Fosphenytoin Sodium

Class: Hydantoins
VA Class: CN400
Chemical Name: 5,5-Diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazoleidinedione disodium salt
Molecular Formula: C16H13N2Na2O6P
CAS Number: 92134-98-0

Introduction

Hydantoin-derivative anticonvulsant; prodrug of phenytoin.1 2 4 6

Uses for Fosphenytoin Sodium

Seizure Disorders

Short-term (up to 5 days) parenteral therapy when the usual means of phenytoin administration are unavailable, inappropriate, or deemed less advantageous.1 Used for the treatment of generalized convulsive status epilepticus,1 4 5 6 10 19 for the prevention and treatment of seizures occurring during neurosurgery, and as a short-term parenteral replacement for oral phenytoin.1 7 27

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IV fosphenytoin sodium is associated with fewer infusion site reactions (e.g., erythema, pain, burning, swelling, pruritus, soft tissue damage, phlebitis, necrosis) and less frequent need for infusion rate reduction, interruption, and/or changes of infusion sites than IV phenytoin sodium,1 2 4 6 9 10 14 15 18 19 22 but with a higher incidence of paresthesia and pruritus.1 2 6 7 9 10 14 22

Use fosphenytoin rather than phenytoin for IM administration.1 2 6 9 10 27

Not indicated for the treatment of absence seizures or seizures associated with hypoglycemia or other metabolic causes.1

Fosphenytoin Sodium Dosage and Administration

General

  • When administering IV loading doses, continuous ECG, BP, and respiratory monitoring is essential during the period of maximal plasma phenytoin concentrations (about 10–20 minutes postinfusion).1 24

Administration

Administer by IV infusion1 2 4 5 6 9 10 19 27 or by IM injection.1 2 6 9 10 23 27 30

IV Administration

Dilution

Dilute in 5% dextrose injection or 0.9% sodium chloride injection to provide a solution containing 1.5–25 mg PE/mL.1

Rate of Administration

Infuse loading dose for status epilepticus at rate of 100–150 mg PE/minute.1

IM Administration

Administered once daily in 1 or 2 injection sites in clinical studies.1 Some patients may require more frequent IM dosing.1

IM administration is not recommended for initial treatment of status epilepticus.1 If IV access is impossible, loading doses of fosphenytoin sodium have been given IM for other indications.1

Dosage

Available as fosphenytoin sodium; dosage expressed in terms of phenytoin sodium equivalents (PE).1 Always prescribe and dispense in terms of PE.1

Each mmol of fosphenytoin is converted into 1 mmol of phenytoin; however, because of differences in molecular weight, each 75 mg of fosphenytoin sodium is equivalent to only 50 mg of phenytoin sodium.1 2

IV and IM dosages (in terms of PE) are the same; 24 25 total daily doses of parenteral fosphenytoin sodium (in terms of PE) generally are equivalent to those of oral phenytoin sodium.1

Adults

Seizure Disorders
Status Epilepticus
IV

15–20 mg PE/kg, followed by maintenance doses of fosphenytoin sodium or parenteral or oral doses of phenytoin.1 Concomitant therapy with an IV benzodiazepine usually is necessary for initial control of status epilepticus.1 4

Nonemergency Loading and Maintenance Dosages
IV or IM

Initiation of anticonvulsant therapy: 10–20 mg PE/kg.1

Initial maintenance dosage: 4–6 mg PE/kg daily.1

Conversion from Oral Phenytoin to Parenteral Fosphenytoin
IV or IM

Same total daily dose (in terms of PE) as oral phenytoin sodium.1 However, plasma phenytoin concentrations may be slightly higher with parenteral fosphenytoin sodium than with oral phenytoin sodium (Dilantin) capsules due to different bioavailabilities (90 and 100%, respectively, in terms of phenytoin concentrations).1

Prescribing Limits

Adults

Seizure Disorders

Do not infuse loading dose at a rate >150 mg PE/minute.1

Safety and efficacy for >5 days have not been systematically evaluated.1

Special Populations

Geriatric Patients

Reduced or less frequent doses may be necessary.1

Cautions for Fosphenytoin Sodium

Contraindications

  • Known hypersensitivity to fosphenytoin or any ingredient in the formulation, phenytoin, or other hydantoins.1

  • Sinus bradycardia, sinoatrial block, second- or third-degree AV block, Adams-Stokes syndrome.1

Warnings/Precautions

Warnings

Always express dosage of fosphenytoin sodium in terms of PE;1 therefore, do not adjust recommended dosage when switching from phenytoin sodium to fosphenytoin sodium or vice versa.1

Status Epilepticus Dosing Regimen

Administration of the recommended IV dose generally takes 5–7 minutes; administration of equimolar doses of phenytoin sodium takes 15–20 minutes.1

IV route is preferred if the primary goal is rapid achievement of therapeutic phenytoin concentrations.1

Discontinuance of Fosphenytoin

Do not discontinue abruptly; reduce dosage, discontinue drug, or make drug substitution gradually.1 However, if an allergic or hypersensitivity reaction occurs, rapid substitution with an anticonvulsant that is structurally unrelated to hydantoins may be necessary.1

Lymphadenopathy

Development of local or generalized lymphadenopathy (e.g., benign lymph node hyperplasia, pseudolymphoma, lymphoma, Hodgkin’s disease) associated with phenytoin.1 If lymphadenopathy develops, observe patient closely for an extended period; if possible, use alternative anticonvulsant.1

Cardiovascular Effects

Potential for hypotension, especially after IV administration of high doses or rapid IV infusions.1 Careful cardiac monitoring is needed when administering IV loading doses.1 If hypotension occurs, may need to reduce the administration rate or discontinue the drug.1

Use with caution in patients with hypotension or severe heart failure.1

Contraindicated in patients with some cardiac conduction disorders. (See Contraindications under Cautions.)1

Hepatic Effects

Acute hepatotoxicity, including infrequent cases of acute hepatic failure, reported with phenytoin.1 If acute hepatotoxicity occurs, discontinue fosphenytoin immediately and do not resume.1

Hematologic Effects

Adverse hematologic effects (e.g., thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression), sometimes fatal, reported with phenytoin.1

Fetal/Neonatal Morbidity and Mortality

Fosphenytoin is embryotoxic and teratogenic in animals.1 Phenytoin may cause fetal harm (e.g., congenital malformations, adverse developmental outcomes) in pregnant women.1

Life-threatening bleeding disorders secondary to decreased concentrations of vitamin K-dependent clotting factors may occur in neonates exposed to phenytoin in utero; administration of vitamin K to the mother prior to delivery and to the neonate after birth prevents these disorders.1

Sensitivity Reactions

Possible increased risk of developing toxic epidermal necrolysis or Stevens-Johnson syndrome in individuals of Asian ancestry who carry the human leukocyte antigen (HLA)-B*1502 allele with phenytoin.32 33 34 Precaution relating to presence of the HLA-B*1502 allele applies to fosphenytoin because fosphenytoin is converted to phenytoin.32 FDA is evaluating the relationship between use of phenytoin and serious dermatologic reactions in individuals with the HLA-B*1502 allele.32 Screening for presence of HLA-B*1502 allele before initiating fosphenytoin or phenytoin therapy not recommended at this time.32 Fosphenytoin or phenytoin should not be used as an alternative to carbamazepine in HLA-B*1502-positive patients.32

If rash occurs, discontinue fosphenytoin.1

Do not resume fosphenytoin if the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic necrolysis is suspected; consider alternative anticonvulsant therapy.1

If the rash is a milder type (measles-like or scarlatiniform), may restart fosphenytoin after the rash has completely disappeared; however, if rash recurs when fosphenytoin is restarted, further fosphenytoin or phenytoin therapy is contraindicated.1

Exercise caution when using structurally similar compounds (e.g., barbiturates, succinimides, oxazolidinediones) in patients who have experienced phenytoin hypersensitivity.1

Major Toxicities

Sensory Disturbances

Severe burning, pruritus, and/or paresthesia (mainly in groin) reported with IV administration; symptoms generally persist for up to 14 or 24 hours for severe or mild reactions, respectively.1 2

Patients receiving doses of 20 mg PE/kg at a rate of 150 mg PE/minute are likely to experience some discomfort; reducing or temporarily stopping the infusion may decrease the incidence and intensity.1

Phosphate Content

Each mg PE provides 0.0037 mmol of phosphate; consider the phosphate content in patients who require phosphate restriction (e.g., patients with severe renal impairment).1

General Precautions

Hyperglycemia

Hyperglycemia reported with phenytoin.1

CNS Effects

Plasma phenytoin concentrations sustained above the optimal range may produce confusional states (e.g., delirium, psychosis, encephalopathy); rarely, irreversible cerebellar dysfunction may develop.1

Determine plasma phenytoin concentrations at the first sign of acute toxicity.1 If concentrations are excessive, reduce the fosphenytoin dosage; if symptoms persist, discontinue the drug.1

Folate Concentrations

Phenytoin may reduce serum folate concentrations.1

Monitoring Plasma Phenytoin Concentrations

Dosage of fosphenytoin (in PE) usually is selected to achieve total plasma phenytoin concentrations of 10–20 mcg/mL (unbound phenytoin concentrations of 1–2 mcg/mL).1

Do not monitor plasma phenytoin concentrations until conversion of fosphenytoin to phenytoin is essentially complete (about 2 hours after conclusion of an IV infusion or 4 hours after an IM injection).1 2 6

Unbound phenytoin fraction may be increased in patients with renal or hepatic impairment or hypoalbuminemia.1 Interpret total plasma phenytoin concentrations with caution in these patients; consider monitoring unbound plasma phenytoin concentrations.1

Purple Glove Syndrome

Purple glove syndrome (PGS), characterized by progressive pain, discoloration, and edema of the distal limb, reported with IV phenytoin.170 171 173 174 175 176 177 178 179 180 181 182 183 184 185 Can occur with or without extravasation.173 174 175 176 177 178 179 180 181 182 PGS also may be possible with fosphenytoin, although risk appears greater with phenytoin.170

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Potential for increased seizure frequency during pregnancy due to alteration of phenytoin pharmacokinetics.1 Monitor plasma phenytoin concentrations and adjust dosage accordingly; restoration of the patient’s usual dosage will probably be necessary postpartum.1

Lactation

Not known whether fosphenytoin is distributed into milk.1 Phenytoin is distributed into milk; nursing is not recommended in women receiving fosphenytoin.1

Pediatric Use

Safety1 and efficacy24 not established in children.1 24

Limited pharmacokinetic data in children 5–10 years of age with status epilepticus indicate that plasma fosphenytoin, total phenytoin, and unbound phenytoin concentration-time profiles following IV loading doses are similar to those achieved in adult patients with status epilepticus receiving comparable doses.1 8

Geriatric Use

Not systematically evaluated in geriatric adults.1

Hepatic Impairment

Use with caution.1 Following IV administration, conversion of fosphenytoin to phenytoin may be increased without a similar increase in phenytoin clearance; the increases in plasma phenytoin concentrations may be associated with an increased incidence and severity of adverse effects.1

Interpret total plasma phenytoin concentrations with caution.1 (See Monitoring Plasma Phenytoin Concentrations under Cautions.)

Phenytoin may exacerbate porphyria; use with caution in patients with this disease.1

Renal Impairment

Use with caution.1 Following IV administration, conversion of fosphenytoin to phenytoin may be increased without a similar increase in phenytoin clearance; the increases in plasma phenytoin concentrations may be associated with an increased incidence and severity of adverse effects.1

Interpret total plasma phenytoin concentrations with caution.1 (See Monitoring Plasma Phenytoin Concentrations under Cautions.)

Common Adverse Effects

Nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, ataxia.1 2 6 7

Interactions for Fosphenytoin Sodium

Phenytoin is metabolized by CYP isoenzymes.1 Phenytoin induces hepatic enzymes.1

No drugs are known to interfere with conversion of fosphenytoin to phenytoin.1

Drug interactions that occur with phenytoin expected to occur with fosphenytoin.1

Protein-bound Drugs

Potential for fosphenytoin or phenytoin to displace or to be displaced by other protein-bound drugs.1 Use with caution.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP inhibitors: Potential for increased plasma phenytoin concentrations.1

Specific Drugs

Drug

Interaction

Comments

Alcohol, acute intake

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Alcohol, chronic intake

Possible decreased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Amiodarone

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Anticoagulants

Efficacy of anticoagulants, including warfarin, impaired1

Possible increased plasma phenytoin concentrations when administered with dicumarol (no longer commercially available in US)1

Monitor plasma phenytoin concentration if pharmacokinetic interaction suspected1

Antidepressants, tricyclic

Increased risk of seizures1

Adjust fosphenytoin dosage as necessary1

Carbamazepine

Possible decreased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Chloramphenicol

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Chlordiazepoxide

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Corticosteroids

Efficacy of corticosteroids impaired1

Diazepam

Pharmacokinetic (including protein binding) interaction unlikely1

Disulfiram

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Doxycycline

Efficacy of doxycycline impaired1

Estrogens

Possible increased plasma phenytoin concentrations1

Efficacy of estrogens impaired1

Monitor plasma phenytoin concentration if interaction suspected1

Ethosuximide

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Fluoxetine

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Furosemide

Efficacy of furosemide impaired1

Halothane

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Histamine H2-receptor antagonists (cimetidine)

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Isoniazid

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Methylphenidate

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Oral contraceptives

Efficacy of oral contraceptives impaired1

Phenobarbital

Possible increased or decreased plasma phenytoin or phenobarbital concentrations1

Monitor plasma concentrations if interaction suspected1

Phenothiazines

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Quinidine

Efficacy of quinidine impaired1

Rifampin

Efficacy of rifampin impaired1

Salicylates

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Succinimides

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Sulfonamides

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Theophylline

Efficacy of theophylline impaired1

Tolbutamide

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Trazodone

Possible increased plasma phenytoin concentrations1

Monitor plasma phenytoin concentration if interaction suspected1

Valproic acid and Valproate sodium

Possible increased or decreased plasma concentrations of phenytoin or valproic acid1

Monitor plasma concentrations if interaction suspected1

Fosphenytoin Sodium Pharmacokinetics

Absorption

Bioavailability

Completely converted to phenytoin following IV or IM administration; conversion half-life is 15 minutes.1 2

Completely bioavailable following IM administration.1 Peak plasma phenytoin concentrations are achieved in about 3 hours.1 Concentrations are similar to those achieved with oral phenytoin sodium.1

Onset

IV loading doses of 15–20 mg PE/kg infused at maximally tolerated rates (100–150 mg PE/minute) result in therapeutic plasma concentrations of unbound phenytoin (about 1–2 mcg/mL) within about 10 minutes.1 2 4 6 7 19 25 26

Onset of action in controlling status epilepticus is similar to that of IV phenytoin sodium.4 26

Distribution

Plasma Protein Binding

Fosphenytoin: 95–99%.1

Phenytoin: 88%.1

Fosphenytoin displaces phenytoin from binding sites.1 In the presence of fosphenytoin, the fraction of unbound phenytoin increases; 70% of phenytoin is bound during the period required for conversion of fosphenytoin to phenytoin (0.5–1 hour postinfusion).1

Special Populations

In patients with renal or hepatic impairment or hypoalbuminemia, fraction of unbound phenytoin is increased.1

Elimination

Metabolism

Fosphenytoin is rapidly metabolized to phenytoin by blood and tissue phosphatases.2 Each mmol of fosphenytoin is metabolized to one mmol of phenytoin.1

Phenytoin is metabolized by hepatic CYP isoenzymes (saturable process).1 A small percentage of individuals metabolize phenytoin slowly.1

Elimination Route

Phenytoin is excreted in urine principally as metabolites.1

Half-life

Phenytoin: 12–28.9 hours.1

Special Populations

Following IV administration in patients with renal and/or hepatic impairment or hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance.1

In geriatric patients, phenytoin clearance may be decreased.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Do not store at room temperature for >48 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Amino acid injection 10%

Dextrose 5% in Ringer’s injection, lactated

Dextrose 5% in sodium chloride 0.45%

Dextrose 5 or 10% in water

Hetastarch 6% in sodium chloride 0.9%

Mannitol 20%

Plasma-Lyte A, pH 7.4

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Potassium chloride

Y-Site CompatibilityHID

Compatible

Lorazepam

Phenobarbital sodium

Incompatible

Fenoldopam mesylate

Midazolam HCl

Actions

  • Prodrug of phenytoin.1 2 4 6 Pharmacologic effects include those of phenytoin.1 2 6

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fosphenytoin Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

75 mg (equivalent to 50 mg phenytoin sodium [PE]) per mL*

Fosphenytoin Sodium Injection

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 30, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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