Fosphenytoin

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 exact mechanism of action as phenytoin. Fosphenytoin is converted into phenytoin by phosphatases in the liver and red blood cells. Fosphenytoin is extensively bound (95%–99%) to human plasma proteins, primarily albumin. 

Its primary mechanism of action is due to the modulation of voltage-gated sodium channels by prolonging the inactivation state of these channels. This effect is mediated by slowing the rate of recovery of voltage-activated Na+ channels, an action that is both voltages and use-dependent.

At therapeutic concentrations, the impact on Na+ channels is selective. However, multiple effects of phenytoin are evident at higher concentrations, including reduction of spontaneous activity and augmentation of responses to GABA. To a minor level, it may also modulate voltage-gated calcium channels and increase sodium-potassium ATPase activity. The amalgamation of multiple mechanisms reduces sustained high-frequency neuronal discharges, stabilizes neuronal membranes, and decreases seizure activity.[2]

Pharmacokinetics

Absorption: When administered by the parenteral route, fosphenytoin is converted to phenytoin. Peak plasma concentrations are achieved at the end of IV infusion. In the case of IM administration, peak plasma concentrations are attained in approximately 30 minutes.

Distribution: Fosphenytoin has high plasma protein binding (95% to 99%) and primarily binds to albumin. The volume of distribution(Vd) of fosphenytoin increases with dose and ranges from 4.3 to 10.8 liters.

Metabolism: Phosphatases play a major role in the metabolism of fosphenytoin. Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate. Phenytoin is metabolized in the liver by CYP2C9 and CYP2C19.

Excretion: Fosphenytoin is not excreted in the urine. Phenytoin derived from the metabolism of fosphenytoin is excreted in the urine primarily as hydantoin metabolites, and 1% to 5% of the fosphenytoin dose is recovered unchanged in the urine. Phenytoin follows zero-order kinetics at higher drug concentrations and first-order kinetics at low drug concentrations.[5]

Administration

There is no oral formulation of fosphenytoin. The most common route of administration is intravenous(IV). An intramuscular (IM) route formulation is also available for adults, not recommended for the neonatal or pediatric population. The benefit of fosphenytoin over phenytoin is its ability to administer with both saline and glucose.[6]

IV Administration

• 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.
• The recommended administration rate for pediatric patients is 1 to 2 mg PE/kg/minute with a maximum of 150 mg PE/minute.[7]

IM Administration

• 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.[8]

Use in Specific Patient Populations

Patient with Hepatic Impairment: The fraction of unbound phenytoin (the active metabolite of fosphenytoin sodium injection) is increased in patients with hepatic impairment and hypoalbuminemia. After IV fosphenytoin sodium administration to patients with hepatic impairment, fosphenytoin conversion to phenytoin may be increased without an equivalent increase in phenytoin clearance which has the potential to increase the severity of adverse events. Hence, monitor unbound phenytoin concentrations in these patients with hepatic impairment.

Patients with Renal Impairment:  The fraction of unbound phenytoin (the active metabolite of fosphenytoin sodium injection) is increased in patients with renal disease. After IV fosphenytoin sodium administration to patients with renal disease, fosphenytoin conversion to phenytoin may be increased without an equivalent increase in phenytoin clearance, which can potentially increase the severity of adverse events. Hence, monitor unbound phenytoin concentrations in patients with renal impairment.

Pregnancy Considerations: In humans, exposure to phenytoin (the active metabolite of fosphenytoin sodium injection) can increase the risks of congenital malformations. Prenatal exposure increases the incidence of major malformations, including orofacial clefts and cardiac defects. Moreover, there is an increased risk of fetal hydantoin syndrome characterized by growth abnormalities (including microcephaly), dysmorphic skull and facial features, hypoplasia of digits and nails, and cognitive deficits. In addition, some malignancies, including neuroblastoma, have been reported in children whose mothers received phenytoin during pregnancy. In addition, a life-threatening bleeding disorder related to reduced levels of vitamin K-dependent clotting factors can occur in infants exposed to phenytoin in utero. This adverse event can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. In addition,  An increase in seizure frequency may occur during pregnancy due to altered phenytoin pharmacokinetics. Therefore, regular measurement of serum phenytoin concentrations may help manage pregnant women for proper dose adjustment.

Breastfeeding Considerations: There is a lack of data regarding using fosphenytoin during breastfeeding. Fosphenytoin is metabolized in the body to phenytoin. Due to low levels of phenytoin in breast milk, the amount ingested by the infant is small, and no problems are seen in breastfed infants except for rare idiosyncratic reactions. Breastfeeding during phenytoin does not affect infant growth or development adversely. If the mother needs phenytoin, discontinuing breastfeeding is not required. However, combination treatment with other sedating anticonvulsants or psychotropics may result in sedation in infants or withdrawal reactions upon discontinuation.[9]

Pharmacogenetic Considerations: Fosphenytoin can cause severe cutaneous adverse reactions (SCARs). Reactions include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Pharmacogenomic studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the reduced function CYP2C9*3 variant, which has also been associated with reduced clearance of phenytoin. Therefore, avoid fosphenytoin as an option to carbamazepine in patients who are positive for HLA-B*1502 or CYP2C9*3 carriers. Clinicians should consider starting fosphenytoin at a low dose for CYP2C9*3 carriers. However, it must be noted that HLA-B*1502 or CYP2C9 genotyping has limitations and must never replace clinical care and management in emergency settings.[10][11]

Adverse Effects

The adverse drug reaction profile of fosphenytoin is similar to that of phenytoin. Moreover, it is essential to note that adverse effects are more associated with IV administration than IM administration.

• The most common adverse effects are nystagmus, dizziness, pruritus, drowsiness, and ataxia. Additional adverse drug reactions include pelvic pain, tachycardia, tongue disorder, paresthesia,  dysarthria, vertigo, diplopia, and deafness.[12] 

• Cardiovascular reactions: There are reports of severe hypotension and cardiac arrhythmias associated with fosphenytoin use.[13]

• Dermatologic reactions: As discussed above, there is a risk of toxic epidermal necrolysis(TEN) and stevens-johnson syndrome (SJS) associated with fosphenytoin use.[10]

• Purple glove syndrome: The mechanism behind purple glove syndrome is microvascular thrombosis and subclinical extravasation. Avoiding small hand veins, adhering to recommended IV administration guidelines, and monitoring the infusion site for reactions decrease this complication.[14]

• Hematopoietic reactions: Hematopoietic complications include thrombocytopenia, leukopenia, agranulocytosis, and pancytopenia.[15] Lymphadenopathy and pseudolymphoma are associated with phenytoin/fosphenytoin use, according to the product labeling.[16]

• Bleeding disorder in neonates- A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and the neonate after birth.[17]

• Hyperphosphatemia: Hyperphosphatemia may occur in patients with end-stage renal disease.[18][19]

• Exacerbation of Porphyria: There is a risk of worsening porphyria with fosphenytoin. Hence exercise caution when using fosphenytoin in patients suffering from porphyria.[20]

• Fetal hydantoin syndrome: There is an increased frequency of significant malformations (such as orofacial clefts and cardiac defects), dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities, and cognitive deficits among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy.[21] 

• Hyperglycemia- Phenytoin may raise the serum glucose concentrations in diabetic patients. Hyperglycemia, resulting from the inhibitory effect of phenytoin (the active metabolite of fosphenytoin) on insulin release, has been reported.[22]

• Angioedema- Postmarketing surveillance reports suggest cases of fosphenytoin-induced angioedema. Clinicians should discontinue fosphenytoin immediately in case of angioedema.[23]

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin.[24]

• Hepatotoxicity- In patients treated with fosphenytoin, case reports identified typical immunoallergic hepatitis and drug rash with eosinophilia and systematic symptoms(DRESS) syndrome.[25]

• US Boxed Warning(severe hypotension and cardiac arrhythmia): The rate of fosphenytoin intravenous (IV) administrations should not exceed 150 mg phenytoin sodium equivalent (PE)/minute due to the risk of severe hypotension and cardiac arrhythmias. Continuous cardiac monitoring is required while administering IV fosphenytoin.[26][27]

Contraindications

The previous hypersensitivity reactions to the same class of drugs are contraindications for fosphenytoin. As fosphenytoin affects ventricular automaticity, there is a risk of exacerbating preexisting cardiac conditions.[3][4] As discussed above, patients with hepatic or renal impairment require close monitoring. A rapid increase in self-displacement of fosphenytoin from plasma proteins leads to increased concentrations and risk of toxicity.[28]

Contraindications to Fosphenytoin Use

• Adams-Stokes syndrome
• History of hepatotoxicity associated with fosphenytoin or phenytoin sodium
• Concomitant use with delavirdine due to decreased effectiveness of the virologic response of delavirdine
• Cardiac conditions, particularly second and third-degree atrioventricular block, sino-atrial block, and sinus bradycardia
• Hypersensitivity to phenytoin, hydantoin drugs, or fosphenytoin itself as hypersensitivity reactions may cause angioedema.[29]

Monitoring

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. 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.[28] Therefore, therapeutic drug monitoring is suggested 2 hours after the completion of IV infusion and 4 hours after intramuscular (IM) injection. Efficacy without adverse effects occurs between total phenytoin concentrations of 10 to 20 mcg/mL (i.e., unbound phenytoin concentrations of 1 to 2 mcg/mL)

Similarly, monitoring depends on the activated drug and includes therapeutic drug monitoring of serum phenytoin. Saliva level may be an option for monitoring, reflecting free phenytoin serum levels. Continuous monitoring of EKG, blood pressure, and respiratory functions during IV administration and up to 20 minutes afterward is also recommended.[2] According to the American academy of neurology, elevated prolactin level measured 10 to 20 minutes after the seizure is a useful marker to differentiate GTCS  from psychogenic nonepileptic seizures (NES) among adults and older children.[30]

Toxicity

Fosphenytoin has a black box warning due to its activated form of phenytoin. In adults, exceeding 150 mg phenytoin equivalents per minute may lead to severe cardiac outcomes, particularly hypotension and cardiac arrhythmias. Therefore, clinicians should perform cardiac monitoring up to 30 minutes after IV infusion. In the case of cardiac abnormalities, the discontinuation or reduction of the drug dosage may be necessary.[31]

Fosphenytoin has the same warning signs as phenytoin. The first to manifest during an acute overdose are nystagmus, ataxia, and dysarthria. The calculated doses appear to differ from patient to patient; however, nystagmus is evident at as little as 20 µg/mL doses, with lethargy and dysarthria presenting at upwards of 40 µg/mL. The Lethal dose of fosphenytoin is 2 to 5 grams in adults. In acute overdosage, the possibility of other CNS depressants, including alcohol, should be considered.[19] 

Treatment is nonspecific since there is no known antidote to fosphenytoin or phenytoin overdosage. The clinicians should examine the adequacy of the respiratory and circulatory systems and ensure relevant supportive measures. According to product labeling, in severe intoxication in the pediatric population, total exchange transfusion is used. Nephrologists should consider hemodialysis in severe cases.[32] Formate and phosphate, the metabolites of fosphenytoin, may lead to signs of toxicity following overdosage. Formate toxicity is associated with severe anion-gap metabolic acidosis. Phosphate in toxic amounts can cause hypocalcemia with paresthesia, muscle spasms, and seizures. Therefore, ionized calcium levels should be monitored to guide the treatment of hypocalcemia.[33]

Enhancing Healthcare Team Outcomes

Fosphenytoin is the prodrug formulation of the commonly used drug phenytoin. Although it is considered a safer formulation of phenytoin, it still maintains a similar adverse drug reaction profile. Fosphenytoin carries a black box warning for severe cardiac outcomes. Severe hypotension and cardiac arrhythmias are significant risk factors of fosphenytoin overdose exceeding 150 mg phenytoin equivalents per minute. In such cases, clinicians should provide support as per ACLS guidelines.[34] [Level 2]

All the healthcare providers involved in taking care of the patient receiving fosphenytoin should be accurate with its indications, pharmacology, adverse effects, monitoring, and toxicity. Internists, neurologists, or intensivists should prescribe fosphenytoin for appropriate indications. Nurses should check IV compatibility and administer fosphenytoin according to product labeling. Pharmacists should ensure proper dosing and report to clinicians in case of drug overdose or interactions. Management of severe hypotension and cardiac arrhythmias requires ICU care under critical care physician supervision. The nephrologist consultation is necessary for severe acute overdose requiring hemodialysis or exchange transfusion.

Clinicians should suggest that pregnant patients register in the North American Antiepileptic Drug (NAAED). This registry gathers information about the adverse drug reactions of antiepileptic drugs during pregnancy, enhancing patient safety and outcomes.[35]

As illustrated above, multiple healthcare providers, including clinicians(MDs, DOs, NPs, PAs), specialists, and nurses, are involved in caring for patients receiving fosphenytoin. Therefore an interprofessional team approach would achieve maximum efficacy and minimize adverse drug reactions translating to better patient outcomes. [Level 5]