Fosphenytoin

Article Author:
Rozaleen Aleyadeh
Article Editor:
Robert Carson
Updated:
8/8/2020 12:02:20 PM
PubMed Link:
Fosphenytoin

Indications

Fosphenytoin is a water-soluble prodrug formulation of phenytoin. It received FDA approval in 1996 for use in epilepsy.[1].

It is most commonly used in acute scenarios as an anti-epileptic drug (AED) and a substitute for phenytoin when there are contraindications. Initially, its use was as a short-term oral substitute for oral phenytoin [2]. However, it quickly gained acceptance as a prophylactic drug for patients undergoing neurosurgery. As an AED in the place of phenytoin, clinicians can also use it for the cessation of generalized tonic-clonic status epilepticus. Its water solubility and decreased risk of adverse effects also make it a better choice of medication when compared to phenytoin. It has also been used off-label in traumatic brain injury to prevent early posttraumatic seizures.[3]

Mechanism of Action

As a phosphate ester prodrug, fosphenytoin converts into the active form of phenytoin in a 1 to 1 ratio.[1] Therefore, it has the same mechanism of action as phenytoin. Its primary mode of action is through the modulation of voltage-gated sodium channels by prolonging the inactivation state of these channels. It inhibits the sustained neuronal activation in the seizure focus, thereby actively stopping the seizure. To a smaller degree, it may also modulate voltage-gated calcium channels and increase sodium-potassium ATPase activity.

Administration

There is no oral formulation of fosphenytoin. Its most common administration route through the intravenously (IV). An intramuscular (IM) route formulation is also available for adults, but it is not the preferred route for the neonatal or pediatric population.

IV administration [4][5]:

  • Intermittent infusion diluted with dextrose 5% or normal saline.
  • The infusion should not exceed 150 mg PE(phenytoin equivalent)/minute as it increases the risk of serious cardiovascular events such as hypotension and arrhythmia.
  • For at-risk patients, the elderly, and cardiac patients, the patient can receive an infusion rate as slow as 25 to 50 mg PE/minute.
  • For pediatric patients, the recommended administration rate is recommended at 1 to 2 mg PE/kg/minute with a maximum of 150 mg PE/minute.

IM administration [5][6]:

  • It is not the preferred route for status epilepticus or pediatric patients.
  • Single daily dose administration using up to 4 injection sites. Patients can tolerate a maximum of 20 mL/site.

Adverse Effects

The side effect profile of fosphenytoin is similar to that of phenytoin. Adverse effects are seen more in association with IV administration than IM administration.

Adverse effects are comparative to phenytoin. The most common adverse effects are nystagmus, dizziness, pruritus, somnolence, and ataxia. However, pruritus more often occurs with fosphenytoin use than phenytoin. There is also documentation of cardiovascular effects in the form of hypotension and cardiac arrhythmias. Researchers noted dose and rate dependency of adverse reactions after the use of IV fosphenytoin.[7]

Side effects seen with IV fosphenytoin and not IV phenytoin are pelvic pain, asthenia, back pain, tachycardia, tongue disorder, paresthesia, extrapyramidal syndrome, dysarthria, vertigo, diplopia, and deafness.

Purple glove syndrome may occur but at a much lower incidence than that with the administration of IV phenytoin.

Additionally, hyperphosphatemia may also occur in patients with end-stage renal disease.[8][9]

Contraindications

Contraindications for fosphenytoin include previous adverse to its activated phenytoin form as well as a history of cardiac conditions or arrhythmias. Due to the effect of the activated drug on ventricular automaticity, patients are at risk of exacerbations of preexisting conditions.[3][10] Patients with hepatic or renal impairment require close monitoring as there is a more rapid increase of self-displacement of fosphenytoin from plasma proteins leading to increased concentrations and risk of toxicity.[11]

Therefore, patients with a history of the following should not take fosphenytoin:

  • Adams-Stokes syndrome
  • Hypersensitivity to phenytoin, hydantoin drugs, or fosphenytoin itself
  • History of hepatotoxicity attributed to fosphenytoin or phenytoin sodium
  • Heart conditions namely second and third-degree atrioventricular block, sino-atrial block, and sinus bradycardia
  • Simultaneous use with delavirdine because of the potential of decreased effectiveness of the virologic response of delavirdine and resistance against it and other non-nucleoside reverse transcriptase inhibitors.

Monitoring

IM administration of fosphenytoin is absorbed within 30 minutes, while the IV administration is absorbed immediately. Around 95 to 99% is protein-bound with a volume of distribution proportional to the dosage and rate of administration, generally ranging from 4.3 L to 10.8 L. It is metabolized to phenytoin by both acid and alkaline phosphatases and pharmacokinetics and excretion is dependent on that of the active phenytoin.[1]

Fosphenytoin has a 100% bioavailability and begins its conversion into phenytoin immediately upon entering circulation. Its half-life for the conversion is 10 to 15 minutes. Essentially, the complete conversion occurs from 1 to 1.5 hours after IV dosing or 3 to 4 hours after IM dosing. Measurement of plasma phenytoin levels is recommended only after the complete conversion of the drug due to the cross-reactivity of fosphenytoin in the immunoassay.[11]

Similarly, monitoring is dependent on the activated drug and includes therapeutic drug monitoring of serum phenytoin. Saliva level may alternatively be an option for monitoring, as it reflects free phenytoin serum levels. Continuous monitoring of ECG, blood pressure, and respiratory functions during IV administration and up to 20 minutes afterward is also recommended.[2]

Toxicity

Fosphenytoin has a black box warning due to its activated form of phenytoin. Exceeding 150 mg phenytoin equivalents per minute in adults may lead to severe cardiac outcomes, particularly hypotension and cardiac arrhythmias. Therefore, cardiac monitoring is recommended for up to 30 minutes of IV infusion. In the case of cardiac abnormalities, the discontinuation or reduction of the dosage of the drug may be necessary.[12]

Fosphenytoin has the same warning signs as that of phenytoin. The first to manifest during an acute overdose are nystagmus, ataxia, and dysarthria. The calculated doses in which these appear differ from patient to patient; however, nystagmus can be seen at as little as 20 µg/mL doses with lethargy and dysarthria presenting at upwards of 40 µg/mL.[9]

The administered dose must not reach 2 to 5 grams, which is the lethal dose in adults. The lethal dose in the pediatric population is unknown.

Enhancing Healthcare Team Outcomes

Fosphenytoin is the prodrug formulation of the commonly used phenytoin. It may be prescribed by an internist, neurologist, or intensivist in the case of convulsive or non-convulsive seizure. Although it is considered a safer formulation of phenytoin, it still maintains a similar side effect profile. Due to its association with phenytoin, fosphenytoin carries a black box warning for dose-dependent severe cardiac outcomes. Severe hypotension and cardiac arrhythmias are a significant risk factor of fosphenytoin overdose exceeding 150 mg phenytoin equivalents per minute. In such cases, patients should receive support as per ACLS guidelines.[13] [Level 2]

To best prescribe and monitor the administration of this medication, it requires an interprofessional team with open communication at every stage. [Level 5]


References

[1] Fischer JH,Patel TV,Fischer PA, Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clinical pharmacokinetics. 2003;     [PubMed PMID: 12489978]
[2] Browne TR, Fosphenytoin (Cerebyx). Clinical neuropharmacology. 1997 Feb;     [PubMed PMID: 9037568]
[3] Luer MS, Fosphenytoin. Neurological research. 1998 Mar;     [PubMed PMID: 9522355]
[4] Meek PD,Davis SN,Collins DM,Gidal BE,Rutecki PA,Burstein AH,Fischer JH,Leppik IE,Ramsay RE, Guidelines for nonemergency use of parenteral phenytoin products: proceedings of an expert panel consensus process. Panel on Nonemergency Use of Parenteral Phenytoin Products. Archives of internal medicine. 1999 Dec 13-27;     [PubMed PMID: 10597754]
[5] Patel SI,Birnbaum AK,Cloyd JC,Leppik IE, Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy. CNS drugs. 2015 Dec;     [PubMed PMID: 26603741]
[6] Pryor FM,Gidal B,Ramsay RE,DeToledo J,Morgan RO, Fosphenytoin: pharmacokinetics and tolerance of intramuscular loading doses. Epilepsia. 2001 Feb;     [PubMed PMID: 11240597]
[7] Gupta M,Tripp J, Phenytoin 2020 Jan;     [PubMed PMID: 31855364]
[8] Newman JW,Blunck JR,Fields RK,Croom JE, Fosphenytoin-induced purple glove syndrome: A case report. Clinical neurology and neurosurgery. 2017 Sep;     [PubMed PMID: 28648954]
[9] Boucher BA,Feler CA,Dean JC,Michie DD,Tipton BK,Smith KR Jr,Kramer RE,Young B,Parks BR Jr,Kugler AR, The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy. 1996 Jul-Aug;     [PubMed PMID: 8840370]
[10] Glauser T,Shinnar S,Gloss D,Alldredge B,Arya R,Bainbridge J,Bare M,Bleck T,Dodson WE,Garrity L,Jagoda A,Lowenstein D,Pellock J,Riviello J,Sloan E,Treiman DM, Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy currents. 2016 Jan-Feb;     [PubMed PMID: 26900382]
[11] Knapp LE,Kugler AR, Clinical experience with fosphenytoin in adults: pharmacokinetics, safety, and efficacy. Journal of child neurology. 1998 Oct;     [PubMed PMID: 9796747]
[12] Tanaka J,Kasai H,Shimizu K,Shimasaki S,Kumagai Y, Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers. European journal of clinical pharmacology. 2013 Mar;     [PubMed PMID: 22918614]
[13] 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. Neurological research. 2002 Dec;     [PubMed PMID: 12500711]