VA Class:CN400

AHFS Class:

• Hydantoins 28:12.12

Generic Name(s):

• Fosphenytoin Sodium

Chemical Name:

• 5,5-Diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazoleidinedione disodium salt

Molecular Formula:

• C^₁₆H^₁₃N^₂Na^₂O^₆P

Fosphenytoin sodium, a prodrug of phenytoin, is a hydantoin-derivative anticonvulsant.1,2,4,6

Seizure Disorders

Fosphenytoin is used for the treatment of generalized tonic-clonic status epilepticus.1,4,5,6,10,19,233 Benzodiazepines (e.g., diazepam, lorazepam, midazolam) are considered the drugs of choice for initial treatment of status epilepticus; IV fosphenytoin (or phenytoin) may be used as a second-line agent if seizures continue.4,233,235,236 Because the full antiepileptic effect of phenytoin (whether given as fosphenytoin or phenytoin) is not immediate, concurrent use of an IV benzodiazepine usually is necessary for rapid control of status epilepticus.1 If administration of fosphenytoin does not terminate seizures, the use of other anticonvulsants, IV barbiturates, general anesthesia, and/or other measures should be considered.1 (See Status Epilepticus under Seizure Disorders: Principles of Anticonvulsant Drug Therapy, in Uses in the Anticonvulsants General Statement 28:12.)

Fosphenytoin also can be used for the prevention and treatment of seizures occurring during neurosurgery and as a short-term parenteral replacement for oral phenytoin; because of the risks associated with parenteral administration of the drug, the manufacturer states that fosphenytoin should be used only when oral phenytoin administration is not possible.1,7,27

There are insufficient data regarding the comparative efficacy of IV fosphenytoin and IV phenytoin in the management of status epilepticus.2,4,6,7,9,10,11,14,15,16,17,18,20,233 Some clinicians state that since therapeutic plasma concentrations of unbound (free) phenytoin (about 1-2 mcg/mL) are attained within about 10 minutes when IV loading doses of fosphenytoin sodium (15-20 mg PE/kg [about 1200 mg PE]) or phenytoin sodium (15-20 mg/kg [about 1200 mg]) are infused at maximally tolerated infusion rates (100-150 mg PE/minute or 50 mg/minute, respectively),2,4,6,7,19,25,26 the onset of action of IV fosphenytoin sodium in controlling status epilepticus is likely to be similar to that of IV phenytoin sodium.4,26 However, duration of infusion usually is longer with phenytoin than with fosphenytoin.5,19

IV fosphenytoin appears to be better tolerated than IV phenytoin, and some experts state that fosphenytoin is preferred when both agents are available.233 There is some evidence indicating that IV fosphenytoin produces less adverse cardiovascular effects (e.g., cardiac arrhythmias, hypotension) than IV phenytoin.15,19,25,233 Although IV administration of fosphenytoin sodium is associated with fewer local reactions (e.g., erythema, pain, burning, swelling, pruritus, soft tissue damage, phlebitis, necrosis) at the infusion site and less frequent need for infusion rate reduction, infusion interruption, and/or changes of infusion sites than IV administration of phenytoin sodium,2,4,6,9,10,14,15,18,19,22,233 IV fosphenytoin is associated with a higher incidence of systemic sensory disturbances (e.g., paresthesia, burning, pruritus).1,2,6,7,9,10,14,22 The higher incidence of local reactions occurring with administration of IV phenytoin sodium is possibly due to the high alkalinity (pH of about 12) of phenytoin sodium injection and/or the presence of vehicles (propylene glycol and ethanol) necessary to solubilize the drug; the aqueous fosphenytoin sodium injection has a pH of 8.6-9 and does not contain these vehicles.1,7,9,10,11

When IM administration is needed (e.g., when IV access is not possible), fosphenytoin rather than phenytoin should be used since fosphenytoin is well absorbed from IM injection sites.1,2,6,9,10,27 Following IM administration of fosphenytoin sodium, the resultant systemic phenytoin concentrations are slightly higher than those achieved with oral use of phenytoin sodium.1,6 However, IM administration of fosphenytoin sodium generally should not be used for the treatment of status epilepticus because of the delay in reaching therapeutic concentrations.1 Phenytoin generally should not be administered IM because of its erratic absorption and localized adverse effects.7,23,25,27,194

General

The dose, concentration, and rate of infusion of fosphenytoin sodium are expressed in terms of phenytoin sodium equivalents (PE); therefore, molecular weight-based adjustments are not necessary when converting between fosphenytoin sodium and phenytoin sodium.1 Fosphenytoin sodium always should be prescribed and dispensed in terms of phenytoin sodium equivalents (PE), and the amount and concentration of fosphenytoin should always be expressed in terms of mg of phenytoin sodium equivalents (mg PE).1

Inadvertent overdosage of fosphenytoin (including fatalities) has occurred when the concentration stated on the drug vial was misinterpreted as the total amount of drug in the vial.1,12,13,21 Therefore, particular care should be taken to ensure that the correct dose of the drug is administered, including careful attention to the concentration of fosphenytoin sodium (expressed in mg PE/mL) present in the vial and the volume of drug (in mL) that is withdrawn from the vial.1,12,21 (See Dosing Errors under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Fosphenytoin therapy should be withdrawn gradually to minimize the possibility of increased seizure frequency, including status epilepticus.1 (See Discontinuance of Therapy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Therapeutic Drug Monitoring

Therapeutic drug monitoring of serum phenytoin concentrations is recommended to guide dosing of fosphenytoin.1 Trough concentrations (obtained just prior to the next scheduled dose) can be used to assess therapeutic effect and patient compliance, while peak concentrations (obtained at the time of expected peak concentration) can be used to assess toxicity.1 The usual therapeutic range for phenytoin is 10-20 mcg/mL (or 1-2 mcg/mL based on unbound [free] phenytoin concentrations); however, some patients may achieve adequate seizure control or experience toxicity with lower or higher concentrations.1,258,269 To obtain an accurate measurement, serum phenytoin concentrations should not be monitored until conversion of fosphenytoin to phenytoin is essentially complete (about 2 hours after completion of an IV infusion or 4 hours after IM injection); prior to complete conversion, over-estimation of serum phenytoin concentrations may occur because of cross-reactivity between fosphenytoin and phenytoin when certain immunoanalytical assay techniques are used.1,2,6

Patients with renal or hepatic impairment and those with hypoalbuminemia have an increased fraction of free phenytoin due to altered protein binding; therefore, free phenytoin concentrations rather than total serum concentrations should be monitored in these patients.1,268

Fosphenytoin sodium is administered by IV infusion1,2,4,5,6,9,10,19,27 or IM injection.1,2,6,9,10,23,27,30 IM administration of fosphenytoin generally is not recommended in pediatric patients, but may be used in nonemergent situations in adults (when IV administration is not possible).1 Fosphenytoin should not be administered IM in the treatment of status epilepticus.1

IV Administration

Fosphenytoin sodium is administered by IV infusion.1

Prior to IV infusion, the commercially available injection must be diluted in 5% dextrose injection or 0.9% sodium chloride injection to provide a solution containing 1.5-25 mg PE/mL.1 The maximum recommended concentration should not exceed 25 mg PE/mL.1 Solutions of fosphenytoin should be inspected visually for particulate matter and discoloration prior to administration.1 Vials are for single dose only; any unused portions should be discarded.1

The manufacturer states that continuous ECG, blood pressure, and respiratory monitoring is essential during IV administration of fosphenytoin.1 Patients should be observed closely during the period when peak serum phenytoin concentrations are expected (about 10-20 minutes after completion of the IV infusion).1

Rate of Administration

In adults with status epilepticus, IV loading doses of fosphenytoin should be administered at a rate of 100-150 mg PE/minute.1 For nonemergent situations in adults, IV loading doses should be administered at a rate not exceeding 150 mg PE/minute.1 In pediatric patients with status epilepticus, IV loading doses of fosphenytoin should be administered at a rate of 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower).1 For nonemergent situations in pediatric patients, IV loading doses should be administered at a rate not exceeding 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower) and maintenance doses should be administered at a rate not exceeding 1-2 mg PE/kg per minute (or 100 mg PE/minute, whichever is slower).1

Because of the risk of cardiovascular complications, the rate of IV administration should not exceed 150 mg PE/minute in adults and 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower) in pediatric patients.1 (See Cardiovascular Toxicity under Warnings/Precautions: Warnings, in Cautions.)

IM Administration

In controlled clinical trials, IM fosphenytoin was administered once daily in 1 or 2 injection sites.1 However, some patients may require more frequent IM dosing.1

Dosage

Dosage of fosphenytoin sodium is expressed in terms of phenytoin sodium equivalents (PE); 1.5 mg of fosphenytoin sodium is equivalent to 1 mg of phenytoin sodium and is referred to as 1 mg PE.1 (See Dosage and Administration: General.) IV and IM dosages of fosphenytoin sodium (in terms of PE) are the same,24,25 and total daily doses of parenteral fosphenytoin sodium (in terms of PE) generally are equivalent to those of oral phenytoin sodium.1

Status Epilepticus

For the treatment of status epilepticus in adults, the manufacturer recommends an IV fosphenytoin loading dose of 15-20 mg PE/kg infused at a rate of 100-150 mg PE/minute.1 Some clinicians recommend a higher initial fosphenytoin dose of 20 mg PE/kg (maximum of 1500 mg PE per dose) administered at a rate not exceeding 150 mg PE/minute; an additional dose of 5-10 mg PE/kg may be given after 10 minutes if seizures continue.4,233,236 The loading dose should be followed by maintenance doses of either fosphenytoin or phenytoin.1 Because of the risks of cardiac and local toxicity associated with IV administration of fosphenytoin, oral phenytoin should be used whenever possible for maintenance dosing.1 If fosphenytoin is used, the recommended initial maintenance dosage in adults is 4-6 mg PE/kg daily (administered in divided doses at an infusion rate not exceeding 150 mg PE/minute).1 Maintenance dosing should begin at the next identified dosing interval.1 Subsequent maintenance dosage should be individualized based on serum phenytoin concentrations.1

For the treatment of status epilepticus in pediatric patients, the manufacturer recommends an IV fosphenytoin loading dose of 15-20 mg PE/kg infused at a rate of 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower).1 The loading dose should be followed by maintenance doses of either fosphenytoin or phenytoin.1 Because of the risks of cardiac and local toxicity associated with IV administration of fosphenytoin, oral phenytoin should be used whenever possible for maintenance dosing.1 If fosphenytoin is used, the recommended initial maintenance dosage in pediatric patients is 2-4 mg PE/kg every 12 hours at an infusion rate of 1-2 mg PE/kg per minute (or 100 mg PE/minute, whichever is slower) beginning 12 hours after the loading dose.1 Subsequent maintenance dosage should be individualized based on serum phenytoin concentrations.1

Because the onset of action of phenytoin is not immediate, concomitant therapy with an IV benzodiazepine usually is necessary for the initial control of status epilepticus.1 (See Uses: Seizure Disorders.)

Nonemergency Loading and Maintenance Dosages

Because of the risks associated with IV fosphenytoin, oral phenytoin should be used whenever possible.1

If fosphenytoin is used for a nonemergent situation (e.g., for prevention or treatment of seizures during neurosurgery), the recommended loading dose in adults is 10-20 mg PE/kg by IV infusion (at a rate not exceeding 150 mg PE/minute) or IM injection.1 The loading dose should be followed by an initial fosphenytoin maintenance dosage of 4-6 mg PE/kg daily, administered in divided doses at an infusion rate not exceeding 150 mg PE/minute.1 Maintenance dosing should begin at the next identified dosing interval.1 Subsequent maintenance dosage should be individualized based on serum phenytoin concentrations.1 (See Therapeutic Drug Monitoring under Dosage and Administration: General.)

If fosphenytoin is used for a nonemergent situation in pediatric patients, the recommended loading dose is 10-15 mg PE/kg administered by IV infusion at a rate of 1-2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower).1 The loading dose should be followed by an initial maintenance dosage of 2-4 mg PE/kg every 12 hours administered by IV infusion at a rate of 1-2 mg PE/kg per minute (or 100 mg PE/minute, whichever is slower) beginning 12 hours after the loading dose.1 Subsequent maintenance dosage should be individualized based on serum phenytoin concentrations.1 (See Therapeutic Drug Monitoring under Dosage and Administration: General.) IM administration of fosphenytoin generally is not recommended in pediatric patients.1

Conversion from Oral Phenytoin to Parenteral Fosphenytoin

Patients being transferred from oral phenytoin to IM or IV fosphenytoin sodium therapy may receive the same total daily dosage in terms of PE.1 When transitioning from phenytoin sodium capsules to parenteral fosphenytoin, serum phenytoin concentrations may be slightly higher because the bioavailability of the capsules is 90%.1

Special Populations

The manufacturer makes no specific dosage recommendations for patients with renal or hepatic impairment or those with hypoalbuminemia.1 (See Renal and Hepatic Impairment and Hypoalbuminemia under Warnings/Precautions: Specific Populations, in Cautions.)

Lower doses or less frequent dosing of fosphenytoin may be necessary in geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

In pregnant patients, serum phenytoin concentrations should be monitored closely and dosage of fosphenytoin should be adjusted as necessary.1 Restoration of the original dosage will probably be necessary postpartum.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

History of hypersensitivity to fosphenytoin or any ingredient in the formulation, phenytoin, or other hydantoins.1

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

History of prior acute hepatotoxicity with fosphenytoin or phenytoin.1

Concomitant use with delavirdine.1

Warnings/Precautions

Warnings

Cardiovascular Toxicity

Severe hypotension and cardiac arrhythmias, including bradycardia, heart block, QT-interval prolongation, ventricular tachycardia, and ventricular fibrillation, have occurred following rapid IV administration of fosphenytoin (and phenytoin), sometimes resulting in asystole, cardiac arrest, and death.1,194 Severe complications appear to be most common in critically ill patients, geriatric patients, and those with hypotension and severe myocardial insufficiency, although cardiac events also have been reported in adults and pediatric patients without underlying cardiac disease or other comorbidities and at recommended dosages and infusion rates.1

To minimize the risk of cardiovascular toxicity, the rate of IV administration of fosphenytoin should not exceed 150 mg PE/minute in adults and should not exceed 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower) in pediatric patients.1 While the risk of toxicity increases with infusion rates above the recommended rates, cardiac events also can occur at or below these rates.1 Cardiac and respiratory monitoring should be performed during and after IV administration of fosphenytoin.1 A reduction in the rate of administration or discontinuance of the drug may be necessary.1

Fosphenytoin is contraindicated in patients with sinus bradycardia, sinoatrial block, second- and third-degree AV block, or Adams-Stokes syndrome because of the drug's effects on ventricular automaticity.1

Sensitivity Reactions

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported in patients receiving phenytoin, the active metabolite of fosphenytoin.1,32,33,34 The onset of these reactions is usually within the first 28 days of therapy.1 Fosphenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug related.1 If manifestations are suggestive of SJS or TEN, fosphenytoin therapy should not be resumed and alternative therapy should be considered.1

Pharmacogenomic Considerations in the Development of Cutaneous Reactions

Limited data suggest an increased risk of SJS and TEN with phenytoin (the active metabolite of fosphenytoin) in individuals of Asian ancestry who carry the human leukocyte antigen (HLA)-B*1502 allele.1,32,33,34,231,232 A strong association has been found between the presence of HLA-B*1502 and an increased risk of developing SJS and TEN in patients with Chinese ancestry receiving carbamazepine; although evidence is more limited, HLA-B*1502 also has been associated with SJS/TEN in such patients receiving structurally similar anticonvulsants such as phenytoin.1,231,232 These anticonvulsants generally should not be used as alternatives to carbamazepine in HLA-B*1502-positive patients.1,231 (See Cautions: Dermatologic and Sensitivity Reactions, in the Anticonvulsants General Statement 28:12.)

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with several anticonvulsant drugs including fosphenytoin and phenytoin.1 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 However, signs and symptoms associated with other organ systems also may occur.1 If signs and symptoms of DRESS occur during fosphenytoin therapy, patients should be evaluated immediately; if an alternative etiology cannot be identified, the drug should be discontinued.1

Hypersensitivity Reactions

Angioedema has been reported in patients receiving fosphenytoin.1 The drug should be discontinued immediately if manifestations of angioedema (e.g., facial, perioral, or upper airway swelling) occur.1

Fosphenytoin and other hydantoins are contraindicated in patients with known hypersensitivity to phenytoin.1 Clinicians also should consider alternatives to structurally similar compounds such as carboxamides, barbiturates, succinimides, and oxazolidinediones in patients who have experienced phenytoin hypersensitivity.1 Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family member, alternatives to fosphenytoin should be considered.1

Other Warnings and Precautions

Dosing Errors

The dose of fosphenytoin sodium should always be expressed in terms of mg of phenytoin sodium equivalents (mg PE).1 This eliminates the need for dose conversions when switching between phenytoin and fosphenytoin.1 For example, 1000 mg PE of fosphenytoin is equivalent to 1000 mg of phenytoin sodium.1 (See Dosage and Administration: General.)

Dosing errors, sometimes resulting in fatal overdosage, have occurred when the labeled information on the fosphenytoin vial was misinterpreted.1 These errors occurred when the concentration stated on the fosphenytoin vial (e.g., 50 mg PE/mL) was misinterpreted as the total amount of drug in the vial (50 mg PE).1 Fosphenytoin is commercially available in 2-mL vials containing a total of 100 mg PE and 10-mL vials containing a total of 500 mg PE.1 These errors have resulted in a two- or ten-fold overdosage since each vial actually contains a total of 100 mg PE or 500 mg PE.1 The total amount of drug in the vial (in mg PE) must not be confused with the concentration of the drug in the vial (in mg PE/mL).1

Discontinuance of Therapy

Because of the possibility of increasing seizure frequency or status epilepticus if fosphenytoin is abruptly discontinued, the drug should be withdrawn gradually, and dosage reductions or drug substitutions should be done gradually.1 In the event of an allergic or hypersensitivity reaction, more rapid substitution with an alternative, non-hydantoin anticonvulsant may be considered.1

Hepatotoxicity

Acute hepatotoxicity, including infrequent cases of acute hepatic failure, has been reported with phenytoin (the active metabolite of fosphenytoin).1 Such events may or may not occur in association with DRESS.1 (See Multi-organ Hypersensitivity under Warnings/Precautions: Sensitivity Reactions, in Cautions.) Other common manifestations include jaundice, hepatomegaly, elevations of serum hepatic aminotransferase concentrations, leukocytosis, and eosinophilia.1 The clinical course of hepatotoxicity appears to be variable and ranges from prompt recovery to fatal outcome.1

If acute hepatotoxicity occurs, fosphenytoin therapy should be discontinued immediately and not resumed.1

Hematologic Effects

Adverse hematologic effects (sometimes fatal), including thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia (with or without bone marrow suppression), have been reported with phenytoin.1

Local or generalized lymphadenopathy (e.g., benign lymph node hyperplasia, pseudolymphoma, lymphoma, Hodgkin's disease) has occurred in patients receiving phenytoin, although a causal relationship has not been established.1 In some cases, manifestations have resembled DRESS.1 (See Multi-organ Hypersensitivity under Warnings/Precautions: Sensitivity Reactions, in Cautions.) Patients who develop lymphadenopathy should be monitored and further evaluated to establish a differential diagnosis; an alternative anticonvulsant should be used if possible.1

Because phenytoin may exacerbate porphyria, fosphenytoin should be used with caution in patients with this disease.1

Sensory Disturbances

Severe burning, pruritus, and/or paresthesia have been reported in healthy individuals receiving IV fosphenytoin sodium (at a dosage of 1200 mg PE administered at a rate of 150 mg PE/minute).1 These adverse effects (mainly reported in the groin) ranged from mild to severe and persisted for up to 14 or 24 hours for severe or mild reactions, respectively.1 The manufacturer states that patients receiving IV fosphenytoin sodium doses of 20 mg PE/kg administered at a rate of 150 mg PE/minute are likely to experience some discomfort, although the incidence and intensity of such discomfort may be decreased by reducing or temporarily stopping the infusion.1 The effect of continued administration of IV fosphenytoin in the presence of these sensations is unknown, but permanent sequelae have not been reported.1,2 Although the mechanism of these sensory disturbances has not been elucidated, administration of other phosphate ester-containing drugs also has been associated with burning, pruritus, and/or tingling, predominantly in the groin area.1

Local Toxicity

Purple glove syndrome (PGS), characterized by progressive pain, discoloration, and edema of the distal limb, has been reported in patients receiving peripheral IV injections of phenytoin; tissue necrosis and limb ischemia requiring fasciotomy, skin grafting, or amputation have occurred rarely.1,170,171,173,174,175,176,177,178,179,180,181,182,183,184 Although the risk appears to be greater with IV phenytoin, several cases also have been reported in patients receiving fosphenytoin.1,170 (See Cautions: Other Adverse Effects and also see Cautions: Precautions and Contraindications, in Phenytoin 28:12.12)

Phosphate Load

Each mg PE of fosphenytoin sodium provides 0.0037 mmol of phosphate.1 The amount of phosphate contained in the drug should be considered, especially in patients who require phosphate restriction (e.g., patients with severe renal impairment).1

Fetal/Neonatal Morbidity and Mortality

Fosphenytoin may cause fetal harm if used during pregnancy.1 Major congenital malformations, including a fetal hydantoin syndrome, have been reported in children born to epileptic women who received phenytoin alone or in combination with other anticonvulsant drugs during pregnancy.1 In addition, phenytoin has demonstrated embryotoxic and teratogenic effects in animals.1 (See Cautions: Pregnancy and Lactation, in Phenytoin 28:12.12.)

Coagulation defects, which may result in life-threatening bleeding disorders, may occur in neonates exposed to phenytoin in utero; because these reactions are related to decreased concentrations of vitamin K-dependent clotting factors, administration of vitamin K to the mother prior to delivery and to the neonate after birth may prevent these complications.1

Slow Metabolizers of Phenytoin

A small percentage of patients receiving phenytoin have been found to metabolize the drug slowly; this appears to be due to genetic variations in hepatic enzyme induction.1 Because serum concentrations of phenytoin may be higher than expected in such individuals, serum concentrations should be checked immediately if early signs of CNS toxicity occur.1

Hyperglycemia

Because phenytoin inhibits insulin release, increased serum glucose concentrations may occur, resulting in hyperglycemia.1 Phenytoin also may increase serum glucose concentrations in patients with diabetes mellitus.1

CNS Toxicity

Serum phenytoin concentrations sustained above the therapeutic range have been associated with confusional states such as delirium, psychosis, or encephalopathy; rarely, irreversible cerebellar dysfunction may develop.1 Since phenytoin is extensively metabolized in the liver, patients with hepatic impairment, geriatric individuals, and those who are severely ill may show early signs of such toxicity.1

Serum phenytoin concentrations should be checked immediately at the first sign of toxicity.1 Dosage of fosphenytoin should be reduced if serum concentrations are found to be excessive; if symptoms persist, therapy should be discontinued.1

Specific Populations

Pregnancy

Use of phenytoin during pregnancy has been associated with an increased risk of congenital malformations and other adverse developmental outcomes.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Reported cases of malignancies, including neuroblastoma, have occurred in children whose mothers received phenytoin during pregnancy.1

Because of altered pharmacokinetics of phenytoin during pregnancy, serum concentrations of phenytoin may decline, possibly increasing the frequency of seizures in pregnant women receiving fosphenytoin.1 If fosphenytoin is administered during pregnancy, serum phenytoin concentrations should be monitored and dosage of fosphenytoin should be adjusted accordingly.1 (See Dosage and Administration: Special Populations.) Because of altered protein binding, phenytoin concentration monitoring in pregnant women should be based on the unbound (free) phenytoin fraction.1

Women who are pregnant while receiving fosphenytoin should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334; registry information also is available at [Web].1

Lactation

It is not known whether fosphenytoin is distributed into milk; however, phenytoin is distributed into milk.1 The known benefits of breast-feeding should be considered along with the woman's clinical need for fosphenytoin and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of fosphenytoin have been established for the treatment of generalized tonic-clonic status epilepticus and for the prevention and treatment of seizures occurring during neurosurgery in pediatric patients of all age groups.1

Geriatric Use

Fosphenytoin has not been evaluated systematically in geriatric patients.1 The pharmacokinetic profile of fosphenytoin in geriatric adults is similar to that in younger adults.1 However, clearance of phenytoin may be reduced in geriatric patients (20% less in patients older than 70 years of age relative to that in adults 20-30 years of age).1 (See Dosage and Administration: Special Populations.)

Renal and Hepatic Impairment and Hypoalbuminemia

Following IV administration of fosphenytoin sodium in patients with renal or hepatic impairment or in those with hypoalbuminemia, conversion of fosphenytoin to phenytoin may be increased without a similar increase in phenytoin clearance.1 The resulting increases in serum phenytoin concentrations may be associated with an increased incidence and severity of adverse effects.1

Since the fraction of free phenytoin may be increased in patients with renal or hepatic impairment and in those with hypoalbuminemia, total serum phenytoin concentrations should be interpreted with caution in such patients; it is recommended that the free phenytoin fraction be monitored in such patients.1,268

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving fosphenytoin include nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia.1,2,6,7 Sensory disturbances such as paresthesia and pruritus have been reported more frequently in patients receiving IV fosphenytoin than in those receiving IV phenytoin.1

The following drug interaction information is based principally on interactions that are known or expected to occur with phenytoin.1 Because phenytoin is the active metabolite of fosphenytoin, the same drug interactions are expected to occur with fosphenytoin.1

Phenytoin is involved in multiple drug interactions because of its extensive plasma protein binding, saturable metabolism, and potent hepatic enzyme-inducing properties.1

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Phenytoin is metabolized by cytochrome P-450 (CYP) isoenzymes 2C9 and 2C19; concomitant use with drugs that inhibit or induce these CYP isoenzymes can alter serum phenytoin concentrations.1,258 Phenytoin is particularly susceptible to inhibitory interactions because of its saturable metabolism.1 Inhibition of phenytoin metabolism may substantially increase serum concentrations of phenytoin and increase the risk of toxicity.1 If a drug interaction is suspected, serum phenytoin concentrations should be monitored and dosage of fosphenytoin should be adjusted as necessary.1

Drugs that can increase serum phenytoin concentrations include, but are not limited to, azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, miconazole, voriconazole), certain selective serotonin-reuptake inhibitors (SSRIs; e.g., fluoxetine, fluvoxamine, sertraline), cimetidine, omeprazole, sulfonamides, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, and warfarin.1,232 Drugs that can decrease serum phenytoin concentrations include, but are not limited to, certain HIV protease inhibitors (e.g., fosamprenavir, nelfinavir, ritonavir), diazepam, diazoxide, folic acid, rifampin, St. John's wort, sucralfate, and theophylline.1 Certain anticonvulsants (e.g., ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate) can increase serum phenytoin concentrations, while others (e.g., carbamazepine, vigabatrin) can decrease serum concentrations of phenytoin; phenobarbital and valproate can either increase or decrease serum phenytoin concentrations.1 Certain antineoplastic agents (e.g., capecitabine, fluorouracil) can increase serum phenytoin concentrations, while others (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate) can decrease serum concentrations of the drug.1

Phenytoin is a potent inducer of CYP isoenzymes and can therefore decrease plasma concentrations and possibly reduce efficacy of many drugs.1,241,258 Dosage adjustments of these drugs may be necessary when phenytoin is added to or withdrawn from concomitant therapy.1 Drugs whose efficacy may be impaired by phenytoin include, but are not limited to, azole antifungals (e.g, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), certain antineoplastic agents (e.g., irinotecan, paclitaxel, teniposide), delavirdine, neuromuscular blocking agents (e.g., cisatracurium, pancuronium, rocuronium, vecuronium), warfarin, corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D.1 Drugs whose plasma concentrations may be decreased by phenytoin include, but are not limited to, certain anticonvulsant agents (e.g., carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine), certain antilipemic agents (e.g., atorvastatin, fluvastatin, simvastatin), certain antiviral agents (e.g., efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), calcium channel-blocking agents (e.g., nifedipine, nimodipine, nisoldipine, verapamil), albendazole, chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, and quetiapine.1 The effect of phenytoin on phenobarbital and valproate concentrations is unpredictable.1 The effect of phenytoin on fosamprenavir varies depending on whether fosamprenavir is administered alone or in conjunction with ritonavir.1

Protein-bound Drugs

Fosphenytoin and phenytoin are extensively bound to plasma proteins and have the potential to displace or be displaced by other protein-bound drugs.1 Although the clinical importance of this interaction is not known, caution is advised.1

Alcohol

Chronic alcohol abuse can decrease serum phenytoin concentrations, while acute alcohol intake can increase concentrations of the drug.1

Delavirdine

Phenytoin can substantially reduce plasma concentrations of delavirdine and result in loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.1 Concomitant use of fosphenytoin and delavirdine is contraindicated.1

Neuromuscular Blocking Agents

Resistance to the nondepolarizing neuromuscular blocking agents cisatracurium, pancuronium, rocuronium, and vecuronium has occurred in patients receiving long-term phenytoin therapy.1 Whether the same effect occurs with other nondepolarizing neuromuscular blocking agents is not known.1 Patients receiving neuromuscular blocking agents should be monitored closely for more rapid than expected recovery from neuromuscular blockade; increased dosage of the neuromuscular blocking agent may be necessary.1

Oral Contraceptives

Phenytoin can induce the metabolism of oral contraceptives and decrease serum concentrations of estrogens and/or progestins.232,258 The resulting decrease in concentrations of the oral contraceptive may lead to contraceptive failure.1,258

Warfarin

Warfarin may inhibit phenytoin metabolism and increase serum phenytoin concentrations; in addition, phenytoin may induce hepatic metabolism of warfarin and/or displace the anticoagulant from its protein-binding sites.1,106,232 Depending on the response, prothrombin time (PT) and international normalized ratios (INR) may be increased or decreased.1 Dosage adjustments may be required when fosphenytoin is added to or withdrawn from concomitant warfarin therapy.1

Description

Fosphenytoin sodium is a hydantoin-derivative anticonvulsant.1,2,4,6 Fosphenytoin sodium, a water-soluble phosphate ester of phenytoin, is a prodrug and has little, if any, anticonvulsant activity until hydrolyzed in vivo to phenytoin.1,2,4,6 The pharmacologic effects of fosphenytoin are attributed to phenytoin.1,2,6 The exact mechanism of action has not been established, but may be due to voltage-dependent blockade of membrane sodium channels, resulting in a reduction in sustained high-frequency neuronal discharges.1

Following parenteral administration, fosphenytoin sodium is rapidly hydrolyzed (by nonspecific phosphatases) in blood and other tissues (conversion half-life of approximately 8-15 minutes after IV administration) to phenytoin, phosphate, and formaldehyde (subsequently converted to formate).1,1,2,4,6,9,19,23 While phosphate and formaldehyde (formate) have potentially important biologic effects, these effects occur at concentrations substantially higher than those attained with recommended dosages of fosphenytoin.1

The dose and concentration of fosphenytoin sodium are expressed in terms of phenytoin sodium equivalents (PE) in order to avoid the need for molecular weight-based adjustments when converting from fosphenytoin sodium to phenytoin sodium or vice versa.1 (See Dosage and Administration: Dosage.)

IV administration of a 15- to 20-mg PE/kg (about 1200 mg PE) loading dose of fosphenytoin sodium at a rate of 100-150 mg PE/minute in adults results (within about 10-30 minutes) in therapeutic plasma concentrations of unbound phenytoin of about 1-2 mcg/mL, which are similar to those achieved with an equivalent dose (15-20 mg/kg; about 1200 mg) of phenytoin sodium administered IV at a rate of 50 mg/minute.2,4,5,7,19,24,26

For further information on chemistry, pharmacology, and pharmacokinetics, see Phenytoin 28:12.12 and see the Anticonvulsants General Statement 28:12.

Advice to Patients

Risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias, with rapid IV administration; advise patients to report any possible manifestations to their clinician.1

Importance of not abruptly discontinuing therapy.1

Importance of immediately reporting early manifestations of hematologic, dermatologic, hypersensitivity, or hepatic reactions such as fever, sore throat, infection, rash, mouth ulcers, easy bruising, lymphadenopathy, facial swelling, petechial or purpuric hemorrhage, anorexia, nausea/vomiting, or jaundice.1 Advise patients to report these manifestations even if they are mild in severity or occur after extended use.1

Importance of seeking immediate medical care if signs or symptoms of angioedema (e.g., facial, perioral, or upper airway swelling) occur.1

Importance of cautioning patients not to use other drugs or alcoholic beverages without first seeking the clinician's advice.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

Warn women of childbearing potential that fosphenytoin can cause teratogenic effects.1 Advise women of childbearing potential to use effective contraceptive methods during fosphenytoin therapy.1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; discuss therapeutic options with their clinician if pregnancy is planned.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the NAAED pregnancy registry.1

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

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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