Vol. VII, No. 6
  November/December 2004

  Tyrone Lin, Pharm.D.

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 Pharmacotherapy
 Update Index

Fosphenytoin (Cerebyx®)

Introduction: Intravenous (IV) administration of anticonvulsants is a therapeutic modality for patients who are actively seizing or who are unable to receive medications by mouth. Currently fosphenytoin (Cerebyx^®; Eisai Inc.), a prodrug of phenytoin, is approved by the Food and Drug Administration (FDA) for short-term IV administration. Fosphenytoin and phenytoin (Dilantin^®; Parke-Davis) are both classified as hydantoins. Fosphenytoin is indicated for the control of generalized convulsive status epilepticus and to prevent and treat seizures occurring during neurosurgery, when other means of phenytoin administration are unavailable, inappropriate, or deemed less advantageous.¹ The amount and concentration of fosphenytoin is expressed in terms of phenytoin sodium equivalents (PE) to avoid the need to perform weight-based adjustments when converting between fosphenytoin and phenytoin doses. To avoid any errors, fosphenytoin should always be prescribed and dispensed in PE units.

The focus of this article is to describe appropriate uses of fosphenytoin in the adult patient population. At The Cleveland Clinic Foundation (CCF), fosphenytoin is restricted to the Departments of Neurology, Neurosurgery, and Emergency Medicine in adult patients and is available for use in all pediatric patients.

Pharmacokinetics: The anticonvulsant effects of fosphenytoin are due to its active metabolite phenytoin. Fosphenytoin requires 8 to 15 minutes for it to be hydrolyzed to phenytoin.^1,2 Fosphenytoin may be administered intramuscularly (IM) or IV, compared to phenytoin, which is administered IV and orally (PO). When administered IM, fosphenytoin has a slower absorption rate (30 minutes to reach therapeutic concentrations) as compared to IV administration (8 to 15 minutes to reach therapeutic concentrations).^1,2

Adverse Effects: Cardiovascular side effects, including hypotension and dysrhythmias, can occur with both fosphenytoin and phenytoin.¹ Unlike fosphenytoin, IV phenytoin has poor water solubility, which requires it to be formulated with propylene glycol.³ Propylene glycol may contribute to some of the cardiovascular adverse effects (e.g., hypotension) associated with IV phenytoin.^3-5 Fosphenytoin's adverse effects, which are attributed to phenytoin, include tinnitus, nystagmus, somnolence, ataxia, and hypotension. One of the most common adverse effects unique to fosphenytoin is pruritus, of which the mechanism has not been fully elucidated. In the product labeling for fosphenytoin, pruritus occurs in 49% of patients who receive fosphenytoin compared to 5% of patients who receive phenytoin.¹ Furthermore, higher infusion rates of fosphenytoin are associated with an increase in the incidence of adverse effects.¹ There have been no reports of fosphenytoin-induced purple glove syndrome (PGS) or local cutaneous reactions (LCR). However, IV phenytoin has been associated with both PGS and LCR. Purple glove syndrome is a progressive distal limb edema, associated with discoloration and pain and is most likely due to the extravasation of the highly basic IV phenytoin solution. Local cutaneous reactions include signs and symptoms of PGS in areas other than the distal limbs.^6,7

Select Clinical Studies
Parenteral Administration: Several clinical studies have compared fosphenytoin and phenytoin to determine if differences exist in efficacy, safety, and pharmacokinetics. Guidelines for selecting a hydantoin in non-emergencies focuses on two patient populations: 1) stabilized patients after a recent acute seizure or status epilepticus, and 2) stabilized patients at increased risk of seizures.⁸ According to the authors' recommendations, if hydantoin therapy is indicated, PO phenytoin can be an appropriate cost-effective alternative due to decreased frequency of adverse effects. Fosphenytoin is recommended over IV phenytoin unless patients meet all of the following criteria: 1) between 7 and 60 years of age, 2) no history of cardiovascular problems, 3) no chronic or acute debilitating illness, emaciation, hyponatremia, peripheral vascular disease, hemodynamic instability, or sepsis, 4) good IV access qualified by the following: a vein at least as large as the antecubital fossa vein, catheter size 20-gauge or larger, preexisting central venous catheter, and 5) pain assessment possible such that intolerance to phenytoin may be recognized. These guidelines were published in 1999 and select expert panel recommendations were vague, such as the statement that IV phenytoin should not be used in patients with chronic or acute debilitating illness. Therefore, additional studies that investigate fosphenytoin and phenytoin should be evaluated to help guide clinicians in the selection of an appropriate therapy.

One of the first fosphenytoin clinical studies enrolled neurosurgical patients and investigated the safety, tolerability, and pharmacokinetics of fosphenytoin compared to IV phenytoin.⁹ The authors performed two studies, one open-label study of IM fosphenytoin (n=118) and one double-blind, randomized study of IV fosphenytoin (n=88) compared to IV phenytoin (n=28). Patients enrolled in the IM fosphenytoin study received an initial loading dose of 8-12 mg PE/kg and maintenance therapy for 3-14 days. Patients enrolled in the IV study received either fosphenytoin 12-14 mg PE/kg administered at 50 mg PE/min or phenytoin 12-14 mg/kg administered at 50 mg/min. The frequency of seizures in all groups was similar (5% IM fosphenytoin, 3% IV fosphenytoin, and 7% IV phenytoin). The rate of adverse effects for IM fosphenytoin administration was 8.5%, mostly comprising central nervous system (CNS) adverse effects such as somnolence and nystagmus. In the IV study, fosphenytoin was better tolerated than phenytoin with a lower incidence of hypotension requiring decreases in infusion rate and burning at the infusion site; however, the overall incidence of adverse events was similar between groups. The authors concluded that IV fosphenytoin was better tolerated than IV phenytoin and required less infusion time. Further studies were done to determine if fosphenytoin was indeed superior to phenytoin based on efficacy, safety, and tolerability.

An open-label, randomized trial in 256 patients was conducted to determine if IV or IM fosphenytoin should replace IV phenytoin in a large, urban university level 1 trauma center emergency department.¹⁰ The average dose administered in both groups was similar (fosphenytoin 826 +/- 229 mg PE [n=202] vs. phenytoin 803 +/- 219 mg [n=77]; p=0.4). However, the total infusion time required was less with fosphenytoin compared to phenytoin, 13 vs. 45 minutes, respectively (p<0.001). The mean infusion rate of fosphenytoin was 89 +/- 26 mg PE/min compared to phenytoin 19 +/- 4 mg/min (p<0.001). Cardiovascular adverse effects, such as hypotension and tachycardia, were similar between groups. Differences in adverse effects included less burning with fosphenytoin compared to IV phenytoin, 0.5% and 9.1%, respectively (p=0.0006), and more pruritus with fosphenytoin (6.4%) as compared to IV phenytoin (0%; p=0.01). The authors also reported no incidence of PGS in either arm of the study, and the length of stay for both groups was similar. Based on this study, fosphenytoin was not added to the open formulary at the institution and was restricted to patients who were in status epilepticus or in patients without IV access.

PGS/LCR:
Two studies described the incidence of PGS and LCR with IV phenytoin. The first study was a retrospective review over a 3-month period to determine the incidence, risk factors, and long-term sequelae of PGS.⁶ Purple glove syndrome developed in 6% (9/152) of patients who received IV phenytoin. It was more likely to occur in patients who were elderly, received higher doses, and in those patients administered phenytoin for acute treatment of seizures. Patients who developed PGS also had a longer length of stay. However, a limitation of this study was its retrospective design. Patients who developed PGS could have been more acutely ill, and therefore, more likely to have a longer length of stay. The authors recommended substituting parenteral fosphenytoin for IV phenytoin to avoid PGS.

Due to the limitations of this first study, a prospective study was conducted to examine the incidence of LCR.⁷ Local cutaneous reactions developed in 25% (29/115) of patients who received IV phenytoin, including mild LCR (edema and discoloration <10 cm in size; n=22), and moderate LCR (edema and discoloration >10 cm in size; n=7). Patients with LCR were more likely to be located in a general ward and have the same length of stay. The authors concluded that LCR are common, but are generally mild and benign. These two studies reflect a much higher incidence of PGS and LCR than other studies. More importantly, however, these two studies did not include data on how IV phenytoin was administered, including site of administration or rate of infusion. Improper administration could have contributed to a much higher incidence of PGS and LCR compared to other studies.¹⁰

Clinicians have become more cognizant of preventing PGS and LCR by administering IV phenytoin as follows: 1) a maximum infusion rate of 50 mg/min with a recommended infusion rate of 20 mg/min or less, 2) diluting phenytoin in normal saline, and administering IV phenytoin through an in-line filter and a 20-gauge needle or larger, and 3) recommended sites of administration include a vein at least as large as the antecubital fossa vein or preferably through a central venous catheter. Following these administration guidelines may explain why the incidence and severity of PGS and LCR have decreased in recent years.^4,5,11,12

Oral Phenytoin Administration:
Even though IV fosphenytoin and IV phenytoin can be administered safely, PO administration of phenytoin may be as appropriate and has the advantage of minimizing potential adverse effects from IV or IM administration. A retrospective review of IV fosphenytoin in an emergency department examined if fosphenytoin was being used when PO phenytoin loading was possible.¹³ Candidates for PO phenytoin use were defined as patients: 1) who were alert and awake on arrival, 2) who had no documentation of emesis, 3) who had not been intubated, and 4) who had no repeated seizures or status epilepticus after arrival in the emergency department. A total of 55 patients were identified during the study period. The investigators found that 45% of patients (n=25) were considered to have received IV fosphenytoin inappropriately (95% CI: 32-59%). The authors concluded that PO phenytoin administration in patients who received fosphenytoin inappropriately could result in significant cost savings with no expected increase in adverse effects. The limitations of this study were that it was retrospective and did not evaluate efficacy or safety.

As a result of this study, a prospective, randomized, controlled trial was conducted.¹⁴ The study objective was to compare the cost effectiveness of three phenytoin loading techniques (IV phenytoin, PO phenytoin, and IV fosphenytoin) in an emergency department based on adverse effects and time to safe discharge (phenytoin concentration >10 mg/L and no adverse effects that prevented discharge). Patients were included in the study if they presented within 48 hours of seizure onset, were >18 years of age, had a history of seizures controlled on PO therapy, and had a subtherapeutic phenytoin level (<5 mg/L). A total of 45 patients were enrolled, with 16 patients receiving PO phenytoin, 14 patients receiving IV phenytoin, and 15 patients receiving IV fosphenytoin. Loading doses were similar, PO phenytoin 20 mg/kg (maximum doses of 400 mg every 2 hours), IV phenytoin 18 mg/kg (infused at 50 mg/min), and IV fosphenytoin 18 mg PE/kg (infused at 150 mg PE/min). The mean time to achieve the therapeutic concentration (>10 mg/L) was similar with IV fosphenytoin and IV phenytoin (0.21 +/- 0.28 hours vs. 0.24 +/- 0.3 hours, respectively; p=0.55). With the PO loading regimen, therapeutic concentrations were reached at 5.6 +/- 0.28 hours (p<0.001). In all groups after the loading dose had been administered, no patients developed seizures with subtherapeutic phenytoin levels. The incidence of adverse effects was significantly less with PO phenytoin compared to IV phenytoin or IV fosphenytoin (n=17 for PO phenytoin, n=27 for IV phenytoin, and n=32 for IV fosphenytoin; p=0.015). Significantly more phlebitis was reported with IV phenytoin (n=11) compared to IV fosphenytoin (n=3; p<0.001). Conversely more pruritus was reported with IV fosphenytoin (n=12) compared to IV phenytoin (n=0; p<0.001). The authors concluded that the incidence of adverse events for IV phenytoin and fosphenytoin were similar, with PO phenytoin having fewer adverse effects.

In summary, published literature provides the following: 1) IV phenytoin has a similar adverse effect profile to fosphenytoin when it is administered as recommended, 2) fosphenytoin does not achieve therapeutic levels faster than IV phenytoin since it takes time to convert to phenytoin, and 3) oral loading of phenytoin is safe and effective with the advantages of having no associated hypotension, no PGS, and less nursing time needed to monitor or administer therapy.

Dosing and Monitoring: Fosphenytoin is administered at 15-20 mg PE/kg when patients are given a loading dose and 4-7 mg PE/kg for maintenance doses. Patients may respond differently due to interpatient variability, therefore, monitoring of drug levels may help guide therapy. Therapeutic monitoring of fosphenytoin levels does not have a role in clinical practice.¹ Phenytoin levels may be helpful to monitor for efficacy and adverse effects. Phenytoin levels are recommended 2 hours after the end of IV fosphenytoin infusion and 4 hours after IM fosphenytoin injection to allow for phenytoin distribution into the tissues.¹

Cost Analysis: Fosphenytoin is more expensive than both PO and IV phenytoin. For an average 70 kg patient who requires one loading dose of 15-20 mg PE/kg, fosphenytoin costs approximately 18 times more than an equal dose of IV phenytoin and 53 times more than PO phenytoin. Table 1 lists the average wholesale prices (AWP) of fosphenytoin and phenytoin.¹⁵

Several cost analysis articles comparing fosphenytoin and phenytoin have been published. In an activity-based-accounting model, Marchetti and colleagues concluded that fosphenytoin was more cost-effective than IV phenytoin mainly due to decreased side effects and a decrease in the use of resources (e.g., physician and nursing time).¹⁶ However, a different conclusion was reached in a recent prospective, randomized, controlled study that was conducted in a 750-bed, urban, university hospital emergency department.¹⁷ The objective was to analyze the cost-effectiveness of PO phenytoin, IV phenytoin, and IV fosphenytoin. Cost-effectiveness was determined by comparing adverse event rates and time to safe emergency department discharge. Oral phenytoin was found to be the least expensive and most cost effective followed by IV phenytoin. Fosphenytoin was found to be the most expensive and identified as not cost justifiable in any setting. Based on this study, at the Los Angeles County and University of Southern California Medical Center, fosphenytoin is restricted to patients in status epilepticus or when therapeutic concentrations need to be attained rapidly.

Conclusion: Appropriate therapeutic uses of fosphenytoin include patients in status epilepticus, patients who are actively seizing, patients without IV access, and when patients have had previous localized reactions to IV phenytoin. Despite faster rates of infusion, fosphenytoin requires time to convert to its parent compound, phenytoin. There have been no studies to date that have shown fosphenytoin to be more efficacious or able to achieve therapeutic levels faster than phenytoin. Recent studies and the product labeling of fosphenytoin demonstrate a similar incidence of adverse effects including cardiovascular effects, such as hypotension and dysrhythmias, between fosphenytoin and IV phenytoin.^1,10,14 Phenytoin's unique serious adverse effects, such as PGS and LCR, are rare and generally self-limiting when administered properly. Proper administration of IV phenytoin and selecting PO phenytoin when appropriate delegates fosphenytoin as a second-line agent. Currently, at CCF, a DUE is being conducted to evaluate the use of fosphenytoin in the adult inpatient population.

References:

1. Product labeling. Cerebyx® Parke-Davis. June 2002. Accessed 3 Sept 2004. Available from: URL: www.eisai.com.
2. Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology 1996;46(Suppl 1):S7-10.
3. Leppik IE, Boucher BA, Wilder BJ, Murthy VS, Watridge C, Graves NM, et al. Pharmacokinetics and safety of a phenytoin prodrug given IV or IM in patients. Neurology 1990;40:456-60.
4. DRUGDEX® System. [cited 2004 Sept 12] Thomson Micromedex, Greenwood Village, Colorado
5. Lexi-comp [monograph on Intranet] [cited 2004 Sept 12] Lexi-comp Inc., producers. Available from URL: http://www.crlonline.com/crlonline.
6. O'Brien TJ, Cascino GD, So EL, Hanna DR. Incidence and clinical consequence of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology 1998;51(4):1034-9.
7. O'Brien TJ, Meara FM, Matthews H, Vadja FJ. Prospective study of local cutaneous reactions in patients receiving IV phenytoin. Neurology 2001;57(8):1508-10.
8. Meek PD, Davis SN, Collins DM, Gidal BE, Rutecki PA, Burnstein AH, et al. Guidelines for nonemergency use of parenteral phenytoin products: proceedings of an expert panel consensus process. Arch Intern Med 1999;159(22):2639-44.
9. Boucher BA, Feler CA, Dean JC, Michie DD, Tipton BK, Smith KR, et al. The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy 1996;16(4):638-45.
10. Coplin WM, Rhoney DH, Rebuck JA, Clements EA, Cochran MS, O'Neil BJ. Randomized evaluation of adverse events and length of stay with routine emergency department use of phenytoin or fosphenytoin. Neurol Res 2002;24:842-8.
11. McEvoy GK, Miller J, Snow EK, Welsh OH, Litvak K, Dewey DR, et al, eds. In : AHFS Drug Information. Bethesda: American Society of Health-System Pharmacists; 2004. http://online.statref.com/Document.aspx?DocId=1& FxId=1&SessionId=419368FVZGMLUJUR&Scroll=1&Index=0.
12. Horowitz BZ. Fosphenytoin farewell. Ann Emer Med 2004;43(3):398-400.
13. Johnson J, Wrenn K. Inappropriate foshenytoin use in the ED. Am J Emerg Med 2001;19(4):293-4.
14. Swadron SP, Rudis MI, Azimian K, Beringer P, Fort D, Orlinsky M. A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med 2004;11:244-52.
15. Cardinal Wholesaler, Inc. Accessed 2005 March 23.
16. Marchetti A, Magar R, Fischer J, Sloan E, Fischer P. Pharmacoeconomic evaluation of intravenous fosphenytoin (Cerebyx®) versus intravenous phenytoin (Dilantin®) in hospital emergency departments. Clin Ther 1996;18(5): 953-66.
17. Rudis MI, Touchette DR, Swadron SP, Chiu AP, Orlinksy M. Cost-effectiveness of oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin in the emergency department. Ann Emerg Med 2004;43:386-97.