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]

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.

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.

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 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.