enteral PHT, in suitable patients (e.g., not administering Lv. PHT for 'maintenance' dosing)27 might have spared three patients in their series this untoward event. The introduction of FOS has highlighted potential complications associated with i.v. PHT use and may have increased care of drug administration; hence, their findings may not represent the present risk of PGS. If their findings were true in our population, we should have observed at least four cases of PGS. Since PGS appears later, we may not have been able to observe this with the present study's design; although no patient returned to the ED with signs or symptoms of PGS within three months of index drug administration. Again, over 60% of the present cohort returned to the ED during the three months following index drug administration. A pharmacoeconomic study did not observe any cases of PGS28.

Presumed cost benefits of FOS include: more rapid i.v. infusion, the ability to give FOS i.m., not needing in-line filters for i.v. administration, and the need for fewer i.v. site changes; these potential savings have not been realized29. There are conflicting data concerning administration costs for either of the drugs28-30. Limitations to these two studies where there was a perceived cost advantage favoring FOS use were: one applied fixed costs in their mode 128, and the other used subjective questionnaires to garner perceived 'efficacy' information 29. A cost minimization analysis removed fixed costs (as is appropriate for such an analysis) and found no cost advantage to FOS use30. True cost-effectiveness analyses cannot be performed without first demonstrating superior efficacy with FOS.

Meta-analysis of 208 patients in three double-blind studies found that fewer patients required i.v. site changes after FOS than after PHT; however, central i.v. lines (which afford greater blood admixture) were excluded and site changes were at the investigators' discretion 31. The present study did not observe any serious phlebitic reactions as reported elsewhere15-18, that may have been related to administration technique and/or the propylene glycol vehicle for PHT (pH 10-- 12.3). Since we did not prospectively track all patients for returns to the ED with phlebitic symptoms, nor admissions to the hospital from the ED, we may have missed some phlebitic reactions occurring after ED discharge; however, the patient population in our catchment uses emergency medical services almost exclusively. Emergency medical services mandates therefore, we believe few potential cases of PGS were lost to follow-up.

One study found similar types and frequencies of AEs between patients receiving i.m. FOS versus oral PHT in a population of epilepsy (n=231) and neurosurgical (n=9) patients already taking oral PHT32. The prevalence of patients in the present cohort who were taking PHT as outpatients (as evidenced by measurable serum PHT concentrations) and the generally good presenting GCS scores suggest that many presumably could receive oral PHT rather than a parenteral compound.

As expected, FOS was administered more rapidly. Our hospital's pre-existing protocol calls for a relatively slow i.v. PHT administration rate (20 mg min^sup -1^ versus the 50 mg min^sup -1^ maximum rate in the product information). The protocol is intended to avoid serious AEs (such as hypotension) or drug extravasation. 'Testing' the i.v. site with a saline flush before administration also is intended to lessen that risk, as flushing it after PHT administration is intended to avoid drug pooling near the i.v. site. This feature of our hospital's i.v. PHT administration protocol biases the magnitude of the difference seen in i.v. administration rates of the two drugs. The much larger variance of FOS administration rates suggests that one may not always be able to take advantage of, or the nurse feels uncomfortable with, the fastest possible FOS administration rate, or we might conjecture that nurses were less comfortable with the newer drug. Product information suggests administering FOS at 100 mg PE min^sup -1^, less than the approved maximum 150 mg PE min^sup -1^; despite this, 6.4% of patients required FOS infusion rate reduction because of an AE. One might presume that the perceived advantage of giving FOS faster might increase the incidence of minor AEs; however, there was only a statistical relation between the rate of infusion and risk of having at least one AE for PHT and not for FOS.

In a population where 32.7% (n=91) of patients received parenteral PE drugs for maintenance dosing because of poor therapeutic compliance (and were not actively seizing, recently had a seizure, having an aura, or post-ictal,) ED LOS was not different between the drug groups. Even that subset of patients who presumably could have taken oral PHT, yet received a parenteral PE drug, had similar ED LOS. Other than the trend for more patients in the FOS group to be having seizures upon arrival, the study design cannot explain why more lorazepam and phenobarbital were used in the FOS group; reasons for the use of other anticonvulsants were not ascertained. It is possible that these patients were 'sicker' or their seizures were more difficult to control and our instrument (not designed for that purpose) failed to measure that difference.

There are advantages to this open-label study. Nurses could be observed in 'everyday' use of the two drugs (versus previous published evaluations); thus, we can comment on features comprising the drugs' use in this setting, including behaviors to minor AEs. We were able to assess changes, or the lack thereof, to be expected if FOS were the only PHT-equivalent drug available. The manufacturer discontinued making its proprietary brand of parenteral PHT as of January 1997. Were it not for the availability of generic PHT, the present results suggest that (in the ED setting) this may result only in an increased cost of therapy for these patients (as previously described).

Since 44% of patients receiving i.v. medication received PHT, information may not have been collected on some patients receiving PHT. Case report forms may not have been completed for patients receiving 'the usual' PE compound, particularly if they did not have any complications. It is unlikely that more patients were prescribed a parenteral PE compound on days when FOS was dispensed.

Proper evaluation of this study requires consideration of the following:

1. The study only looked at parenteral PE compounds.

2. Both were given in doses with the goal of providing therapeutic PHT serum concentrations.

3. Reasons for drug use were similar between the groups (although appropriateness of oral PHT for some of these patients is arguable).

4. The study was prospective but unmasked, possibly yielding some prejudicial errors of interpretation (though we believe this feature to have benefitted the investigation).

5. Potential AEs were not weighed against seizure risk or cost. The issue of cost effectiveness has not been answered sufficiently for ED patients receiving parenteral PHT or FOS.

Some results may not be financially important. The ED is billed as a per-use, not time spent, charge; however, increased waiting times may translate into patient dissatisfaction. Again, factors other than AED administration determined LOS.

Our Pharmacy and Therapeutics Committee did not find this preliminary evidence to be compelling enough, amidst cost concerns, to add FOS to the hospital's open formulary. Completely replacing our hospital's formulary with FOS instead of i.v. PHT would increase pharmacy costs by more than $200,000 per year when we are not seeing significant numbers of serious AEs and when the pharmacy is being asked to display austerity in its selection of agents. Thus, FOS is restricted for use in patients without i.v. access or those in SE.

The issue of cost-effectiveness deserves further study both for ED use (as others have undertaken28-30,33) and for repetitive dosing. We call for thoughtful evaluation of the possible use of enteral PHT in the ED27. Process of care variables not explained by this study's design need clarification. Administering FOS to reduce ED LOS or the incidence of serious AEs is not supported by the present findings with the drug given by personnel familiar with i.v. PHT use.


In conclusion: PHT-equivalent doses of FOS may be infused over a shorter time; FOS use did not decrease ED LOS which appears unrelated to administration time; With our hospital's i.v. PHT administration policy, the incidence of AEs seen with i.v. PHT equals that of FOS in routine ED use.


Supported in part by the National Institutes of Health grant NS-38905 (Dr Coplin). Fosphenytoin for this study was provided by Parke-Davis. We thank the nurses, pharmacists, and other personnel of our Emergency Department for their assistance in this drug evaluation.


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William M. Coplin*^, Denise H. Rhoney*(sec), Jill A. Rebuck(para), Elizabeth A. Clements(para), Mary S. Cochran* and Brian J. O'Neil^^

*Department of Neurology (Division of Neuro-Critical Care), ^Department of Neurological Surgery

^^Department of Emergency Medicine, School of Medicine, (sec)College of Pharmacy and Allied Health Professions

Wayne State University; (para)Department of Pharmacy Services, Detroit Receiving Hospital, Detroit Medical Center,

Detroit, Mi, USA

Correspondence and reprint requests to: William M. Coplin, MD, Director, Neuro-Critical Care, Departments of Neurology and Neurological Surgery, Wayne State University, 4201 St. Antoine - 8D-UHC, Detroit, MI 48201, USA. [] Accepted for publication March 2002.

Copyright Forefront Publishing Group Dec 2002
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