Introduction

Following parenteral administration of fosphenytoin, it is converted to the anticonvulsant phenytoin. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin include those of phenytoin. However, the hydrolysis of fosphenytoin to phenytoin yields two 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 labeling.

Mechanism of Action

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

After IV 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 include modulation of voltage-dependent sodium channels 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 and Drug Metabolism

Fosphenytoin

Absorption/Bioavailability: Intravenous: When fosphenytoin is administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion. Fosphenytoin has a half-life of approximately 15 minutes.

Intramuscular: Fosphenytoin is completely bioavailable following IM administration of fosphenytoin. Peak concentrations occur at approximately 30 minutes postdose. Plasma fosphenytoin concentrations following IM

administration are lower but more sustained than those following IV 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 liters.

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 CLINICAL PHARMACOLOGY, Introductionand PRECAUTIONS, Phosphate Load).

Phenytoin (after fosphenytoin administration)

In general, IM 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 IV 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 parenteral phenytoin sodium is administered at 50 mg/min (see DOSAGE AND ADMINISTRATION, WARNINGS).

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

Following administration of single IV 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 IV administration, with a half-life of approximately 15 minutes. Fosphenytoin is also completely converted to phenytoin following IM administration and plasma total phenytoin concentrations peak in approximately 3 hours.

Distribution: Phenytoin is highly bound to plasma proteins, primarily albumin, although to a lesser extent than fosphenytoin. 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).

Metabolism and Elimination: Phenytoin derived from administration of fosphenytoin is extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1% to 5% of the fosphenytoin dose) is recovered in urine. Phenytoin hepatic metabolism is saturable, and following administration of single IV 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 to 28.9 hr) following fosphenytoin administration at these doses are similar to those after equal doses of parenteral phenytoin sodium and tend to be greater at higher plasma phenytoin concentrations.

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 AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. After IV 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. 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 are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION).

Gender and Race: Gender and race have no significant impact on fosphenytoin or phenytoin pharmacokinetics.

Pediatrics: 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.

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 (Table 1).

TABLE 1. Infusion Tolerance of Equivalent
Loading Doses of IV Fosphenytoin and IV 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, IM fosphenytoin was as well-tolerated as IM placebo. IM fosphenytoin resulted in a slight increase in transient, mild to moderate local itching (23% of patients vs 11% of IM placebo-treated patients at any time during the study). This study also demonstrated that equimolar doses of IM fosphenytoin may be substituted for oral phenytoin sodium with no dosage adjustments needed when initiating IM or returning to oral therapy. In contrast, switching between IM and oral phenytoin requires dosage adjustments because of slow and erratic phenytoin absorption from muscle.

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 IV 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 are most commonly encountered in elderly or gravely ill patients. Therefore, careful cardiac monitoring is needed when administering IV 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 these 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.

Usage in Pregnancy

Clinical:

1.

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.

2.

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 develop-mental 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 two- to three-fold that in the general population. However, the relative contributions 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.

1.

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.

Preclinical: Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2 basis), which produced peak maternal plasma phenytoin concentrations of approximately 20 mcg/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however, there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at a nonmaternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats.

No effects on embryo-fetal development were observed when rabbits were given up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.

General

(fosphenytoin specific)

Sensory Disturbances

Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered IV 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 IV fosphenytoin at a dose of 1200 mg PE at the maximum rate of administration (150 mg 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.

IV Loading in Renal and/or Hepatic Disease or in Those With Hypoalbuminemia

After IV 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 CLINICAL PHARMACOLOGY: Special Populations, and DOSAGE AND ADMINISTRATION: 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 the 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 10 to 20 mcg/mL, (unbound phenytoin concentrations of 1 to 2 mcg/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 IV infusion and 4 hours after IM 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 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 pharmacokinetics and protein binding of fosphenytoin, phenytoin, and diazepam were not altered when diazepam and fosphenytoin were concurrently administered in single submaximal doses.

The most significant drug interactions following administration of fosphenytoin are expected to occur with drugs that interact with phenytoin. Phenytoin is extensively bound to serum 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 that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, dicumarol, disulfiram, estrogens, ethosuximide, fluoxetine, H2-antagonists, halothane, isoniazid, methylphenidate, phenothiazines, phenylbutazone, salicylates, succinimides, sulfonamides, tolbutamide, trazodone.

•

Drugs that may decrease plasma phenytoin concentrations include: carbamazepine, chronic alcohol abuse, reserpine.

•

Drugs that may either increase or decrease plasma phenytoin concentrations include: phenobarbital, valproic acid, and sodium valproate. Similarly, the effects of phenytoin on phenobarbital, valproic acid and sodium plasma valproate concentrations are unpredictable.

•

Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and fosphenytoin dosage may need to be adjusted.

•

Drugs whose efficacy is impaired by phenytoin include: anticoagulants, corticosteroids, coumarin, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, rifampin, quinidine, theophylline, vitamin D.

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 also 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).

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of fosphenytoin has not been studied. Assessment of the carcinogenic potential of phenytoin in mice and rats is ongoing.

Structural chromosome aberration frequency in cultured V79 Chinese hamster lung cells was increased by exposure to fosphenytoin in the presence of metabolic activation. No evidence of mutagenicity was observed in bacteria (Ames test) or Chinese hamster lung cells in vitro, and no evidence for clastogenic activity was observed in an in vivo mouse bone marrow micronucleus test.

No effects on fertility were noted in rats of either sex given fosphenytoin. Maternal toxicity and altered estrous cycles, delayed mating, prolonged gestation length, and developmental toxicity were observed following administration of fosphenytoin during mating, gestation, and lactation at doses of 50 mg PE/kg or higher (approximately 40% of the maximum human loading dose or higher on a mg/m2 basis).

Pregnancy

Teratogenic Effects; Category D: (see WARNINGS)

Nursing Mothers

It is not known whether fosphenytoin is excreted in human milk.

Following administration of phenytoin sodium, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breast-feeding is not recommended for women receiving fosphenytoin.

Pediatric Use

The safety of fosphenytoin in pediatric patients has not been established.

Geriatric Use

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

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 - IV Administration to Patients With Epilepsy or Neurosurgical Patients: Table 2 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with IV 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 2. Treatment-Emergent Adverse Event Incidence Following IV 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 - IM Administration to Patients With Epilepsy: Table 3 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 IM fosphenytoin substituted for oral phenytoin sodium or continuing oral phenytoin sodium. Both treatments were administered for 5 days.

TABLE 3. Treatment-Emergent Adverse Event Incidence Following Substitution of IM 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 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 infarction, 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.

Dosing in 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 CLINICAL PHARMACOLOGY: Special Populations). Unbound phenytoin concentrations may be more useful in these patient populations. After IV fosphenytoin 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 PRECAUTIONS).

Elderly Patients: Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

Pediatric: The safety of fosphenytoin in pediatric patients has not been established.