Fosphenytoin Sodium

Pronunciation: fos-FEN-i-toin SOE-dee-um
Class: Anticonvulsant, Hydantoin

Trade Names

Cerebyx
- Injection, solution, concentrate 75 mg/mL (equivalent to phenytoin sodium 50 mg/mL)

Pharmacology

Fosphenytoin is a prodrug that is converted to the active metabolite phenytoin. Appears to act at motor cortex by inhibiting spread of seizure activity. Possibly works by promoting sodium efflux from neurons, thereby stabilizing threshold against hyperexcitability.

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Pharmacokinetics

Absorption

T max is approximately 30 min (IM). Bioavailability is 100% with IM dosing.

Distribution

Protein binding is 95% to 99%, approximately 88% for phenytoin. Vd is 4.3 to 10.8 L.

Metabolism

Fosphenytoin converts to phenytoin by hydrolysis. Phenytoin is extensively metabolized in the liver.

Elimination

The conversion half-life of fosphenytoin to phenytoin is approximately 15 min; the mean half-life is 12 to 28.9 h (phenytoin). Fosphenytoin is primarily excreted in the urine as metabolites.

Special Populations

Renal Function Impairment

Increased fraction of unbound phenytoin may occur.

Hepatic Function Impairment

Increased fraction of unbound phenytoin may occur.

Elderly

Cl decreases approximately 20% in patients older than 70 yr of age.

Children

No major pharmacokinetic differences were observed between children and adults with status epilepticus when receiving comparable doses.

Gender

No significant impact on fosphenytoin or phenytoin pharmacokinetics.

Race

No significant impact on fosphenytoin or phenytoin pharmacokinetics.

Hypoalbuminemia

Increased fraction of unbound phenytoin may occur.

Indications and Usage

Short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate, or less advantageous; treatment of generalized convulsive status epilepticus; prevention and treatment of seizures occurring during neurosurgery; short-term substitution for oral phenytoin.

Contraindications

Hypersensitivity to fosphenytoin, phenytoin, or other hydantoins; patients with sinus bradycardia, sino atrial block, second- and third-degree AV block, and Adams-Stokes syndrome.

Dosage and Administration

Status epilepticus
Adults Initial/Loading dose

IV 15 to 20 mg as phenytoin sodium equivalent /kg administered IV at 100 to 150 mg of phenytoin sodium equivalent/min.

Prevention of seizures occurring during neurosurgery
Adults Loading dose

IV / IM 10 to 20 mg of phenytoin sodium equivalent/kg

Maintenance dosing for seizures
Adults

IV / IM 4 to 6 mg of phenytoin sodium equivalent/kg/day.

General Advice

  • Do not administer solution if particulate matter or discoloration is noted.
  • May use dextrose 5% or saline 0.9% solution for dilution prior to administration to a concentration ranging from 1.5 to 25 mg of phenytoin sodium equivalent/mL.
  • Do not mix with other drugs.
  • Administer IV no faster than 150 mg of phenytoin sodium equivalent/min to reduce risk of hypotension.
  • To avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium, the fosphenytoin dose is expressed as phenytoin sodium equivalent.
  • Fosphenytoin IM or IV can be substituted for oral phenytoin therapy at the same total daily dose.
  • If rapid phenytoin loading is the primary goal, IV administration of fosphenytoin is preferred.

Storage/Stability

Store in refrigerator at 36° to 46°F. Do not keep at room temperature for more than 48 h.

Drug Interactions

Acetaminophen

The potential hepatotoxicity of acetaminophen may be increased when long-term doses of hydantoins are coadministered. The therapeutic effects of acetaminophen may be reduced with simultaneous phenytoin therapy.

Alcohol

Acute alcohol ingestion may increase phenytoin plasma levels, while long-term use may decrease plasma concentrations. Monitor phenytoin plasma concentrations and adjust the fosphenytoin dose as needed.

Amiodarone

May cause increased serum phenytoin concentrations with symptoms of toxicity. Phenytoin may decrease amiodarone serum levels. Monitor drug concentrations and observe patients for phenytoin toxicity or loss of amiodarone therapeutic effect when this combination is used. Adjust the dose of either drug as needed.

Anticoagulants (eg, warfarin)

May cause increased phenytoin serum concentrations with possible toxicity. Increased and decreased PT/INR responses have been reported. May increase or decrease the anticoagulant effect of warfarin. Monitor the response of the patient and adjust the dose of either drug as needed.

Antineoplastic agents (eg, bleomycin), chloral hydrate, ciprofloxacin, corticosteroids, diazoxide, enteral nutrition therapy, folic acid, reserpine, sirolimus, vigabatrin

Phenytoin serum concentrations may be reduced, decreasing the efficacy. Monitor phenytoin serum levels and adjust the fosphenytoin dose appropriately.

Azole antifungal agents (eg, itraconazole, ketoconazole, voriconazole)

Phenytoin plasma levels may be elevated, increasing the risk of toxicity, while itraconazole, ketoconazole, and voriconazole plasma levels may be reduced, decreasing efficacy. If coadministration cannot be avoided, monitor phenytoin plasma concentrations and observe the clinical response of the patient. Adjust the dose of either drug as needed.

Barbiturates (eg, phenobarbital)

The effect of barbiturates on hydantoins is unpredictable. Phenobarbital may either increase or decrease plasma phenytoin concentrations. The addition of phenytoin may increase barbiturate serum concentrations. Monitor serum concentrations of both drugs, seizure activity, and clinical symptoms when initiating or discontinuing either drug. Adjust treatment as needed.

Benzodiazepines (eg, midazolam), cimetidine, disulfiram, erlotinib, fluorouracil, fluoxetine, fluvoxamine, halothane, isoniazid, methylphenidate, omeprazole, phenacemide, salicylates (eg, aspirin), sertraline, succinimides (ethosuximide), sulfonamides (eg, sulfadiazine), ticlopidine, trazodone, trimethoprim

Phenytoin serum concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Monitor phenytoin concentrations and observe the clinical response of the patient. Adjust the fosphenytoin dose as needed.

Carbamazepine

The effect of carbamazepine on phenytoin is variable. Phenytoin decreases serum carbamazepine levels. Monitor serum concentrations of both drugs, particularly when starting or stopping one drug. Adjust the dose of either or both drugs as needed.

Chloramphenicol

May cause increased serum phenytoin concentrations with potential toxicity. Chloramphenicol concentrations may be increased or decreased. Measure concentrations of both drugs and observe the patient for signs of phenytoin toxicity. Adjust the dose of either drug as needed.

Corticosteroids, digoxin, doxycycline, everolimus, felodipine, gefitinib, haloperidol, imatinib, irinotecan, ixabepilone, levodopa, loop diuretics (eg, furosemide), maraviroc, methadone, mexiletine, mirtazapine, nisoldipine, praziquantel, quetiapine, quinidine, temsirolimus, teniposide, tolvaptan, vitamin D

The effects of these agents may be impaired. Monitor for a decrease in therapeutic effect and increase the dose of these agents as needed.

Cyclosporine

Cyclosporine concentrations may be decreased, resulting in a decrease in the immunosuppressive activity, which may predispose patients to transplant rejection. Measure cyclosporine concentrations and monitor for evidence of transplant rejection. Adjust the cyclosporine dose as needed.

Disopyramide

Disopyramide concentrations and bioavailability may be decreased, while anticholinergic actions may be enhanced. Monitor the response of the patient and adjust the disopyramide dose as needed.

Dronedarone, NNRT inhibitors (eg, etravirine), posaconazole, tyrosine kinase receptor inhibitors (eg, dasatinib, lapatinib, nilotinib)

Plasma concentrations of these agents may be reduced by phenytoin, decreasing the pharmacologic effects. Avoid coadministration.

Estrogens (eg, conjugated estrogens, ethinyl estradiol), hormonal contraceptives, progestins (eg, levonorgestrel, norgestrel)

Phenytoin levels may be increased by estrogens or hormonal contraceptives. Pharmacologic effects of estrogens, hormonal contraceptives, and progestins may be decreased. Alternative or nonhormonal contraception is recommended during hydantoin therapy. Also, monitor phenytoin concentrations and observe the clinical response of the patient. Adjust the fosphenytoin dose as needed.

Exemestane

Exemestane plasma concentrations may be reduced, decreasing the pharmacologic effects. The recommended dosage of exemestane is 50 mg once daily after a meal if fosphenytoin is coadministered. If fosphenytoin is discontinued, reduce the exemestane dosage to 25 mg once daily with a meal.

Felbamate

Serum phenytoin concentrations may be increased, possibly resulting in an increase in the pharmacologic and toxic effects of phenytoin. Phenytoin may also decrease felbamate concentrations. Monitor phenytoin and felbamate concentrations, and observe patients for changes in seizure control. Adjust the dose of either drug as needed.

HMG-CoA reductase inhibitors (eg, atorvastatin, simvastatin)

HMG-CoA reductase inhibitor concentrations may be reduced, decreasing the pharmacologic effect. Monitor the clinical response of the patient. If an interaction is suspected, consider administering alternative therapy. Pravastatin may be less likely to interact.

Metyrapone

Phenytoin may cause subnormal response to metyrapone. Consider using oral metyrapone doses of as much as twice the usual amount.

Nondepolarizing muscle relaxants (eg, cisatracurium, pancuronium, vecuronium)

Nondepolarizing muscle relaxants may have a shorter than expected duration of action or be less effective. Nondepolarizing muscle relaxant dosages may need to be increased. Monitor for reduced effectiveness.

Phenothiazines (eg, fluphenazine, prochlorperazine, thioridazine)

An increase in the pharmacologic effects of phenytoin and a decrease in the effectiveness of thioridazine may be observed. Measure phenytoin concentrations and monitor the patient for signs of toxicity. Adjust the fosphenytoin dose as needed.

Primidone

May increase concentrations of primidone and primidone metabolites, increasing the effects. Closely monitor primidone and primidone metabolites and patient response following any alteration in phenytoin therapy. Adjust the primidone dose as needed.

Protease inhibitors (eg, lopinavir/ritonavir)

Certain protease inhibitors and phenytoin plasma concentrations may be reduced during coadministration, decreasing the therapeutic effects of both drugs. Measure phenytoin concentrations. Adjust the dose of fosphenytoin or lopinavir/ritonavir as needed.

Rifamycins (eg, rifabutin, rifampin)

Serum phenytoin levels may be decreased, resulting in a possible decrease in the pharmacologic effects of phenytoin. Phenytoin may impair efficacy of rifampin. Measure phenytoin concentrations and observe the response of the patient when rifabutin or rifampin is initiated or discontinued. Adjust the fosphenytoin dose as needed. An increased rifampin dosage may be necessary.

Sodium valproate, valproic acid

Coadministration may either increase or decrease plasma phenytoin concentrations, while those of valproic acid may be decreased. Phenytoin toxicity may occur at therapeutic total plasma concentrations. Monitor the levels of the free concentrations of phenytoin and serum valproic acid levels. Adjust dose of either drug as needed.

Sympathomimetics (eg, dopamine)

May cause profound hypotension and possibly cardiac arrest. Use fosphenytoin with extreme caution.

Tacrolimus

Tacrolimus serum concentrations may be reduced, decreasing the efficacy, while phenytoin concentrations may be elevated, increasing the pharmacologic effects and adverse reactions. Monitor serum concentrations of both tacrolimus and phenytoin. Adjust the dose of fosphenytoin or tacrolimus as needed.

Theophyllines

Effects of either agent may be decreased. When either medication is added to or deleted from a patient's regimen, monitor plasma levels of each drug and adjust the doses as needed.

Tolbutamide

Serum phenytoin levels may be increased. Measure phenytoin concentrations. If an interaction is suspected, adjust the fosphenytoin dose as needed. Phenytoin may cause an increase in blood glucose levels, necessitating a higher dose of sulfonylurea for control of hyperglycemia

Topiramate

Topiramate may increase the effects of phenytoin, while phenytoin may decrease the pharmacologic effects of topiramate. Measure phenytoin concentrations and observe the response of the patient when topiramate is initiated or discontinued. Adjust the fosphenytoin dose as needed. A decreased topiramate dose may be needed when fosphenytoin is stopped after concurrent use.

Tricyclic antidepressants (eg, amitriptyline)

May precipitate seizures, necessitating fosphenytoin dosage adjustments. The pharmacologic effects of phenytoin may be elevated, increasing the pharmacologic effects and risk of toxicity. Measure phenytoin concentrations and observe the response of the patient when a tricyclic antidepressant is started or stopped. If an interaction is suspected, adjust the fosphenytoin dose as needed.

Laboratory Test Interactions

Phenytoin may interfere with metyrapone and dexamethasone tests, causing inaccurate results because of increased metabolism of these agents. Phenytoin may cause decrease in serum levels of protein-bound iodine.

Adverse Reactions

Cardiovascular

Hypotension (8%); vasodilatation (6%); tachycardia (2%); hypertension (at least 1%).

CNS

Nystagmus (44%); dizziness (31%); somnolence (20%); ataxia (11%); tremor (10%); headache (9%); incoordination, stupor (8%); asthenia, extrapyramidal syndrome, paresthesia (4%); agitation, decreased reflexes (3%); brain edema, dysarthria, hypesthesia, vertigo (2%); abnormal thinking, increased reflexes, intracranial hypertension, nervousness, speech disorder (at least 1%).

Dermatologic

Pruritus (49%); face edema, rash (at least 1%).

EENT

Tinnitus (9%); diplopia, taste perversion (3%); amblyopia, deafness (2%).

GI

Nausea (9%); dry mouth, tongue disorder (4%); vomiting (3%); constipation (at least 1%).

Hematologic-Lymphatic

Ecchymosis (7%).

Lab Tests

Increased levels of alkaline phosphatase, GGT, and glucose.

Local

Injection-site pain, injection-site reaction (at least 1%).

Metabolic-Nutritional

Hypokalemia (at least 1%).

Musculoskeletal

Back pain (2%); myasthenia (at least 1%).

Respiratory

Pneumonia (at least 1%).

Miscellaneous

Pelvic pain (4%); chills, fever, infection (at least 1%).

Precautions

Monitor

Continuous monitoring of the ECG, BP, and respiratory function is essential; observe patients throughout the period of maximal serum phenytoin concentrations, approximately 10 to 20 min after fosphenytoin infusion. Periodically measure plasma phenytoin levels.


Pregnancy

Category D .

Lactation

Undetermined (fosphenytoin); excreted in breast milk (phenytoin).

Children

Safety and efficacy not established.

Special Risk Patients

Use drug with caution in patients with hepatic or renal impairment, hypotension, severe myocardial insufficiency, and alcohol abuse.

Age

Age does not affect fosphenytoin pharmacokinetics. Phenytoin dosing requirements are variable and should be individualized.

CV effects

Following administration of phenytoin, severe CV reactions and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Careful cardiac monitoring is needed when administering IV loading doses of fosphenytoin.

Hematologic effects

Hematopoietic complications, some fatal, have been reported. These included agranulocytosis, granulocytopenia, leukopenia, pancytopenia, and thrombocytopenia.

Hepatotoxicity

Acute hepatotoxicity, including infrequent cases of hepatic failure, has been reported with phenytoin. These have been associated with a hypersensitivity syndrome, which usually occurs in the first 2 mo and includes fever, lymphadenopathy, and skin eruptions.

Hyperglycemia

May result because of the inhibitory effect of phenytoin on insulin release.

Lymphadenopathy

Local or generalized lymphadenopathy, including benign lymph node hyperplasia, Hodgkin disease, lymphoma, and pseudolymphoma have been reported.

Phosphate load

Consider phosphate load due to content of phosphates in fosphenytoin injection in patients who have phosphate restriction (eg, severe renal impairment).

Porphyria

May be exacerbated.

Postpartum

A potentially life-threatening bleeding disorder related to reduced levels of vitamin K–dependent clotting factors may occur in the newborn. This drug-induced condition can be prevented with vitamin K administration to the mother prior to birth and to the neonate after delivery.

Rash

Discontinue treatment if a rash appears.

Risk to fetus

Prenatal exposure may increase the risk for congenital malformations and other adverse developmental outcomes (eg, cardiac defects, nail and digit hypoplasia, orofacial clefts).

Risk to mother

Seizure frequency may increase during pregnancy because of altered pharmacokinetics.

Sensory disturbances

Severe burning, itching, and paresthesia have been reported.

Serum folate

Folate serum concentrations may be reduced.

Slow metabolizers

A small percentage of individuals treated with phenytoin have been shown to metabolize the drug slowly, possibly because of limited enzyme availability and lack of induction.

Withdrawal

Abrupt withdrawal may precipitate status epilepticus. Dosage must be reduced or other anticonvulsant medicine substituted gradually.

Overdosage

Symptoms

Fosphenytoin

Asystole, bradycardia, cardiac arrest, death, hypocalcemia, hypotension, lethargy, metabolic acidosis, nausea, syncope, tachycardia, vomiting.

Phenytoin

Ataxia, circulatory and respiratory depression leading to death, coma, dysarthria, hyperreflexia, hypotension, lethargy, nausea, nystagmus, slurred speech, tremor, vomiting.

Patient Information

  • Explain to family and patient that the medication is a short-term substitute for the regular use of phenytoin.
  • Explain to family and patient that sedation or drowsiness might occur as a result of the medication.
  • Instruct patients to avoid alcohol and other CNS drugs while taking this medication.
  • Warn patient to never suddenly discontinue the medication; discontinuation may lead to status epilepticus.
  • Advise patients with diabetes that this medicine may affect the blood sugar and to monitor blood sugar levels closely.
  • Counsel patients that hormonal birth control may not work as well while using this medication. Advise them to use an extra form of birth control (eg, condoms) to prevent pregnancy.

Copyright © 2009 Wolters Kluwer Health.

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