PHARMACOLOGY

Introduction: Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin. For every mmol of fosphenytoin administered, 1 mmol of phenytoin is produced.
The pharmacological and toxicological effects of fosphenytoin include those of phenytoin. However, the hydrolysis of fosphenytoin to phenytoin yields 2 metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which is in turn metabolized via a folate dependent mechanism. Although phosphate and formaldehyde (formate) have potentially important biological effects, these effects typically occur at concentrations considerably in excess of those obtained when fosphenytoin is administered under conditions of use recommended in this labelling.

Mechanism of Action: Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin.

After i.v. administration to mice, fosphenytoin blocked the tonic phase of maximal electroshock seizures at doses equivalent to those effective for phenytoin. In addition to its ability to suppress maximal electroshock seizures in mice and rats, phenytoin exhibits anticonvulsant activity against kindled seizures in rats, audiogenic seizures in mice, and seizures produced by electrical stimulation of the brainstem in rats. The cellular mechanisms of phenytoin thought to be responsible for its anticonvulsant actions includemodulation of voltage-dependent sodiumchannels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and enhancement of the sodium-potassium ATPase activity of neurons and glial cells. The modulation of sodium channels may be a primary anticonvulsant mechanism because this property is shared with several other anticonvulsants in addition to phenytoin.

Pharmacokinetics: Drug Metabolism: Fosphenytoin: Absorption/Bioavailability: I.V.: When fosphenytoin is administered by i.v. infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion.
Fosphenytoin has a half-life of approximately 15 minutes.
I.M.: Fosphenytoin is completely bioavailable following i.m. administration of fosphenytoin. Peak concentrations occur at approximately 30 minutes postdose. Plasma fosphenytoin concentrations following i.m. administration are lower but more sustained than those following i.v. administration due to the time required for absorption of fosphenytoin from the injection site.

Distribution: Fosphenytoin is extensively bound (95 to 99%) to human plasma proteins, primarily albumin. Binding to plasma proteins is saturable with the result that the percent bound decreases as total fosphenytoin concentrations increase. Fosphenytoin displaces phenytoin from protein binding sites. The volume of distribution of fosphenytoin increases with fosphenytoin dose and rate, and ranges from 4.3 to 10.8 L.

Metabolism and Elimination: The conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes.
The mechanism of fosphenytoin conversion has not been determined, but phosphatases probably play a major role. Fosphenytoin is not excreted in urine. Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate (see Introduction and Precautions, Phosphate Load for Renally Impaired Patients).

Phenytoin (after Fosphenytoin Administration): In general, i.m. administration of fosphenytoin generates systemic phenytoin concentrations that are similar enough to oral phenytoin sodium to allow essentially interchangeable use.
The pharmacokinetics of fosphenytoin following i.v. administration of fosphenytoin, however, are complex, and when used in an emergency setting (e.g., status epilepticus), differences in rate of availability of phenytoin could be critical. Studies have therefore empirically determined an infusion rate for fosphenytoin that gives a rate and extent of phenytoin systemic availability similar to that of a 50 mg/min phenytoin sodium infusion.
A dose of 15 to 20 mg PE/kg of fosphenytoin infused at 100 to 150 mg PE/min yields plasma free phenytoin concentrations over time that approximate those achieved when an equivalent dose of phenytoin sodium (e.g., parenteral phenytoin sodium) is administered at 50 mg/min (see Dosage and Warnings). See Figure 1.

Figure 1: Cerebyx
Mean plasma unbound phenytoin concentrations following i.v. administration of 1200 mg PE of CEREBYX infused at 100mg PE/min (triangles) or 150 mg PE/min (squares) and 1200 mg phenytoin sodium infused at 50mg/min (diamonds) to healthy subjects (N = 12). Inset shows time course for the entire 96-hour sampling period.

Following administration of single i.v. fosphenytoin doses of 400 to 1200 mg PE, mean maximum total phenytoin concentrations increase in proportion to dose, but do not change appreciably with changes in infusion rate. In contrast, mean maximum unbound phenytoin concentrations increase with both dose and rate.

Absorption/Bioavailability: Fosphenytoin is completely converted to phenytoin following i.v. administration, with a half-life of approximately 15 minutes. Fosphenytoin is also completely converted to phenytoin following i.m. administration and plasma total phenytoin concentrations peak in approximately 3 hours.

Distribution: Phenytoin has an apparent volume of distribution of 0.6 L/kg and is highly bound (90%) to plasma proteins, primarily albumin. Free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. In the absence of fosphenytoin, approximately 12% of total plasma phenytoin is unbound over the clinically relevant concentration range. However, fosphenytoin displaces phenytoin from plasma protein binding sites. This increases the fraction of phenytoin unbound (up to 30% unbound) during the period required
for conversion of fosphenytoin to phenytoin (approximately 0.5 to 1 hour postinfusion). Following administration ofsingle i.v. fosphenytoin doses of 400 to 1200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose. Mean total phenytoin half-life values (12.0 to 28.9 hr) following fosphenytoin administration at these doses are similar to those after equal doses of parenteral phenytoin and tend to be greater at higher plasma phenytoin concentrations. The concentration of phenytoin in cerebrospinal fluid, brain, and saliva approximates the
level of free phenytoin in plasma.

Metabolism and Elimination: Phenytoin is biotransformed in the liver by oxidative metabolism. The major pathway involves 4-hydroxylation, which accounts for 80% of all metabolites. CYP2C9 plays the major role in the metabolism of phenytoin (90% of net intrinsic clearance), while CYP2C19 has a minor involvement in this process (10% of net intrinsic clearance). This relative contribution of CYP2C19 to phenytoin metabolism may however increase at higher phenytoin concentrations. Because the cytochrome systems involved in phenytoin hydroxylation in the liver are saturable at high serum concentrations, small incremental doses of phenytoin may increase the half-life
and produce very substantial increases in serum levels when these are in or above the upper therapeutic range.
The clearance of phenytoin has been shown to be impaired by CYP2C9 inhibitors such as phenylbutazone and sulphaphenazole. Impaired clearance has also been shown to occur in patients administered CYP2C19 inhibitors such as ticlopidine.
Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and eliminated in the urine partly through glomerular filtration but, more importantly via tubular secretion. Less than 5% of the dose is excreted as unchanged phenytoin.

Special Populations: Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see Dosage). Unbound phenytoin concentrations may be more useful in these patient populations. After i.v. administration of fosphenytoin to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar
increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see Precautions).

Age: The effect of age was evaluated in patients 5 to 98 years of age, however, no systematic studies in geriatric patients have been conducted. Patient age had no significant impact on fosphenytoin pharmacokinetics. Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Phenytoin dosing requirements vary between patients and must be individualized (see Dosage).

Gender and Race: Gender and race have no significant impact on fosphenytoin or phenytoin pharmacokinetics.
Clinical Studies: Infusion tolerance was evaluated in clinical studies. One double-blind study assessed infusion-site tolerance of equivalent loading doses (15 to 20 mg PE/kg) of fosphenytoin infused at 150 mg PE/min or phenytoin infused at 50 mg/min. The study demonstrated better local tolerance (pain and burning at the infusion site), fewer disruptions of the infusion, and a shorter infusion period for fosphenytoin-treated patients (see Table 1).

Table 1: Cerebyx
Infusion Tolerance of Equivalent Loading Doses of I.V. Fosphenytoin and I.V. Phenytoin

a Percent of patients.

Fosphenytoin-treated patients, however, experienced more systemic sensory disturbances (see Precautions, Sensory Disturbances). Infusion disruptions in fosphenytoin-treated patients were primarily due to systemic burning, pruritus, and/or paresthesia while those in phenytoin-treated patients were primarily due to pain and burning at the infusion site (see Table 1).

In a double-blind study investigating temporary substitution of fosphenytoin for oral phenytoin, i.m. fosphenytoin was as well-tolerated as i.m. placebo. I.M. fosphenytoin resulted in a slight increase in transient, mild to moderate local itching (23% of patients versus 11% of i.m. placebo-treated patients at any time during the study). This study also demonstrated that equimolar doses of i.m. fosphenytoin may be substituted for oral phenytoin sodium with no dosage adjustments needed when initiating i.m. or returning to oral therapy. In contrast, switching between i.m. and oral phenytoin requires dosage adjustments because of slow and erratic phenytoin absorption from muscle.

INDICATIONS

For short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate or deemed less advantageous. The safety and effectiveness of fosphenytoin in this use has not been systematically evaluated for more than 5 days.
Fosphenytoin can be used for the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery. It can also be substituted, short-term, for oral phenytoin.

CONTRAINDICATIONS

Patients who have demonstrated hypersensitivity to fosphenytoin or its ingredients, or phenytoin or other hydantoins.
Because of the effect of parenteral phenytoin on ventricular automaticity, fosphenytoin is contraindicated in patients with sinus bradycardia, sino-atrial block, second- and third-degree AV block, and Adams-Stokes syndrome.

WARNINGS

Doses of fosphenytoin are expressed as their phenytoin sodium equivalents in this monograph (PE=phenytoin sodium equivalent).
Do not, therefore, make any adjustment in the recommended doses when substituting fosphenytoin for phenytoin sodium or vice versa.
The following warnings are based on experience with fosphenytoin or phenytoin.
Status Epilepticus Dosing Regimen: Do not administer fosphenytoin at a rate greater than 150 mg PE/min.
The dose of i.v. 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 Dilantin 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 i.v. administration of phenytoin at rates greater than 50 mg/min. If rapid phenytoin loading is a primary goal, i.v. administration of fosphenytoin is preferred because the time to achieve therapeutic plasma phenytoin concentrations is greater following i.m. than that following i.v. administration (see Dosage).

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.

Cardiovascular Depression: Hypotension may occur, especially after i.v. administration at high doses and high rates of administration. Following administration of phenytoin, severe cardiovascular reactions and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications aremost commonly encountered in elderly or gravely ill patients. Therefore, careful cardiac monitoring is needed when administering i.v. loading doses of fosphenytoin. Reduction in rate of administration or discontinuation of dosing may be needed.
Fosphenytoin should be used with caution in patients with hypotension and severe myocardial insufficiency.

Rash: Fosphenytoin should be discontinued if a skin rash appears. If the rash is exfoliative, purpuric, or bullous, or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered. If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further fosphenytoin or phenytoin administration is contraindicated.

Hepatic Injury: Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These incidents have been associated with a hypersensitivity syndrome characterized by fever, skin eruptions, and lymphadenopathy, and usually occur within the first 2 months of treatment. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In patients with acute hepatotoxicity, fosphenytoin should be immediately discontinued and not readministered.

Hemopoietic System: Hemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports that have suggested a relationship between phenytoin and the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, e.g., fever, rash, and liver involvement. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Alcohol Use: Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may decrease plasma concentrations.

Pregnancy: Clinical: Risks to Mother: An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see Precautions, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated.

Risks to the Fetus: If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported
cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or 2- to 3-fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.
Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy and to select the regimen which would provide the least risk to mother and fetus.

Postpartum Period: 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 to the neonate after birth.

PRECAUTIONS

General (Fosphenytoin Specific): Sensory Disturbances: Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered i.v. fosphenytoin at a dose of 1200 mg PE at the maximum rate of administration (150 mg PE/min). The severe sensory disturbance lasted from 3 to 50 minutes in 6 of these subjects and for 14 hours in the seventh subject. In some cases, milder sensory disturbances persisted for as long as 24 hours. The location of the discomfort varied among subjects with the groin mentioned most frequently as an
area of discomfort. In a separate cohort of 16 normal volunteers (taken from 2 other studies) who were administered i.v. fosphenytoin at a dose of 1200mg PE at themaximumrate of administration (150mg PE/min), none experienced severe disturbances, but most experienced mild to moderate itching or tingling.

Patients administered fosphenytoin at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree. The occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion.

The effect of continuing infusion unaltered in the presence of these sensations is unknown. No permanent sequelae have been reported thus far. The pharmacologic basis for these positive sensory phenomena is unknown, but other phosphate ester drugs, which deliver smaller phosphate loads, have been associated with burning, itching, and/or tingling predominantly in the groin area.
Phosphate Load: The phosphate load provided by fosphenytoin (0.0037 mmol phosphate/mg PE fosphenytoin) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment.

I.V. Loading in Renal and/or Hepatic Disease or in ThoseWith Hypoalbuminemia: After i.v. administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see Pharmacology, Special Populations and Dosage, Dosing in Special Populations).

General (Phenytoin Associated): Fosphenytoin is not indicated for the treatment of absence seizures.
A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined.
Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity.

Additionally, caution should be exercised if using structurally similar (e.g., barbiturates, succinimides, oxazolidinediones, and other related compounds) in these same patients.
Phenytoin has been infrequently associated with the exacerbation of porphyria. Caution should be exercised when fosphenytoin is used in patients with this disease.
Hyperglycemia, resulting from phenytoin’s inhibitory effect on insulin release, has been reported. Phenytoin may also raise serum glucose concentrations in diabetic patients. Plasma concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium”, “psychosis”, or “encephalopathy”, or rarely, irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, determination of plasma phenytoin concentrations is recommended (see Precautions Laboratory Tests). Fosphenytoin dose reduction is
indicated if phenytoin concentrations are excessive; if symptoms persist, administration of fosphenytoin should be discontinued.
The liver is the primary site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. Phenytoin and other hydantoins are not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.
Phenytoin has the potential to lower serum folate levels.

Laboratory Tests: Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 40 to 80 µmol/L (10 to 20 µg/mL), (unbound phenytoin concentrations of 4 to 8 µmol/L (1 to 2 µg/mL)). Following fosphenytoin administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of i.v. infusion and 4 hours after i.m. injection.

Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx/TDxFLx (fluorescence polarization) and Emit 2000 (enzyme multiplied), may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. The TDx/TDxFLx assay is not recommended while unconverted fosphenytoin is present in plasma, due to an unacceptable margin of error (overestimation) in the phenytoin measurement.
The difference between predicted and actual phenytoin concentrations at 4 hours postdose is =20 µmol/L (=5 µg/mL). The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by fosphenytoin dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved.

Drug Interactions: No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. Conversion could be affected by alterations in the level of phosphatase activity, but given the abundance and wide distribution of phosphatases in the body it is unlikely that drugs would affect this activity enough to affect conversion of fosphenytoin to phenytoin. Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin. Although, it is unknown whether this could result in clinically significant effects, caution is advised when administering fosphenytoin with other drugs that significantly bind to serum albumin.

The most significant drug interactions following administration of fosphenytoin are expected to occur with drugs that interact with phenytoin. Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement.
Phenytoin is metabolized by hepatic cytochrome P450 enzymes and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.
The most commonly occurring drug interactions are listed below.

Drugs which may increase phenytoin serum levels: Various drugs which may increase phenytoin serum levels either by decreasing its rate of metabolism by the hepatic CYP450 2C9 and 2C19 enzymatic systems (e.g., omeprazole, ticlopidine), by competing for protein binding sites (e.g. salicylates, sulfisoxazole, tolbutamide), or by a combination of both processes (e.g. phenylbutazone, valproate sodium). The following drug classes are also included. Table 2 summarizes the drug classes which may potentially increase phenytoin serum levels:

Table 2: Cerebyx

Drugs which may decrease phenytoin plasma levels: Table 3 summarizes the drug classes which may potentially decrease phenytoin plasma levels:

Table 3: Cerebyx

Drugs which may either increase or decrease phenytoin serum levels: Table 4 summarizes the drug classes which may either increase or decrease phenytoin serum levels:

Table 4: Cerebyx

Similarly, the effects of phenytoin on carbamazepine, phenobarbital, valproic acid and sodium plasma valproate concentrations are unpredictable.
Drugs which blood levels and/or effects may be altered by phenytoin: Table 5 summarizes the drug classes which blood levels and/or effects may be altered by phenytoin:

Table 5: Cerebyx

Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and fosphenytoin dosage may need to be adjusted.
Coadministration of phenytoin with lamotrigine doubles the plasma clearance and reduces the elimination half-life of lamotrigine by 50%. This clinically important interaction requires dosage adjustment.
Monitoring of plasma phenytoin concentrations may be helpful when possible drug interactions are suspected (see Laboratory Tests).

Drug/Laboratory Test Interactions: Phenytoin may decrease serum concentrations of T4. It may also produce artifactually low results in dexamethasone or metyrapone tests. Phenytoin may cause increased serum concentrations of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).
Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration (see Laboratory Tests).

Lactation: It is not known whether fosphenytoin is excreted in human milk.
Following administration of Dilantin, phenytoin appears to be excreted in low concentrations in human milk.
Therefore, breast-feeding is not recommended for women receiving fosphenytoin.

Children: The safety of fosphenytoin in pediatric patients has not been established. Only limited pharmacokinetic data are available in children (N=8; age 5 to 10 years). In these patients with status epilepticus who received loading doses of fosphenytoin, the plasma fosphenytoin, total phenytoin, and unbound phenytoin concentration-time profiles did not signal any major differences from those in adult patients with status epilepticus receiving comparable doses.

Geriatrics: No systematic studies in geriatric patients have been conducted. Phenytoin clearance tends to decrease with increasing age (see Pharmacology, Special Populations).

Occupational Hazards: Effects on Ability to Drive and Operate Machines: Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that this medication does not affect their ability to engage in these activities.

ADVERSE EFFECTS

The more important adverse clinical events caused by the i.v. use of fosphenytoin or phenytoin are cardiovascular collapse and/or CNS depression. Hypotension can occur when either drug is administered rapidly by the i.v. route. The rate of administration is very important; for fosphenytoin, it should not exceed 150 mg PE/min.

The adverse clinical events most commonly observed with the use of fosphenytoin in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With 2 exceptions, these events are commonly associated with the administration of i.v. phenytoin. Paresthesia and pruritus, however, were seen much more often following fosphenytoin administration and occurred more often with i.v. fosphenytoin administration than with i.m. fosphenytoin administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of =15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of fosphenytoin infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting
an allergic process were not seen (see Precautions, Sensory Disturbances).

Approximately 2% of the 859 individuals who received fosphenytoin in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).
Dose and Rate Dependency of Adverse Events Following I.V. Fosphenytoin: The incidence of adverse events tended to increase as both dose and infusion rate increased. In particular, at doses of =15 mg PE/kg and rates =150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates.

Incidence in Controlled Clinical Trials: All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the tables and listings below with the frequencies representing the proportion of individuals exposed to fosphenytoin or comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the
course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

Incidence in Controlled Clinical Trials—I.V. Administration To Patients With Epilepsy or Neurosurgical Patients:
Table 6 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with i.v. fosphenytoin at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and fosphenytoin administration would have resulted in equivalent systemic exposure to phenytoin.

Table 6: Cerebyx

Treatment-emergent Adverse Event Incidence Following I.V. Administration at the Maximum Dose and Rate to Patients With Epilepsy or Neurosurgical Patients (Events in at Least 2% of Fosphenytoin-treated Patients)

Incidence in Controlled Trials—I.M. Administration to Patients With Epilepsy: Table 7 lists treatment-emergent adverse events that occurred in at least 2% of fosphenytoin-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either i.m. fosphenytoin substituted for oral phenytoin sodium or continuing oral phenytoin sodium. Both treatments were administered for 5 days.

Table 7: Cerebyx
Treatment-emergent Adverse Event Incidence Following Substitution of I.M. Fosphenytoin for Oral phenytoin sodium in Patients With Epilepsy (Events in at Least 2% of Fosphenytoin-treated Patients)

Adverse Events During All Clinical Trials: Fosphenytoin has been administered to 859 individuals during all clinical trials. All adverse events seen at least twice are listed in the following, except those already included in previous tables and listings. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 individuals; infrequent adverse events are those occurring in 1/100 to 1/1000 individuals.

Body As a Whole: Frequent: fever, injection-site reaction, infection, chills, face edema, injection-site pain. Infrequent: sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis.

Cardiovascular: Frequent: hypertension. Infrequent: cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation, sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly, cerebral infarct, postural hypotension, pulmonary embolus, QT interval prolongation, thrombophlebitis, ventricular extrasystoles, congestive heart failure.

Digestive: Frequent: constipation. Infrequent: dyspepsia, diarrhea, anorexia, gastrointestinal hemorrhage, increased salivation, liver function tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis, ileus.

Endocrine: Infrequent: diabetes insipidus.

Hematologic and Lymphatic: Infrequent: thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia.

Metabolic and Nutritional: Frequent: hypokalemia. Infrequent: hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis.

Musculoskeletal: Frequent: myasthenia. Infrequent: myopathy, leg cramps, arthralgia, myalgia.

Nervous: Frequent: reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness, hypesthesia. Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, brain edema, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis.

Respiratory: Frequent: pneumonia. Infrequent: pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased, epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis.

Skin and Appendages: Frequent: rash. Infrequent: maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule.

Special Senses: Frequent: taste perversion. Infrequent: deafness, visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss.

Urogenital: Infrequent: urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis.

Post-Marketing Experience: There have been post-marketing reports of anaphylactoid reaction, anaphylaxis, confusion, and dyskinesia.

OVERDOSAGE

The median lethal dose of fosphenytoin given i.v. in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.

Symptoms: Because fosphenytoin is a prodrug of phenytoin, the following information may be helpful. Initial symptoms of acute phenytoin toxicity are nystagmus, ataxia and dysarthria. Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma and hypotension. Depression of respiratory and circulatory systems leads to death. There are marked variations among individuals with respect to plasma phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 80 µmol/L (20 µg/mL), ataxia at 120 µmol/L
(30 µg/mL), and dysarthria and lethargy appear when the plasma concentration is over 160 µmol/L (40 µg/mL).

However, phenytoin concentrations as high as 200 µmol/L (50 µg/mL) have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in plasma phenytoin concentrations over 400 µmol/L (100 µg/mL), with complete recovery.
Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis and death have been reported in cases of overdosage with fosphenytoin.

Treatment: Treatment is nonspecific since there is no known antidote to fosphenytoin or phenytoin overdosage.
The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins.
Total exchange transfusion has been used in the treatment of severe intoxication in children. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
Formate and phosphate are metabolites of fosphenytoin and thereforemay contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with severe aniongap metabolic acidosis. Large amounts of phosphate, delivered rapidly, could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. Ionized free calcium levels can be measured and, if low, used to guide treatment.

DOSAGE

The dose, concentration in dosing solutions, and infusion rate of i.v. fosphenytoin is expressed as phenytoin sodium equivalents (PE) to avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). Fosphenytoin has important differences in administration from those for parenteral phenytoin sodium (see below).
Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 40 to 80 µmol/L (10 to 20 µg/mL), (unbound phenytoin concentrations of 4 to 8 µmol/L (1 to 2 µg/mL)). Following fosphenytoin administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of i.v. infusion and 4 hours after i.m. injection.

Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx/TDxFLx (fluorescence polarization) and Emit 2000 (enzyme multiplied), may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. The TDx/TDxFLx assay is not recommended due to an unacceptable margin of error. The difference between predicted and actual phenytoin concentrations at 4 hours postdose is =20 µmol/L (=5 µg/mL). The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by fosphenytoin dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples fo