Fosphenytoin

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.07.2021
Released 02.23.1999
Expires For CME 03.07.2024

Fosphenytoin

Author: K K Jain MD†

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Fosphenytoin

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Introduction

Historical note and terminology

Fosphenytoin sodium is a water-soluble prodrug intended for parenteral administration. Its active metabolite is phenytoin. Unlike phenytoin, fosphenytoin does not require propylene glycol and high alkalinity to bring it into solution. Fosphenytoin is rapidly and completely absorbed after intramuscular or intravenous administration. Intravenous fosphenytoin produces fewer local side effects than intravenous phenytoin and has not been associated with serious cardiovascular adverse events. Therefore, it is a useful replacement for parenteral phenytoin. Fosphenytoin was approved by the United States Food and Drug Administration in 1996.

Pharmacology

Fosphenytoin is a prodrug of phenytoin.

Fosphenytoin (chemical structure)

(Contributed by Dr. K K Jain.)

Pharmacodynamics. Following intramuscular injection, fosphenytoin is converted into anticonvulsant phenytoin by nonspecific phosphatases in the blood. The mechanism of action is like that of phenytoin. Modulation of sodium channels is the primary anticonvulsant mechanism. Fosphenytoin has equivalent anticonvulsant activity to phenytoin against seizures induced by maximal electroshock in mice following intraperitoneal, oral, or intravenous administration.

Pharmacokinetics. The important features of fosphenytoin pharmacokinetics are as follows and vary according to whether it is administered by intravenous or intramuscular injection:

	• Following intravenous infusion, maximum plasma phenytoin concentrations are reached at the end of the infusion and have a half-life of approximately 15 minutes.
	• Following intramuscular injection, peak plasma concentrations are reached in 30 minutes. Plasma concentrations following intramuscular injection are lower than those following intravenous injection but are more sustained.
	• The bioavailability of phenytoin after fosphenytoin is virtually 100%.
	• The ratio of mean area under the curve of phenytoin after intravenous and intramuscular fosphenytoin is 1:17.
	• Fosphenytoin is nearly completely bound to human plasma proteins and displaces phenytoin from protein binding sites.
	• One mmol of fosphenytoin gives rise to 1 mmol of phenytoin and yields 2 metabolites: phosphate and formaldehyde. The latter is converted into formate, which in turn is metabolized by a folate-dependent mechanism. However, the concentrations of these 2 metabolites do not suffice to produce any important biological effects when fosphenytoin is administered in therapeutic doses.
	• Metabolism and elimination of phenytoin following administration of fosphenytoin is like that described for phenytoin. The major site of metabolism is the liver with excretion in urine.
	• In patients with epilepsy, plasma concentrations of free and total phenytoin are maintained in the therapeutic range for several days after conversion from orally administered phenytoin to intramuscular fosphenytoin.
	• Fosphenytoin sodium injection given orally is absorbed more rapidly and to a significantly greater extent than phenytoin sodium injection given orally to healthy volunteers (10).
	• Fosphenytoin loading doses of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations, but obese female patients need a larger weight-based dose than male patients to achieve similar phenytoin concentrations (04).
	• Because of multiple factors that affect the pharmacokinetics of acutely ill patients, the currently used method of calculating a fosphenytoin reloading dose does not consistently result in therapeutic concentrations (1.5 to 2.5 mcg/mL). A study has shown that of the fosphenytoin reloading doses administered, 48% resulted in a therapeutic concentration of free phenytoin on the subsequent day, with the remaining 52% resulting in nontherapeutic levels (15). The authors’ evaluation of reloading dose calculation strategies indicated that creation of a new pharmacokinetic model with less emphasis on volume of distribution may more consistently result in therapeutic concentrations.

Clinical trials

Noncomparative studies. A 4-center, open-label study of fosphenytoin was conducted in 43 patients with epilepsy maintained on monotherapy with oral phenytoin twice a day. Patients received an intravenous or intramuscular dose of fosphenytoin at a dose equivalent to the morning dose of phenytoin. The intravenous infusion rate was 75 mg per minute, and intramuscular doses were given as 1 or 2 injections. Fosphenytoin was found to be an effective parenteral anticonvulsant with better tolerability than currently available parenteral preparations of phenytoin.

Comparative studies. A randomized study in patients with subtherapeutic phenytoin concentrations who presented within 48 hours of a seizure showed no significant difference between intravenous loading with phenytoin and fosphenytoin, although both were superior to oral loading.

A retrospective observational cohort study found that patients at risk of seizures were discharged from the emergency department earlier with the loading of intramuscular fosphenytoin compared to intravenous phenytoin (01).

A randomized clinical trial of levetiracetam versus fosphenytoin for seizure prevention in traumatic brain injury or subarachnoid hemorrhage showed that levetiracetam is associated with better outcome than fosphenytoin (19). However, apart from severity of generalized slowing, focal slowing and epileptiform discharges on EEG were not associated with outcomes in these patients.

A retrospective study of seizure prophylaxis in children with supratentorial intracranial hemorrhage that compared fosphenytoin and levetiracetam found the latter to be somewhat more effective in the control of seizures, although there was a significant difference in the onset of late seizures after 1 week (02).

Goals and duration of treatment

The goal of fosphenytoin use is for the control of seizures by loading dose and maintenance doses of either fosphenytoin intramuscular or phenytoin oral. If intravenous fosphenytoin does not achieve control of seizures, use of other anticonvulsants and measures should be considered. One alternative is the control of seizures with intravenous diazepam and maintenance with intramuscular fosphenytoin.

Oral phenytoin is the most cost-effective loading method in most settings, and intravenous fosphenytoin is the most expensive option. The adverse effect profiles of intravenous fosphenytoin and phenytoin are similar in the published literature, and there is no evidence of clear benefit that would justify the higher price of the fosphenytoin compared to phenytoin (05). Another cost-effectiveness analysis in traumatic brain injury patients showed that prophylaxis starting with fosphenytoin is more cost-effective than levetiracetam at all reasonable prices whereas both were equally effective in reducing the seizure potential (06).

Guidelines of the American Epilepsy Society recommended intravenous phenytoin or fosphenytoin (if available) as the antiepileptic of choice after benzodiazepines (08). A comparative study of fosphenytoin and continuous intravenous midazolam as second-line treatment for pediatric status epilepticus in Japan showed that efficacy of both was similar (14). In a retrospective study, a loading dose of 20 mg/kg intravenous fosphenytoin was effective as well as safe in controlling seizures in 88% of children with status epilepticus. Seizure control and adverse effects had only a weak relation with serum phenytoin levels achieved in this study (18).

Special considerations

Anesthesia. No relevant information.

Pregnancy. Precautions for pregnant women using phenytoin are as follows:

	• An increase of seizure frequency may occur during pregnancy because of altered phenytoin absorption or metabolism. Periodic measurements of phenytoin levels to guide dosage adjustment are recommended.
	• Several reports suggest an association between the use of antiepileptic drugs, including phenytoin, in pregnancy and a higher incidence of birth defects. For details see the Physicians’ Desk Reference.
	• Neonatal coagulation defects have been reported within the first 24 hours in babies born to mothers receiving phenytoin. Vitamin K has been shown to correct or prevent this defect.
	• Only small amounts of phenytoin are found in breastmilk and usually cause no difficulties in breastfed infants. Breastfeeding during phenytoin monotherapy has not been reported to adversely affect infant development. If phenytoin is required by the mother, breastfeeding need not be discontinued.

Pediatric. Safety in pediatric patients has not been established.

Geriatric. Fosphenytoin excretion is decreased in the elderly. Lower doses and a slower rate of administration should be used.

Hepatic and renal disease. An increase in systemic adverse effects may occur following intravenous fosphenytoin loading doses in patients with renal or hepatic disease who have a decreased ability to bind fosphenytoin and phenytoin. Close monitoring and reduction in the infusion rate by 25% to 50% are recommended when intravenous loading doses of fosphenytoin are administered in these patients (07).

Fosphenytoin should be used with caution in end-stage renal disease because of the risk of hyperphosphatemia.

Adverse effects

In volunteers, fosphenytoin is well tolerated at intravenous doses up to 1200 mg phenytoin equivalents, using infusion rates 3 times the maximum recommended for phenytoin. In patients with epilepsy, transient postinjection cramping in the leg, tingling, mild irritation at the injection site, dizziness, ataxia, and nystagmus have all been reported. Pendular nystagmus is attributed to instability of the oculomotor neural integrator due to delays in feedback from the cerebellum and resolves following postictal recovery (17). Phenytoin-induced dyskinesias have been reported in infants but are rare. Hemidyskinesias with nystagmoid eye movements developed in an infant with Sturge-Weber syndrome following use of intravenous fosphenytoin but resolved after discontinuation of this drug (20). Right cerebral infarction was the presumed underlying cause of phenytoin-induced hemidyskinesia.

Paresthesias of the groin, back, lower abdomen, and head or neck rarely occur during infusion of phenytoin but have been reported in up to 30% of volunteers and patients receiving fosphenytoin. These paresthesias usually occur during intravenous administration of higher doses and at higher infusion rates and resolve rapidly without sequelae. Purple glove syndrome is a rare complication of intravenous phenytoin use that usually presents with pain, swelling, and discoloration at the injection site, which spreads to the distal limb (03). A case of purple glove syndrome has been reported in a patient receiving fosphenytoin, which resolved following discontinuation of therapy and treatment with methylprednisolone (13).

The most important adverse reaction following the use of intravenous fosphenytoin is cardiovascular collapse and CNS depression. Hypotension can occur when the rate of administration is faster than 150 mg per minute. In patients presenting with acute cerebral symptoms, intravenous infusion of fosphenytoin may cause significant decrease in blood pressure, which is not seen in similar patients receiving intravenous levetiracetam (09). In a study, hypotension occurred in 39% of patients receiving an intravenous infusion of fosphenytoin for status epilepticus, and old age as well as systemic infection increased the risk of hypotension (11). The U.S. Food and Drug Administration's Adverse Event Reporting System databank contains numerous reports of adverse cardiac events likely related to fosphenytoin infusion, including cardiac deaths. It is recommended that cardiac monitoring be used when administering intravenous fosphenytoin to high-risk patients.

The emergence of treatment-related adverse events has been studied in clinical trials in patients who were on oral phenytoin therapy and were switched to intramuscular fosphenytoin. Headache, nausea, vomiting, and nystagmus are reported more frequently in patients receiving intramuscular fosphenytoin.

Management. Most of the adverse effects subside spontaneously and may require observation of patients a few hours longer following the administration of fosphenytoin.

	• Severe reaction at the site of administration may require changing the site of injection for any subsequent administration.
	• If hypotension develops, intravenous infusion may be stopped until the blood pressure normalizes and the infusion should be restarted at a lower rate.

References

01: Aaronson PM, Belgado BS, Spillane JP, Kunisaki TA. Evaluation of intramuscular fosphenytoin vs intravenous phenytoin loading in the ED. Am J Emerg Med 2011;29(9):983-8. PMID 20685063
02: Bansal S, Blalock D, Kebede T, Dean NP, Carpenter JL. Levetiracetam versus (fos)phenytoin for seizure prophylaxis in pediatric patients with intracranial hemorrhage. J Neurosurg Pediatr 2014;13(2):209-15. PMID 24286154
03: Chokshi R, Openshaw J, Mehta NN, Mohler E 3rd. Purple glove syndrome following intravenous phenytoin administration. Vasc Med 2007;12(1):29-31. PMID 17451091
04: DasGupta R, Alaniz C, Burghardt D. Evaluation of intravenous phenytoin and fosphenytoin loading doses: influence of obesity and sex. Ann Pharmacother 2019;53(5):458-63.** PMID 30522345
05: Eriksson K, Keränen T, Kälviäinen R. Fosphenytoin. Expert Opin Drug Metab Toxicol 2009;5(6):695-701. PMID 19473113
06: Cotton BA, Kao LS, Kozar R, Holcomb JB. Cost-utility analysis of levetiracetam and phenytoin for posttraumatic seizure prophylaxis. J Trauma 2011;71(2):375-9. PMID 21825941
07: Fischer JH, Patel TV, Fischer PA. Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet 2003;42(1):33-58. PMID 12489978
08: Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016;16(1):48-61. PMID 26900382
09: Kassab MY, Lobeck IN, Majid A, Xie Y, Farooq MU. Blood pressure changes after intravenous fosphenytoin and levetiracetam in patients with acute cerebral symptoms. Epilepsy Res 2009;87(2-3):268-71. PMID 19854616
10: Kaucher KA, Acquisto NM, Rao GG, et al. Relative bioavailability of orally administered fosphenytoin sodium injection compared with phenytoin sodium injection in healthy volunteers. Pharmacotherapy 2015;35(5):482-8. PMID 26011141
11: Kim HK, Hwang IG, Koh IS, Kim DW. Incidence and risk factors of hypotension after intravenous fosphenytoin administration. J Clin Pharm Ther 2017;42(5):561-6.** PMID 28439951
12: Nakazawa M, Akasaka M, Hasegawa T, et al. Efficacy and safety of fosphenytoin for acute encephalopathy in children. Brain Dev 2015;37(4):418-22. PMID 25008803
13: Newman JW, Blunck JR, Fields RK, Croom JE. Fosphenytoin-induced purple glove syndrome: a case report. Clin Neurol Neurosurg 2017;160:50-3. PMID 28648954
14: Nishiyama M, Nagase H, Tomioka K, et al. Fosphenytoin vs. continuous midazolam for pediatric febrile status epilepticus. Brain Dev 2018;40(10):884-90. PMID 30144969
15: Noval M, Seung H, Armahizer M. Evaluation of fosphenytoin therapeutic drug monitoring in the neurocritical care unit. Drugs R D 2020;20(1):17-22. PMID 31925752**
16: Pon D, Hwang J, Lo T, Zyl CV. Decreased responsiveness to oxycodone: a case of a pharmacokinetic drug interaction? J Opioid Manag 2015;11(4):357-61. PMID 26312962
17: Shaikh AG. Fosphenytoin induced transient pendular nystagmus. J Neurol Sci 2013;330(1-2):121-2. PMID 23647839
18: Srivastava K, Bhartiya S, Gavli V, Patil R, Rajadhyaksha S. Efficacy, tolerability and serum phenytoin levels after intravenous fosphenytoin loading dose in children with status epilepticus. Indian Pediatr 2020;57(3):218-21. PMID 32198860
19: Steinbaugh LA, Lindsell CJ, Shutter LA, Szaflarski JP. Initial EEG predicts outcomes in a trial of levetiracetam vs. fosphenytoin for seizure prevention. Epilepsy Behav 2012;23(3):280-4. PMID 22342434
20: Thodeson DM, Reiber DC, Dolce AM, Sirsi D. Fosphenytoin-induced dyskinesias in an infant with Sturge-Weber syndrome. Neurology 2016;86(16):1561-2. PMID 27164450

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Fosphenytoin

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Fosphenytoin

Fosphenytoin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview.
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to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

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	• Intravenous fosphenytoin has been used for the management of neuropathic pain, particularly, acute trigeminal neuralgia crisis.
	• Intravenous fosphenytoin was reported to be safe and effective for treatment of acute encephalopathy with seizures in children (12).

	• Patients who have a demonstrated hypersensitivity to fosphenytoin, any of its ingredients, or to phenytoin.
	• Patients with sinus bradycardia, sinoatrial block, second- and third-degree atrioventricular block, and Adams-Stokes syndrome.

Fosphenytoin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

This is an article preview.
Start a Free Account
to access the full version.