DOSES OF FOSPHENYTOIN ARE ALWAYS EXPRESSED IN TERMS OF MILLIGRAMS OF PHENYTOIN SODIUM EQUIVALENTS (mg PE). 1 mg PE IS EQUIVALENT TO 1 mg PHENYTOIN SODIUM.

DO NOT, THEREFORE, MAKE ANY ADJUSTMENT IN THE RECOMMENDED DOSES WHEN SUBSTITUTING FOSPHENYTOIN FOR PHENYTOIN SODIUM OR VICE VERSA. FOR EXAMPLE, IF A PATIENT IS RECEIVING 1000 mg PE OF FOSPHENYTOIN, THAT IS EQUIVALENT TO 1000 mg OF PHENYTOIN SODIUM.

The following warnings are based on experience with fosphenytoin or phenytoin.

Dosing Errors 

Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial. 

Medication errors associated with fosphenytoin have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten-fold overdoses of fosphenytoin since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of fosphenytoin should always be expressed in milligrams of phenytoin equivalents (mg PE) (see DOSAGE AND ADMINISTRATION). Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 mL or 500 mg PE/10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of fosphenytoin is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some fosphenytoin medication errors from occurring.

Status Epilepticus Dosing Regimen

Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, do not administer fosphenytoin at a rate greater than 150 mg PE/min.

The dose of IV fosphenytoin (15 to 20 mg PE/kg) that is used to treat status epilepticus is administered at a maximum rate of 150 mg PE/min. The typical fosphenytoin infusion administered to a 50 kg patient would take between 5 and 7 minutes. Note that the delivery of an identical molar dose of phenytoin using parenteral phenytoin sodium or generic phenytoin sodium injection cannot be accomplished in less than 15 to 20 minutes because of the untoward cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min.

If rapid phenytoin loading is a primary goal, IV administration of fosphenytoin is preferred because the time to achieve therapeutic plasma phenytoin concentrations is greater following IM than that following IV administration (see DOSAGE AND ADMINISTRATION).

Cardiovascular Risk Associated with Rapid Infusion

As non-emergency therapy, intravenous fosphenytoin should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV fosphenytoin, oral phenytoin should be used whenever possible. 

Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous fosphenytoin. Reduction in rate of administration or discontinuation of dosing may be needed. 

Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. 

Withdrawal Precipitated Seizure, Status Epilepticus

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Fosphenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan Hypersensitivity below). 

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding fosphenytoin as an alternative for carbamazepine patients positive for HLA-B*1502. 

The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.