PRESCRIBING INFORMATION PRODUCT MONOGRAPH

CEREBYX *

(Fosphenytoin Sodium Injection, 75 mg/mL

)

Equivalent to 50 mg/mL Phenytoin Sodium

ANTIEPILEPTIC AGENT

DATE OF PREPARATION: July 5, 2005 DATE OF REVISION: Control No. 099616

NAME OF DRUG

CEREBYX * (Fosphenytoin Sodium Injection, 75 mg/mL) Equivalent to 50 mg/mL Phenytoin Sodium

PHARMACOLOGIC CLASSIFICATION

ANTIEPILEPTIC AGENT

IMPORTANT NOTE:

Throughout all CEREBYX

ACTIONS AND CLINICAL PHARMACOLOGY

Introduction

Following parenteral administration of CEREBYX (Fosphenytoin Sodium Injection), fosphenytoin 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 CEREBYX 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 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 CEREBYX 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 CEREBYX. 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 CEREBYX dose and rate, and ranges from 4.3 to 10.8 litres.

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, Introduction and PRECAUTIONS, Phosphate Load for Renally Impaired Patients).

Phenytoin (after CEREBYX Administration)

In general, IM administration of CEREBYX 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 CEREBYX, however, are complex, and when used in an emergency setting (eg, status epilepticus), differences in rate of availability of phenytoin could be critical. Studies have therefore empirically determined an infusion rate for CEREBYX 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 CEREBYX 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 (eg, 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 of CEREBYX infused at 100 mg PE/min (triangles) or 150 mg PE/min (squares) and 1200 mg Dilantin 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 CEREBYX 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 has an apparent volume of distribution of 0.6L/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 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 (12.0 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 intestival 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 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, 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 20-30 years of age). Phenytoin dosing requirements vary between patients and must be individualized (see DOSAGE AND ADMINISTRATION).

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 (15-20 mg PE/kg) of CEREBYX 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 CEREBYX- treated patients (Table 1).

TABLE 1. Infusion Tolerance of Equivalent Loading Doses of IV CEREBYX and IV Phenytoin

IV CEREBYX N = 90 IV Phenytoin N = 22 Local Intolerance 9%a 90% Infusion Disrupted 21% 67% Average Infusion Time 13 min 44 min

a

Percent of patients.

CEREBYX-treated patients, however, experienced more systemic sensory disturbances (see PRECAUTIONS, Sensory Disturbances). Infusion disruptions in CEREBYX-treated patients were primarily due to systemic burning, pruritus, and/or paraesthesia 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 CEREBYX for oral phenytoin, IM CEREBYX was as well-tolerated as IM placebo. IM CEREBYX resulted in a slight increase in transient, mild to moderate local itching (23% of patients versus 11% of IM placebo-treated patients at any time during the study). This study also demonstrated that equimolar doses of IM CEREBYX 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.

CONTRAINDICATIONS

CEREBYX (Fosphenytoin Sodium Injection) is contraindicated in patients who have demonstrated hypersensitivity to CEREBYX or its ingredients, or phenytoin or other hydantoins. Because of the effect of parenteral phenytoin on ventricular automaticity, CEREBYX is contraindicated in patients with sinus bradycardia, sino-atrial block, second- and third-degree A-V block, and Adams-Stokes syndrome.

WARNINGS

DOSES OF CEREBYX (FOSPHENYTOIN SODIUM INJECTION) 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 CEREBYX FOR PHENYTOIN SODIUM OR VICE VERSA.

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

Status Epilepticus Dosing Regimen

Do not administer CEREBYX at a rate greater than 150 mg PE/min.

The dose of IV CEREBYX (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 CEREBYX 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 intravenous administration of phenytoin at rates greater than 50 mg/min.

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

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 judgement 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 CEREBYX. Reduction in rate of administration or discontinuation of dosing may be needed. CEREBYX should be used with caution in patients with hypotension and severe myocardial insufficiency.

Rash

CEREBYX 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 CEREBYX 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, leucocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In patients with acute hepatotoxicity, CEREBYX 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, leucopenia, 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, eg, 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.

Use 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 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 two- to three- 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: (CEREBYX Specific)

Sensory Disturbances

Severe burning, itching, and/or paraesthesia were reported by 7 of 16 normal volunteers administered IV CEREBYX (Fosphenytoin Sodium Injection) 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 CEREBYX 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 CEREBYX 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 CEREBYX (0.0037 mmol phosphate/mg PE CEREBYX) 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)

CEREBYX 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 (eg, 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 CEREBYX 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). CEREBYX dose reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, administration of CEREBYX 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 umol/L [10 to 20 ug/mL], (unbound phenytoin concentrations of 4 to 8 umol/L [1 to 2 ug/mL]). Following CEREBYX 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 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 umol/L [<=5 ug/mL] The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by CEREBYX 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 CEREBYX with other drugs that significantly bind to serum albumin. The most significant drug interactions following administration of CEREBYX 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 1 summarizes the drug classes which may potentially increase phenytoin serum levels:

Drugs which may decrease phenytoin plasma levels

Table 2 summarizes the drug classes which may potentially decrease phenytoin plasma levels:

Drugs which may either increase or decrease phenytoin serum levels

Table 3 summarizes the drug classes which may either increase or decrease phenytoin serum levels:

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 4 summarizes the drug classes which blood levels and/or effects may be altered by phenytoin:

Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and CEREBYX 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 CEREBYX administration (see Laboratory Tests).

Use in Nursing Mothers

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 CEREBYX.

Use in Children

The safety of CEREBYX 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 CEREBYX, 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.

Use in the Elderly

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

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.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

The median lethal dose of fosphenytoin given intravenously 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, laboured breathing, ptosis, and hypoactivity.

Symptoms:

Because CEREBYX (Fosphenytoin Sodium Injection) 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 umol/L [20 ug/mL], ataxia at 120 umol/L [30 ug/mL], and dysarthria and lethargy appear when the plasma concentration is over 160 umol/L [40 ug/mL]. However, phenytoin concentrations as high as 200 umol/L [50 ug/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 umol/L [100 ug/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 CEREBYX.

Treatment:

Treatment is nonspecific since there is no known antidote to CEREBYX 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 therefore may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with severe anion-gap metabolic acidosis. Large amounts of phosphate, delivered rapidly, could potentially cause hypocalcemia with paraesthesia, muscle spasms, and seizures. Ionized free calcium levels can be measured and, if low, used to guide treatment.

DOSAGE AND ADMINISTRATION

The dose, concentration in dosing solutions, and infusion rate of IV CEREBYX (Fosphenytoin Sodium Injection) 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. CEREBYX should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). CEREBYX 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 40-80 umol/L [10 to 20 ug/mL], (unbound phenytoin concentrations of 4-8 umol/L [1 to 2 ug/mL]. Following CEREBYX 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 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 umol/L [5 ug/mL]. The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by CEREBYX 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. Products with particulate matter or discolouration should not be used. Prior to IV infusion, dilute CEREBYX in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL.

Status Epilepticus

The loading dose of CEREBYX is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of CEREBYX infusions. Because the full antiepileptic effect of phenytoin, whether given as CEREBYX or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of CEREBYX, or phenytoin, either orally or parenterally. If administration of CEREBYX does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered. IM CEREBYX should not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration. If IV access is impossible, loading doses of CEREBYX have been given by the IM route for other indications.

Non-emergent Loading and Maintenance Dosing

The loading dose of CEREBYX is 10 - 20 mg PE/kg given IV or IM. The rate of administration for IV CEREBYX should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of CEREBYX infusions. The initial daily maintenance dose of CEREBYX is 4 - 6 mg PE/kg/day.

IM or IV Substitution For Oral Phenytoin Therapy

CEREBYX can be substituted for oral phenytoin sodium therapy at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as CEREBYX, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV CEREBYX is substituted for oral phenytoin sodium therapy. The rate of administration for IV CEREBYX should be no greater than 150 mg PE/min. In controlled trials, IM CEREBYX was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.

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 CEREBYX 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 CEREBYX administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

Pediatric:

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

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Fosphenytoin Sodium, Heptahydrate Chemical Name: 5,5-diphenyl-3-[(phosphonooxy)methyl]-2-4-imidazolidinedione disodium heptahydrate salt Molecular formula: C16H13N2O6PNa2i7H2O Molecular weight: 532.35 Molecular structure:

H2O

Description: White to pale yellow solid. Freely soluble in buffer over a pH range of 5.0 to 9.0. Dissociation Constants: pKa = 6.2

Composition

Each CEREBYX (Fosphenytoin Sodium Injection) vial contains 75 mg/mL fosphenytoin sodium as heptahydrate, equivalent to 50 mg/mL phenytoin sodium after administration. Each vial also contains Water for Injection and tromethamine buffer (12 mg/mL) adjusted to pH 8.6 to 9.0 with either hydrochloric acid or sodium hydroxide.

Stability and Storage Recommendations

Store under refrigeration at 2deg to 8degC. The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should be discarded.

Compatibility

CEREBYX added to 5% dextrose or 0.9% saline solution for injection in a concentration range from 2.5 to 40 mg/mL is stable for 8 hours at room temperature or 24 hours when stored under refrigeration (2deg to 8degC). CEREBYX is for parenteral use only. As with all parenteral formulations, CEREBYX vials should be inspected visually for particulate matter and discolouration before administration whenever solution and container permit. Products with particulate matter or discolouration should be discarded.

AVAILABILITY OF DOSAGE FORMS

CEREBYX (Fosphenytoin Sodium Injection, 75 mg/mL) is supplied in 2 mL or 10 mL single-dose vials: 2 mL Vials: Packages of 5 vials (equivalent to 100 mg phenytoin sodium per 2 mL vial, or 50 mg/mL) 10 mL Vials: Packages of 1 vial (equivalent to 500 mg phenytoin sodium per 10 mL vial, or 50 mg/mL).

PHARMACOLOGY

Animal Pharmacology

In the maximal electroshock test with rodents, fosphenytoin and phenytoin are equipotent anticonvulsants on a molar basis. The time course of anticonvulsant actions for fosphenytoin and phenytoin do not differ greatly in mice. Fosphenytoin and phenytoin have approximately equipotent antiarrhythmic activity in vivo, but phenytoin is more potent in most in vitro tests. These data suggest that the predominant pharmacological actions of fosphenytoin are due to metabolic conversion of fosphenytoin to phenytoin and subsequent action of phenytoin on pharmacologically relevant sites in brain or cardiovascular tissue. Both phenytoin and fosphenytoin prevent ischemic brain damage in several models of cerebral stroke. Fosphenytoin is highly bound (>91%) to dog and human plasma proteins, predominantely to albumin. Absolute bioavailability of IM fosphenytoin is essentially 100% in dog, based on phenytoin AUC data. Phenytoin pharmacokinetic parameters are similar in dogs following IV fosphenytoin and phenytoin administration. [14C]Fosphenytoin radioequivalents are not retained by rodent tissues. IM fosphenytoin does not cause tissue damage to dog hindlimb muscles nor drug precipitation at the injection site. Fosphenytoin is rapidly converted in vivo to phenytoin by phosphatases in rat and dog. Metabolism and urinary excretion profile of IV fosphenytoin and phenytoin are similar in dog. 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) glucuronide is the major metabolite in rat urine; whereas 5-(m-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) glucuronide is the major urinary metabolite in dog. Urinary excretion is the major elimination pathway of [14C]fosphenytoin and its metabolites in rat. At toxicologically relevant doses, total phenytoin exposure in rats following IM fosphenytoin is reduced slightly relative to an IV dose, while phenytoin exposure in dogs is similar following IM and IV fosphenytoin.

TOXICOLOGY

The results of animal toxicology studies (acute, multiple-dose, reproductive, and genetic toxicity) are summarized in Tables 4-10. The toxicologic profile of the prodrug fosphenytoin is similar to that of phenytoin. Generally, CNS effects were seen at equimolar doses with both compounds. Effects on serum hepatic enzymes and liver weights observed in multidose studies in rats and dogs with fosphenytoin are known effects of phenytoin in animals and are consistent with microsomal enzyme induction. Microscopic changes in the liver were attributed to increased cellular glycogen content and secondary to phenytoin-induced hyperglycemia which occurs after fosphenytoin administration. Malformations seen in rats given fosphenytoin are consistent with those seen in rats given phenytoin. The clastogenic effects of fosphenytoin in vitro are not linked to mutagenic activity as both the bacterial and mammalian cell mutagenicity assays were negative. Because the clastogenic activity of fosphenytoin was restricted to an in vitro assay at concentrations considerably higher than maximum therapeutic plasma concentrations of 20 ug/mL and clastogenic activity was not detected in vivo at doses which substantially exceed the maximum therapeutic dose, the in vitro clastogenic activity of fosphenytoin was not considered biologically relevant. Local irritation following IV or IM administration was less severe with fosphenytoin than with phenytoin.

TABLE 4. Fosphenytoin Single-Dose Toxicity Studies in Rodents

(Page 1 of 2)

IV = Intravenous; SAL = Saline (0.9% NaCl) control; VC = Vehicle control; NOED = No observed effect dose; MNLD = Maximum nonlethal dose; MLD = Combined-sex median lethal dose; SD = Sprague-Dawley.

1. Dose expressed as milligram/kilogram phenytoin equivalents. Approximate fosphenytoin dose can be derived by multiplying the

phenytoin equivalent dose by 1.5.

Phenytoin Sodium Injection USP; vehicle = 40% propylene glycol and 10% alcohol, pH adjusted to 12.

Duration of infusion = 30 minutes.

Fosphenytoin dosing solution concentrations ranged from 2.50 to 32.5 mg/mL. Phenytoin dosing solution concentrations ranged from 1.65 to 22.0 mg/mL.

Vehicle = l-arginine HCl, pH adjusted to 8.8.

Fosphenytoin dosing solution concentrations ranged from 7.5 to 50 mg/mL. Phenytoin dosing solution concentrations ranged from 4.50 to 30.0 mg/mL.

Vehicle = Tris buffer, pH adjusted to 8.8.

Estimated; value could not be calculated using Moving Average Interpretation or Probit Analyses Method

Fosphenytoin dosing solution concentrations ranged from 5.0 to 65 mg/mL. Phenytoin dosing solution concentrations ranged from 3.3 to 44 mg/mL.

TABLE 4. Fosphenytoin Single-Dose Toxicity Studies in Rodents

(Page 2 of 2)

Age Observation Period Fosphenytoina Phenytoinb

(mg/kg)

Rat (SD) IM SAL Fosphenytoina

SD = Sprague-Dawley; IM = Intramuscular; SAL = Saline (0.9% NaCl) control; NOED = No observed effect dose;

MNLD = Maximum nonlethal dose; MLD = Combined-sex median lethal dose; IP = Intraperitoneal; VC = Vehicle control.

1. Dose expressed as milligram/kilogram phenytoin equivalents. Approximate fosphenytoin dose can be derived by multiplying the phenytoin equivalent dose by 1.5.

2. Phenytoin Sodium Injection USP; vehicle = 40% propylene glycol and 10% alcohol, pH adjusted to 12.

3. Duration of infusion = 30 minutes.

e

Vehicle = l-arginine HCl, pH adjusted to 8.8.

g

Vehicle = Tris buffer, pH adjusted to 8.8.

1. Dose volume for 337 mg/kg phenytoin group was 6.74 mL/kg.

2. Fosphenytoin dosing solution concentrations ranged from 10 to 100 mg/mL. Phenytoin dosing solution concentrations ranged from 6.8 to 50 mg/mL.

3. N = 5 rats/sex.

4. Fosphenytoin dosing solution concentrations ranged from 5.0 to 75 mg/mL. Phenytoin dosing solution concentrations ranged from 3.3 to 50 mg/mL.

5. Fosphenytoin dosing solution concentrations ranged from 2.50 to 37.5 mg/mL. Phenytoin dosing solution concentrations ranged from 1.65 to 25.0 mg/mL.

TABLE 5. Fosphenytoin Escalating-Dose Toxicity Studies in Nonrodents

Species (Strain)

Dose (mg/kg)

NZW = New Zealand White; IV = Intravenous; NOED = No observed effect dose; NA = Not available; MTD = Maximum tolerated dose; IM = Intramuscular.

1. Dose expressed as milligram/kilogram phenytoin equivalents. Approximate fosphenytoin dose can be derived by multiplying the

phenytoin equivalent dose by 1.5.

Phenytoin Sodium Injection USP; vehicle = 40% propylene glycol and 10% alcohol, pH adjusted to 12.

Duration of infusion = 30 minutes.

Vehicle = l-arginine HCl, pH adjusted to 8.8.

Fosphenytoin dosing solution concentrations ranged from 1.0 to 8.0 mg/mL. Phenytoin dosing solution concentrations ranged from 0.68 to 5.40 mg/mL.

Animals observed for 14 days after last dose.

Vehicle = Tris buffer, pH adjusted to 8.8.

Fosphenytoin dosing solution concentrations ranged from 5.0 to 30 mg/mL. Phenytoin dosing solution concentrations ranged from 3.0 to 18 mg/mL.

Fosphenytoin dosing solution concentration = 75 mg/mL. Phenytoin dosing solution concentration = 50 mg/mL.

Age

Duration

(mg/kg) Results

Deaths at 107 and 160 mg/kg. Dose-related lethargy, ataxia, and head tremors at >=66.7 mg/kg. Decreased body weight gain and food consumption, glucosuria, and increased ALT, ALP, and BUN at 107 and 160 mg/kg. No pathologic findings.

Death, hypoactivity, dyspnea, dilated pupils, prostration, ataxia, hypothermia, decreased body weight gain in males, transient decreases in food consumption, increased urine volumes, and glucosuria in both sexes at 100 mg/kg. No pathologic findings.

No deaths. Ataxia, hypoactivity, and salivation at

40 and 100 mg/kg. Decreased body weight gain and food consumption in males at 100 mg/kg. Reversible increases in ALT and ALP at 100 mg/kg. Increased liver:body weight in males at 100 mg/kg and females at all doses; reversible at 20 and

40 mg/kg. Reversible dose-related injection-site irritation at

>=

20 mg/kg and vacuolation of hepatocytes at 100 mg/kg.

Deaths at 133 and 167 mg/kg. Dose-related lethargy, prostration, ataxia, and/or tremors at >=66.7 mg/kg. Decreased body weight gain, transient decreases in food consumption, and increased urine volumes in males at >=100 mg/kg. Injection-related gross pathologic changes in muscle in 1 animal each at 100 and

167 mg/kg.

Increased liver weights in females at all doses. Deaths, dilated pupils, hypoactivity, excessive salivation, decreased body weight, increased AST, ALT, and ALP, hyperglycemia, glucosuria, and intracytoplasmic hepatocellular vacuolation with fosphenytoin at 100 mg/kg. Similar findings were noted with phenytoin. Local

100 irritation with both compounds.

SD = Sprague-Dawley; IV = Intravenous; VC = Vehicle control; ALT = Alanine aminotransferase; ALP = Alkaline phosphatase; BUN = Blood urea nitrogen; SAL = Saline (0.9% NaCl) control; IM = Intramuscular; PHT = Phenytoin; AST = Aspartate aminotransferase;

1. Dose expressed as milligram/kilogram phenytoin equivalents. Approximate fosphenytoin dose can be derived by multiplying the

phenytoin equivalent dose by 1.5.

Vehicle = Tris buffer, pH adjusted to 8.8.

Fosphenytoin dosing solution concentrations ranged from 3.0 to 24 mg/mL.

Fosphenytoin dosing solution concentrations ranged from 2.0 to 15 mg/mL.

Three additional animals per sex included in control and/or drug-treated groups and utilized only for determination of drug concentrations.

Fosphenytoin dosing solution concentrations ranged from 15 to 75 mg/mL.

Five animals per sex per group were euthanized after a 4-week withdrawal period (Week 8).

Fosphenytoin dosing solution concentration = 75 mg/mL.

Five additional animals per sex per group utilized only for determination of drug concentrations.

Phenytoin Sodium Injection USP, administered at 100 mg/kg, dosing solution concentration = 50 mg/mL; group terminated at Week 9.

Age Duration (mg/kg) Results

Dog (beagle) 2M + 2F, 24

11-12 months

IV Bolus

(2.0 mL/kg)c

7 Days

VCb 6.7

13.3

26.7

33.3

No deaths. Dose-related incidence of diarrhea, salivation, and emesis at >=13.3 mg/kg. In addition, ataxia at 26.7 and

33.3 mg/kg. No significant changes in clinical laboratory parameters. No pathologic findings.

Dog (beagle) 4M + 4F, 40

7-8 months

IV Bolus

(2.0 mL/kg)d

2 Weeks

SAL

VCb 10

33.3

No deaths. Hypoactivity, emesis, excessive salivation, and ataxia at 20 and 33.3 mg/kg. In addition, tremors at 33.3 mg/kg. No significant changes in clinical laboratory parameters. No pathologic findings.

Dog (beagle) 4M + 4F, 24

10-12 months

IV Bolus

(0.67 mL/kg)e

4 Weeksf

VCb 10

33.3

No deaths. Dose-related incidence of emesis at >=10 mg/kg and transient salivation, ataxia, and erythema of gums at >=20 mg/kg. Tremors and hypoactivity at 33.3 mg/kg. Increased ALP at

33.3 mg/kg at Weeks 4 and 8. Increased salivary gland weights in both sexes at 33.3 mg/kg and females at 20 mg/kg at Week 4. Increased liver:body weight in males at 20 and 33.3 mg/kg; reversible at 20 mg/kg. Hypertrophy of salivary glands in males at 33.3 mg/kg at Weeks 4 and 8.

Dog (beagle) 2M + 2F, 24

9-10 months

IM

(0.2-1.0 mL/kg)g

2 Weeks

SAL 10

33.3

No deaths. Dose-related incidence of emesis and ataxia at >=33.3. Sporadic convulsions, diarrhea, and/or tonic stance at 40 and

50 mg/kg. In addition, prostration and excessive salivation at 50 mg/kg. No significant changes in clinical laboratory parameters. No pathologic findings.

Dog (beagle) 4M + 4F, 40

7-9 months

IM

(0.2-0.8 mL/kg)g

13 Weeks

SAL PHTh 10

No deaths. Emesis and excessive salivation at all doses. In addition, ataxia, hypoactivity, diarrhea, increased ALP, increased liver weights, and intracytoplasmic hepatocellular vacuolation with fosphenytoin at 40 mg/kg. Similar findings were noted with phenytoin. Local irritation with fosphenytoin at 20 and 40 mg/kg and with phenytoin.

IV = Intravenous; VC = Vehicle control; SAL = Saline (0.9% NaCl) control; ALP = Alkaline phosphatase; IM = Intramuscular; PHT = Phenytoin;

1. Dose expressed as milligram/kilogram phenytoin equivalents. Approximate fosphenytoin dose can be derived by multiplying the

phenytoin equivalent dose by 1.5.

Vehicle Control = Tris buffer, pH adjusted to 8.8.

Fosphenytoin dosing solution concentrations ranged from 5.0 to 25 mg/mL.

Fosphenytoin dosing solution concentrations ranged from 7.5 to 25 mg/mL.

Fosphenytoin dosing solution concentrations ranged from 22.4 to 75.0 mg/mL.

One animal per sex per group was euthanized after a 4-week withdrawal period (Week 8).

Fosphenytoin dosing solution concentration = 75 mg/mL.

Phenytoin Sodium Injection USP, administered at 40 mg/kg, dosing solution concentration = 50 mg/mL.

TABLE 8. Fosphenytoin Special Toxicity Studies

(Page 1 of 2)

Species (Strain)

Sex/Group, Total Study Designa Results

Venous and Perivascular Irritationb

Rabbits (NZW) 6 Males, 66

Dosing: Single 30-min IV infusion or SC injection FOS (mg/mL):VCc, 10, 25, 50, 75

PHTd (mg/mL):VC, 6.7, 16.9, 33.7, 50

Observation: 24 hours

Parameters: Gross and microscopic examinations

No significant differences in perivascular or venous irritation between fosphenytoin and saline controls. Significant venous and perivascular irritation and high incidence of thrombus formation with phenytoin.

Intramuscular Irritationb

Rabbits (NZW) 12 Males, 12

Dosing: Single IM injection

FOS (mg/mL):VCe, 25, 50, 75, 100

PHTd (mg/mL):VC, 50

Observation: 24 hours

Parameters: Gross and microscopic examinations

Fosphenytoin less irritating than saline or phenytoin. Trace to mild hemorrhage, acute inflammation and necrosis with saline, phenytoin vehicle, and phenytoin.

Rabbits (NZW) 4 Males, 28

Dosing: 5 daily IM injections FOS (mg/mL):VCe, 50, 75, 100

PHTd (mg/mL):VC, 50

Observation: 5 days

Parameters: Serum CPK, gross and microscopic examinations

Hemorrhage in all control and treatment groups. Necrosis with phenytoin; less severe with fosphenytoin at 75 and 100 mg/mL. Increased CPK with phenytoin vehicle, phenytoin, and fosphenytoin.

Glucosuriaf

Rats (SD) 10 Males, 30

Dosing: Single 30-min IV infusion FOSe (mg/kg): 100

PHTd (mg/kg): 100

Dose Volume: 10 mL/kgg

Observation: 48 hours

Parameters: Clinical signs, serum and urine glucose concentrations

Similar increases in serum and urinary glucose concentrations with fosphenytoin and phenytoin.

NZW = New Zealand White; IV = Intravenous; SC = Subcutaneous; FOS = Fosphenytoin; VC = Vehicle control; PHT = Phenytoin; IM = Intramuscular; CPK = Creatine phosphokinase; SD = Sprague-Dawley;

1. All in vivo studies included saline (0.9% NaCl) control group.

2. Concentrations based on the weight of the sodium salt of fosphenytoin or phenytoin.

3. Vehicle = l-arginine HCl, pH adjusted to 8.8.

4. Phenytoin Sodium Injection USP, Vehicle = 40% propylene glycol and 10% alcohol, pH adjusted to 12.

5. Vehicle = Tris buffer, pH adjusted to 8.8.

6. Dose expressed as milligram/kilogram phenytoin equivalents. Approximate fosphenytoin dose can be derived by multiplying the phenytoin equivalent dose by 1.5.

7. Fosphenytoin dosing solution concentration = 15 mg/mL. Phenytoin dosing solution concentration = 10 mg/mL.

TABLE 8. Fosphenytoin Special Toxicity Studies

(Page 2 of 2)

Species (Strain)

Sex/Group, Total Study Designa Results

CNS Safety Screenf

Mice (CD-1) 6 Males, 90

Dosing: Single IP injection

FOS (mg/kg): VCe, 33.3, 66.7, 133, 333, 667

PHTd (mg/kg): VCh, 33, 69, 134, 337, 675

Dose Volume: 20 mL/kgi

Observation: Approximately 4 hours

Parameters: Clinical signs and behavioral changes

Deaths at 333 and 667 mg/kg fosphenytoin, and 337 and 675 mg/kg phenytoin. Similar incidence and severity of CNS effects observed with fosphenytoin and phenytoin.

Cardiovascular Safety Screenf

Dogs (beagle) 4 Females, 20

Dosing: Single IV injection FOS (mg/kg): VCe, 18 PHTd (mg/kg): VC, 18 Dose Volume: 1 mL/kgj Observation: 60 minutes

Parameters: Cardiovascular, blood drug concentrations

No deaths. Gradual decrease in hr, LVdP/dt, and MABP with fosphenytoin and immediate decreases in these parameters with phenytoin. Significant increase in LVEDP with phenytoin. Maximum plasma phenytoin concentrations were 22.1 ug/mL 5 minutes

postdose and 49.4 ug/mL 30 seconds postdose following administration of fosphenytoin and phenytoin, respectively.

Human Blood Compatibilityb

In vitro Concentrations:

FOS (mg/mL): 0.15 to 75

PHTd (mg/mL): 0.10 to 50

Parameters: Hemolysis, plasma protein flocculation

No hemolysis or plasma protein flocculation with fosphenytoin. Hemolysis at 5.0 to

50 mg/mL and mild plasma protein flocculation with phenytoin at 20 mg/mL.

CNS = central nervous system; IP = intraperitoneal; FOS = fosphenytoin; VC = vehicle control; PHT = phenytoin;

IV = intravenous; hr = heart rate; LVdP/dt = left ventricular contractility; MABP = mean arterial blood pressure; LVEDP = left ventricular end diastolic pressure;

1. All in vivo studies included saline (0.9% NaCl) control group

2. Concentrations based on the weight of the sodium salt of fosphenytoin or phenytoin.

1. Phenytoin Sodium Injection USP, Vehicle = 40% propylene glycol and 10% alcohol, pH adjusted to 12.

2. Vehicle = Tris buffer, pH adjusted to 8.8.

3. Dose expressed as milligram/kilogram phenytoin equivalents. Approximate fosphenytoin dose can be derived by multiplying the phenytoin equivalent dose by 1.5.

1. Vehicle was tested in 3 groups of animals at 100% or diluted to 66% or 32% with saline (0.9% NaCl).

2. Fosphenytoin dosing solution concentrations ranged from 2.5 to 50 mg/mL. Phenytoin dosing solution concentrations ranged from 1.65 to 33.75 mg/mL.

3. Fosphenytoin dosing solution concentration = 27 mg/mL. Phenytoin dosing solution concentration = 18 mg/mL

TABLE 9. Fosphenytoin Reproductive Toxicity Studies

(Page 1 of 2)

Species (Strain) Sex/Group, Total Age

Route (Vehicle) [Dose Volume]

Daily Dosea (mg/kg)

Treatment

Regimen Results

FERTILITY AND GENERAL REPRODUCTION

Male

Rat (SD) 40, 200

12-13 Weeks

IM

(Tris Buffer) [2 mL/kg]

UC VC 16.7

75 days prior to and through mating

Paternal toxicity at 50 and 100 mg/kg. No effects on fertility or reproduction.

Female

Rat (SD) 40, 200

15 Weeks

IM

(Tris Buffer) [2 mL/kg]

UC VC 16.7

15 Days Prior to Mating through

Lactation Day 21

Maternal and reproductive toxicity at

50 and 100 mg/kg. Developmental toxicity at all doses including teratogenicity at

16.7 and 100 mg/kg.

TERATOLOGY

Exploratory

Rat (SD) 3F, 9 NA

IV Bolus (Tris Buffer) [2,3,10 mL/kg]

100 10 days All animals euthanized moribund by Day 4. No trauma at injection site.

Dose Range-Finding

Rat (SD) 5F, 35

20 Weeks

IV Bolus (Tris Buffer) [2 mL/kg]

VC 6.7

16.7

33.3

66.7

Gestation Days 7

through 17

Maternal toxicity at 16.7, 33.3, and

66.7 mg/kg. Developmental toxicity at 50 and 66.7 mg/kg. No adverse effects at

6.7 mg/kg. MTD = 66.7 mg/kg.

Definitive

Rat (SD) 40F, 200

12-13 Weeks

IV Bolus (Tris Buffer) [2 mL/kg]

UC VC 6.7

33.3

66.7

Gestation Days 7

through 17

Four deaths, decreased maternal body weight gain and food consumption, decreased birth and male offspring weights at Week 13 at 66.7 mg/kg. No teratogenicity or behavioral toxicity.

SD = Sprague-Dawley; IM = Intramuscular; UC = Untreated control; VC = Vehicle control; IV = Intravenous; NA = Not available; MTD = Maximum tolerated dose.

a

Doses expressed as milligram/kilogram phenytoin equivalents; fosphenytoin dosing solution concentrations ranged from 5 to

75 mg/mL. Approximate fosphenytoin dose can be derived by multiplying the phenytoin equivalent dose by 1.5.

TABLE 9. Fosphenytoin Reproductive Toxicity Studies

(Page 2 of 2)

Species (Strain) Sex/Group, Total Age

Route (Vehicle) [Dose Volume]

Daily Dosea (mg/kg)

Treatment

Regimen Results

TERATOLOGY (continued)

Exploratory

Rabbit (NZW) 3F, 6

NA

IV Bolus (Tris Buffer) [1,2 mL/kg]

33.3 13 Days No clinical signs or effects on body weight or food consumption. No trauma at injection site.

Dose Range-Finding

Rabbit (NZW) 5F, 35

7-8 months

IV Bolus (Tris Buffer) [1-2 mL/kg]

VC 3.3

16.7

33.3

66.7

Gestation Days 6 through 18

Maternal toxicity at 33.3, 50, and

66.7 mg/kg. Developmental toxicity at

66.7 mg/kg. No adverse effects at

3.3 mg/kg. MTD = 33.3 mg/kg.

Definitive

Rabbit (NZW) 20F, 100

7-8 months

IV Bolus (Tris Buffer) [1 mL/kg]

UC VC 6.7

16.7

33.3

Gestation Days 6 through 18

No deaths. Decreased body weight gain and food consumption at 16.7 and

33.3 mg/kg. No maternal reproductive or fetal toxicity, and no teratogenicity.

PERINATAL-POSTNATAL TOXICITY

Rat (SD) 25F, 125

12 Weeks

IV Bolus (Tris Buffer) [2 mL/kg]

UC VC 16.7

33.3

66.7

Gestation Day 15 through

Lactation Day 20

Maternal and perinatal-postnatal toxicity at

33.3 and 66.7 mg/kg. Subtle behavioral

toxicity at 33.3 and 66.7 mg/kg.

NZW = New Zealand White; IV = Intravenous; NA = Not available; VC = Vehicle control; MTD = Maximum-tolerated dose; UC = Untreated control; SD = Sprague-Dawley.

a

Doses expressed as milligram/kilogram phenytoin equivalents; fosphenytoin dosing solution concentrations ranged from 5 to 75

mg/mL. Approximate fosphenytoin dose can be derived by multiplying the phenytoin equivalent dose by 1.5.

TABLE 10. Fosphenytoin Genetic Toxicity Studies

Concentration Range

Test or Dose Results

Mutagenicity

Mutagenesis in Salmonella

typhimurium

Point mutation assay in V79 Chinese hamster lung cells

312.5-5000 ug/platea Nonmutagenic in the absence or presence of S9.

500-4000 ug/mLa No mutation at HGPRT locus in the absence or presence of S9.

Clastogenicity

Structural chromosome aberration assay in V79 chinese hamster lung cells

500-4000 ug/mLa(-S9)

125-4000 ug/mLa(+S9)

Clastogenic at >=3000 ug/mL only in the presence of S9.

Micronucleus assay 33.3, 66.7, 133 mg/kgb No increase in micronucleus frequency.

HGPRT = Hypoxanthine-quanine phosphoribosyltransferase; S9 = Postmitochondrial supernatant from livers of rats induced by Aroclor 1254.

1. Concentrations based on the weight of fosphenytoin

2. Doses expressed as mg phenytoin equivalents; fosphenytoin dosing solution concentrations ranged from 5 to 20 mg/mL; dose volume = 10 mL/kg.

REFERENCES

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