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Fosphenytoin

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
Brands: Cerebyx

Medically reviewed by Drugs.com. Last updated on Oct 28, 2019.

Warning

    Cardiovascular Risk Associated with Rapid IV Administration
  • Must be administered IV slowly.1 (See Cardiovascular Toxicity under Cautions.)

  • Do not exceed rate of 150 mg phenytoin sodium equivalents (PE)/minute in adults.1

  • Do not exceed rate of 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower) in pediatric patients.1

  • Carefully monitor cardiac function during and after IV administration; reduction in infusion rate or drug discontinuance may be needed.1

Introduction

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

Uses for Fosphenytoin

Status Epilepticus

Treatment of generalized tonic-clonic status epilepticus.1 4 5 6 10 19 233

Benzodiazepines (e.g., diazepam, lorazepam, midazolam) are considered 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

IV fosphenytoin appears to be better tolerated than IV phenytoin (e.g., fewer adverse cardiovascular effects), and some experts state that fosphenytoin is preferred when both agents are available.233

Compared with IV phenytoin, 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, infusion interruption, and/or changes of infusion sites,1 2 4 6 9 10 14 15 18 19 22 but is associated with a higher incidence of systemic sensory disturbances (e.g., burning, paresthesia, pruritus).1 2 6 7 9 10 14 22

Seizures Occurring During Neurosurgery

Prevention and treatment of seizures occurring during neurosurgery.1 7 27

Replacement Therapy for Oral Phenytoin

May be used as a short-term parenteral replacement for oral phenytoin;1 because of risks associated with parenteral administration, manufacturer states fosphenytoin should only be used when oral phenytoin not possible.1

Fosphenytoin Dosage and Administration

General

  • Dose, concentration, and infusion rate of fosphenytoin sodium are expressed in terms of phenytoin sodium equivalents (PE); molecular weight-based adjustments are therefore not necessary when converting between fosphenytoin and phenytoin.1 Always prescribe and dispense fosphenytoin sodium in terms of phenytoin sodium equivalents (PE), and always express the amount and concentration of fosphenytoin in terms of mg of PE (mg PE).1

  • Inadvertent overdosage (including fatalities) has occurred when the concentration stated on vial (e.g., 50 mg PE/mL) was misinterpreted as the total amount of drug in vial (50 mg PE).1 12 13 21 Take particular care to ensure that correct dose is administered.1 Ensure that correct volume of drug (in mL) is withdrawn from vial.1 12 21 (See Dosing Errors under Cautions.)

  • Because of cardiac and local toxicity risks associated with IV fosphenytoin, use oral phenytoin whenever possible.1

  • Withdraw fosphenytoin therapy gradually to avoid precipitating seizures or status epilepticus.1 (See Discontinuance of Therapy under Cautions.)

Therapeutic Drug Monitoring

  • Monitor serum phenytoin concentrations to guide dosing.1

  • Trough concentrations (obtained just prior to 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

  • Usual therapeutic range 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

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

  • Patients with renal or hepatic impairment and those with hypoalbuminemia have an increased fraction of free phenytoin; monitor free phenytoin concentrations rather than total serum concentrations in these patients.1 268

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

IM administration generally not recommended in pediatric patients, but may be used in nonemergent situations in adults (when IV administration is not possible).1 (See IM Administration under Dosage and Administration.)

IV Administration

Monitor ECG, BP, and respiratory status during IV administration.1 Closely observe patient during period when peak serum phenytoin concentrations are expected (about 10–20 minutes after completion of IV infusion).1

Must dilute commercially available injection prior to IV infusion.1

Dilution

Dilute in 5% dextrose injection or 0.9% sodium chloride injection to provide a solution containing 1.5–25 mg PE/mL.1 Do not exceed maximum recommended concentration of 25 mg PE/mL.1

Rate of Administration

In adults with status epilepticus, administer IV loading doses at a rate of 100–150 mg PE/minute.1 For nonemergent situations in adults, administer IV loading doses at a rate not exceeding 150 mg PE/minute.1

In pediatric patients with status epilepticus, administer IV loading doses 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, administer IV loading doses at a rate not exceeding 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower) and maintenance doses at a rate not exceeding 1–2 mg PE/kg per minute (or 100 mg PE/minute, whichever is slower).1

Because of risk of cardiovascular complications, do not exceed rate of 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 Cautions.)

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 generally not recommended in pediatric patients, but may be used in nonemergent situations in adults (when IV administration is not possible).1

IM administration not recommended for treatment of status epilepticus.1

Dosage

Dosage 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 Always prescribe and dispense fosphenytoin in terms of PE.1 (See General under Dosage and Administration.)

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

Pediatric Patients

Status Epilepticus
IV

Manufacturer recommends loading dose of 15–20 mg PE/kg by IV infusion at a rate of 2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower).1 Some clinicians recommend a higher initial 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

Following loading dose, administer maintenance doses of fosphenytoin or phenytoin.1 Because of risks associated with IV fosphenytoin, use oral phenytoin whenever possible.1 If fosphenytoin is used, recommended initial maintenance dosage is 2–4 mg PE/kg every 12 hours by IV infusion at a rate of 1–2 mg PE/kg per minute (or 100 mg PE/minute, whichever is slower); begin maintenance dosing 12 hours after the loading dose.1

Individualize subsequent maintenance dosage based on serum phenytoin concentrations.1

Nonemergent Situations
IV

If fosphenytoin is used for a nonemergent situation (e.g., prevention and treatment of seizures during neurosurgery), recommended loading dose is 10–15 mg PE/kg by IV infusion at a rate of 1–2 mg PE/kg per minute (or 150 mg PE/minute, whichever is slower).1

Following loading dose, administer initial maintenance dosage of 2–4 mg PE/kg every 12 hours by IV infusion at a rate of 1–2 mg PE/kg per minute (or 100 mg PE/minute, whichever is slower); begin maintenance dosing 12 hours after the loading dose.1

Individualize subsequent maintenance dosage based on serum phenytoin concentrations.1

Parenteral Substitution for Oral Phenytoin Therapy
IV or IM

Patients being transferred from oral phenytoin sodium to IV or IM fosphenytoin sodium therapy may receive same total daily dosage in terms of PE.1 IM administration generally not recommended in pediatric patients.1

When transitioning from phenytoin sodium capsules to parenteral fosphenytoin, serum phenytoin concentrations may be slightly higher because bioavailability of the capsules is 90%.1

Adults

Status Epilepticus
IV

Manufacturer recommends loading dose of 15–20 mg PE/kg by IV infusion at a rate of 100–150 mg PE/minute.1 Some clinicians recommend a higher initial 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

Following loading dose, administer maintenance doses of fosphenytoin or phenytoin.1 Because of risks associated with IV fosphenytoin, use oral phenytoin whenever possible.1 If fosphenytoin is used, recommended initial maintenance dosage is 4–6 mg PE/kg daily in divided doses by IV infusion at a rate not exceeding 150 mg PE/minute.1 Begin maintenance dosing at the next identified dosing interval.1

Individualize subsequent maintenance dosage based on serum phenytoin concentrations.1

Nonemergent Situations
IV or IM

If fosphenytoin is used for a nonemergent situation (e.g., prevention and treatment of seizures during neurosurgery), recommended loading dose is 10–20 mg PE/kg by IV infusion (at a rate not exceeding 150 mg PE/minute) or IM injection.1

Following loading dose, administer initial maintenance dosage of 4–6 mg PE/kg daily in divided doses at a rate not exceeding 150 mg PE/minute.1 Begin maintenance dosing at the next identified dosing interval.1

Individualize subsequent maintenance dosage based on serum phenytoin concentrations.1

Parenteral Substitution for Oral Phenytoin Therapy
IV or IM

Patients being transferred from oral phenytoin sodium to IV or IM fosphenytoin sodium therapy may receive 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 bioavailability of the capsules is 90%.1

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Lower doses or less frequent dosing may be required in geriatric patients.1 (See Geriatric Use under Cautions.)

Pregnancy

Monitor serum phenytoin concentrations closely (concentrations may decline) and adjust dosage as necessary.1 Restoration of original dosage will probably be necessary postpartum.1 (See Pregnancy under Cautions.)

Cautions for Fosphenytoin

Contraindications

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

  • Sinus bradycardia, SA block, second- or third-degree 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

Rapid IV administration of fosphenytoin has caused severe hypotension and cardiac arrhythmias, including bradycardia, heart block, QT-interval prolongation, ventricular tachycardia, and ventricular fibrillation; sometimes resulted in asystole, cardiac arrest, and death.1 194

Severe complications reported more commonly in critically ill patients, geriatric patients, and those with hypotension and severe myocardial insufficiency.1 However, cardiac events also reported in adults and pediatric patients without underlying cardiac disease or other comorbidities and at recommended dosages and infusion rates.1

Do not exceed recommended rates of administration.1 (See Boxed Warning.) Risk of toxicity increases with infusion rates above recommended rates; however, cardiac events also can occur at or below these rates.1

Carefully monitor cardiac and respiratory function during and after IV administration; reduce rate of administration or discontinue drug if necessary.1

Contraindicated in patients with certain cardiac conduction disorders because of the drug's effect on ventricular automaticity.1 (See Contraindications under Cautions.)

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), reported with phenytoin.1 Onset is usually within first 28 days, but can occur later.1

Discontinue fosphenytoin at the first sign of a rash unless it is clearly not drug related; do not resume if SJS/TEN is suspected and consider alternative therapy.1

Pharmacogenomic Considerations in the Development of Cutaneous Reactions

Limited data suggest an increased risk of SJS/TEN 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 presence of HLA-B*1502 and risk of SJS/TEN in patients with Chinese ancestry receiving carbamazepine; although evidence more limited, HLA-B*1502 also associated with SJS/TEN in such patients receiving structurally similar anticonvulsants such as phenytoin.1 231 232

Fosphenytoin generally should not be used as an alternative to carbamazepine in HLA-B*1502-positive patients.1 231

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) reported; can be fatal or life-threatening.1 Clinical presentation is variable but typically includes fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement (e.g., eosinophilia, hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).1

If manifestations of DRESS occur, evaluate patient immediately.1 If an alternative etiology cannot be identified, discontinue fosphenytoin.1

Hypersensitivity Reactions

Angioedema reported.1 If manifestations (e.g., facial, perioral, or upper airway swelling) occur, discontinue drug immediately.1 (See Contraindications under Cautions.)

Structurally similar compounds such as carboxamides, barbiturates, succinimides, and oxazolidinediones should not be used in patients who have experienced phenytoin hypersensitivity; consider alternatives.1 Also consider alternatives to fosphenytoin if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family member.1

General Precautions

Dosing Errors

Inadvertent overdosage, sometimes fatal, has 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 12 13 21

Do not confuse total amount of drug in vial (in mg PE) with concentration of drug in vial (in mg PE/mL).1 (See General under Dosage and Administration.)

Discontinuance of Therapy

Abrupt withdrawal can increase seizure frequency, including status epilepticus; reduce dosage, discontinue drug, or substitute with another anticonvulsant gradually.1 In the event of an allergic or hypersensitivity reaction, may consider more rapid substitution with an alternative non-hydantoin anticonvulsant.1

Hepatotoxicity

Acute hepatotoxicity, including infrequent cases of acute hepatic failure, reported with phenytoin.1 May or may not occur in association with DRESS.1 (See Multi-organ Hypersensitivity under Cautions.)

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

Local or generalized lymphadenopathy (e.g., benign lymph node hyperplasia, pseudolymphoma, lymphoma, Hodgkin's disease) also reported, although a causal relationship not established.1 In some cases, manifestations have resembled DRESS.1 (See Multi-organ Hypersensitivity under Cautions.) If lymphadenopathy develops, further evaluate to establish a differential diagnosis; switch to an alternative anticonvulsant if possible.1

May exacerbate porphyria; use with caution in patients with this condition.1

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

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 of such discomfort.1

Local Toxicity

Purple glove syndrome (PGS), characterized by progressive pain, discoloration, and edema of the distal limb, reported with IV fosphenytoin and IV phenytoin.1 170 171 173 174 175 176 177 178 179 180 181 182 183 184 Can occur with or without extravasation and may develop as late as several days after injection.1 173 174 175 176 177 178 179 180 181 182 Risk appears to be greater with phenytoin than fosphenytoin.170

Phosphate Load

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Fosphenytoin is embryotoxic and teratogenic in animals.1

Evidence of substantial risk of congenital malformations, fetal hydantoin syndrome (e.g., craniofacial abnormalities, nail and digital hypoplasia, prenatal growth deficiency, microcephaly, cognitive deficiency), and other developmental toxicity with phenytoin.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 may prevent these disorders.1

Slow Metabolizers of Phenytoin

A small percentage of individuals have been shown to metabolize phenytoin slowly; this appears to be genetically determined and may be due to limited enzyme availability and lack of induction.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 may produce confusional states (e.g., delirium, psychosis, encephalopathy); rarely, irreversible cerebellar dysfunction may develop.1

Check serum phenytoin concentrations immediately at the first sign of toxicity.1 Reduce fosphenytoin dosage if serum concentrations are excessive; if symptoms persist, discontinue therapy.1

Specific Populations

Pregnancy

May cause fetal harm if used during pregnancy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Malignancies, including neuroblastoma, reported rarely in children whose mothers received phenytoin during pregnancy.1

Potential for increased seizure frequency during pregnancy due to alteration of phenytoin pharmacokinetics.1 Monitor serum phenytoin concentrations and adjust dosage accordingly.1 Because of altered protein binding, monitor free phenytoin fraction in pregnant women.1

North American Antiepileptic Drug (NAAED) pregnancy registry at 888-233-2334; registry information also available at [Web].1

Lactation

Not known whether fosphenytoin is distributed into milk; however, phenytoin is distributed into milk.1 Consider known benefits of breast-feeding 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 established for treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery in pediatric patients of all ages.1

Geriatric Use

Not systematically evaluated in geriatric patients.1 Clearance may be reduced.1

Hepatic Impairment

Following IV administration, conversion of fosphenytoin to phenytoin may be increased without a similar increase in phenytoin clearance; this may increase incidence and severity of adverse effects.1

Since fraction of free phenytoin may be increased in patients with hepatic impairment, monitor free phenytoin concentration rather than total serum concentration in such patients.1 268

Renal Impairment

Following IV administration, conversion of fosphenytoin to phenytoin may be increased without a similar increase in phenytoin clearance; this may increase incidence and severity of adverse effects.1

Since fraction of free phenytoin may be increased in patients with renal impairment, monitor free phenytoin concentration rather than total serum concentration in such patients.1 268

Patients with Hypoalbuminemia

Since fraction of free phenytoin may be increased in patients with hypoalbuminemia, monitor free phenytoin concentration rather than total serum concentration in such patients.1 268

Common Adverse Effects

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

Interactions for Fosphenytoin

Drug interactions that are known or expected to occur with phenytoin also are expected to occur with fosphenytoin.1 Phenytoin is involved in multiple drug interactions because of extensive plasma protein binding, saturable metabolism, and potent hepatic enzyme-inducing properties.1

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Phenytoin is metabolized by CYP2C9 and CYP2C19.1 Phenytoin is a potent inducer of CYP isoenzymes.1 241 258

Concomitant use with drugs that inhibit or induce CYP2C9 and CYP2C19 can alter serum phenytoin concentrations.1 258 Phenytoin is particularly susceptible to inhibitory interactions because of saturable metabolism.1

Because of its potent CYP-inducing properties, phenytoin can decrease plasma concentrations and possibly reduce efficacy of many drugs.1 241 258

Protein-bound Drugs

Fosphenytoin and phenytoin are extensively bound to plasma proteins and have potential to displace or be displaced by other protein-bound drugs.1 Clinical importance not known.1 Use with caution.1

Specific Drugs

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

Drug

Interaction

Comments

Albendazole

Possible decreased plasma concentrations of albendazole1

Dosage adjustment of albendazole may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Alcohol abuse, acute

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Alcohol intake, chronic

Possible decreased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Amiodarone

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Anticonvulsants

Certain anticonvulsants may increase (e.g., ethosuximide, oxcarbazepine, methsuximide, felbamate, topiramate) or decrease (e.g., vigabatrin, carbamazepine) serum phenytoin concentrations1

Phenytoin may decrease plasma concentrations of lamotrigine, felbamate, carbamazepine, oxcarbazepine and topiramate1

Phenobarbital and valproate may increase or decrease serum phenytoin concentrations; effect of phenytoin on phenobarbital and valproate concentrations is unpredictable1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of some anticonvulsants may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Antifungals, azoles

Certain antifungal agents (e.g., fluconazole, itraconazole, ketoconazole, miconazole, voriconazole) may increase serum phenytoin concentrations1

Efficacy of certain antifungals (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole) may be impaired by phenytoin1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of some antifungal agents may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Antineoplastic agents

Certain antineoplastic agents may increase (e.g., capecitabine, fluorouracil) or decrease (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate) serum phenytoin concentrations1

Efficacy of certain antineoplastic agents (e.g., irinotecan, paclitaxel, teniposide) may be impaired by phenytoin1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of some antineoplastic agents may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Calcium-channel blocking agents

Phenytoin may decrease plasma concentrations of nifedipine, nimodipine, nisoldipine, and verapamil1

Dosage adjustment of the calcium-channel blocking agent may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Chloramphenicol

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Chlordiazepoxide

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Chlorpropamide

Possible decreased plasma chlorpropamide concentrations1

Dosage adjustment of chlorpropamide may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Cimetidine

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Clozapine

Possible decreased plasma clozapine concentrations1

Dosage adjustment of clozapine may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Corticosteroids

Efficacy may be impaired by phenytoin1

Dosage adjustment of the corticosteroid may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Cyclosporine

Possible decreased plasma cyclosporine concentrations1

Dosage adjustment of cyclosporine may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Delavirdine

Phenytoin can substantially decrease serum concentrations of delavirdine, resulting in loss of virologic response and possible resistance1

Concomitant use contraindicated1

Diazepam

Possible decreased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Diazoxide

Possible decreased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Digoxin

Possible decreased plasma digoxin concentrations1

Dosage adjustment of digoxin may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Disopyramide

Possible decreased plasma disopyramide concentrations1

Dosage adjustment of disopyramide may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Disulfiram

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Doxycycline

Efficacy may be impaired by phenytoin1

Dosage adjustment of doxycycline may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Efavirenz

Possible decreased plasma efavirenz concentrations1

Dosage adjustment of efavirenz may be necessary when phenytoin is added to or withdrawn from concomitant therapy195

Estrogens

Possible increased serum phenytoin concentrations1

Efficacy of estrogens may be impaired by phenytoin1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of estrogens may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Folic acid

Possible decreased serum phenytoin concentrations1

Possible decreased plasma concentrations of folic acid1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of folic acid may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Furosemide

Efficacy may be impaired by phenytoin1

Dosage adjustment of furosemide may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

HIV protease inhibitors (PIs)

Some HIV PIs (e.g., fosamprenavir, nelfinavir, ritonavir) may decrease serum phenytoin concentrations1

Phenytoin may decrease plasma concentrations of nelfinavir, ritonavir, lopinavir/ritonavir, indinavir, and saquinavir1

Effect of phenytoin on fosamprenavir varies depending on whether fosamprenavir is administered alone or in conjunction with ritonavir1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of some HIV PIs may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

HMG-CoA reductase inhibitors (statins)

Fluvastatin may increase serum phenytoin concentrations1

Phenytoin may decrease plasma concentrations of atorvastatin, fluvastatin, and simvastatin1

Fluvastatin: Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Atorvastatin, fluvastatin, simvastatin: Dosage adjustment of the statin may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Isoniazid

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Methadone

Possible decreased plasma methadone concentrations1

Dosage adjustment of methadone may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Methylphenidate

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Mexiletine

Possible decreased plasma mexiletine concentrations1

Dosage adjustment of mexiletine may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Neuromuscular blocking agents

Cisatracurium, pancuronium, rocuronium, vecuronium: Resistance to these nondepolarizing neuromuscular blocking agents has occurred in patients receiving long-term phenytoin therapy; whether same effect occurs with other nondepolarizing neuromuscular blocking agents not known1

Monitor closely for more rapid than expected recovery from neuromuscular blockade; increase dosage of the neuromuscular blocking agent if necessary1

Omeprazole

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Oral contraceptives

Phenytoin can induce metabolism and decrease concentrations of estrogens and/or progestins;232 258 may lead to contraceptive failure1 258

Phenothiazines

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Praziquantel

Possible decreased plasma praziquantel concentrations1

Dosage adjustment of praziquantel may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Quetiapine

Possible decreased plasma quetiapine concentrations1

Dosage adjustment of quetiapine may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Quinidine

Efficacy may be impaired by phenytoin1

Dosage adjustment of quinidine may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Rifampin

Possible decreased serum phenytoin concentrations1

Efficacy of rifampin may be impaired by phenytoin1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of rifampin may be required when phenytoin is added to or withdrawn from concomitant therapy1

Salicylates

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

SSRIs

Some SSRIs (e.g., fluoxetine, fluvoxamine, sertraline) may increase serum phenytoin concentrations1

Phenytoin may impair efficacy of paroxetine and sertraline 1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of paroxetine and sertraline may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

St. John's wort

Possible decreased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Sucralfate

Possible decreased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Sulfonamides

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Theophylline

Possible decreased serum phenytoin concentrations1

Efficacy of theophylline may be impaired by phenytoin1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Dosage adjustment of theophylline may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Ticlopidine

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Tolbutamide

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Trazodone

Possible increased serum phenytoin concentrations1

Monitor serum phenytoin concentrations and adjust dosage of phenytoin accordingly1

Vitamin D

Efficacy may be impaired by phenytoin1

Dosage adjustment of vitamin D may be necessary when phenytoin is added to or withdrawn from concomitant therapy1

Warfarin

Warfarin may increase serum phenytoin concentrations; phenytoin may induce hepatic metabolism of warfarin and/or displace the anticoagulant from its protein-binding sites1 106 232

PT/INR response may be increased or decreased1

Closely monitor patient and adjust dosage of warfarin or fosphenytoin as necessary1

Fosphenytoin 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.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 (approximately 0.5–1 hour post-infusion).1

Special Populations

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

In pregnant women, phenytoin clearance reaches a peak in the third trimester and returns to pre-pregnancy levels a few weeks or months following delivery.1

Elimination

Metabolism

Fosphenytoin is rapidly metabolized to phenytoin by blood and tissue phosphatases.1 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 (See Slow Metabolizers of Phenytoin under Cautions.)

Elimination Route

Fosphenytoin is not excreted in urine.1 However, 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

Dextrose 5% in Ringer’s injection, lactated

Dextrose 5% in sodium chloride 0.45%

Dextrose 5 or 10% in water

Plasma-Lyte A, pH 7.4

Ringer’s injection, lactated

Sodium chloride 0.9%

Drug Compatibility
Admixture CompatibilityHID

Compatible

Hetastarch in sodium chloride 0.9%

Mannitol

Potassium chloride

Y-Site CompatibilityHID

Compatible

Ceftolozane sulfate-tazobactam sodium

Lorazepam

Meropenem-vaborbactam

Phenobarbital sodium

Tedizolid phosphate

Incompatible

Fenoldopam mesylate

Isavuconazonium sulfate

Midazolam HCl

Actions

  • Prodrug of phenytoin.1 2 4 6

  • Pharmacologic effects attributed to phenytoin.1 2 6

  • Mechanism of action may be due to voltage-dependent blockade of membrane sodium channels, resulting in a reduction in sustained high-frequency neuronal discharges.1

  • May produce hypotension following IV administration.1

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.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* 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

50 mg (as phenytoin sodium equivalents [PE]) per mL*

Cerebyx

Pfizer

Fosphenytoin Sodium Injection

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 28, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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