Fosphenytoin Sodium

Trade Names:
Cerebyx
- Injection 150 mg (phenytoin sodium 100 mg)
- Injection 750 mg (phenytoin sodium 500 mg)

Pharmacology

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Fosphenytoin is a prodrug, which 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.

Pharmacokinetics

Absorption

T _max is about 30 min. Bioavailability is 100% with IM dosing.

Distribution

Protein binding is 95% to 99%, about 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 half-life is about 15 min; the mean half-life is 12 to 28.9 (phenytoin). Fosphenytoin is primarily excreted in the urine as metabolites.

Special Populations

Increased fraction of unbound phenytoin may occur.

Increased fraction of unbound phenytoin may occur.

Cl decreases about 20% in patients over 70 yr.

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

Dosage and Administration

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 equivalents (PE).

IV

15 to 20 mg PE/kg.

IV / IM

10 to 20 mg PE/kg

4 to 6 PE/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.
• Do not mix with other drugs.
• Administer IV no faster than 150 mg/min to reduce risk of hypotension.

Storage/Stability

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

Drug Interactions

Acute alcohol ingestion may increase phenytoin plasma levels, while chronic use may decrease plasma concentrations.

Phenytoin serum concentrations may be elevated, increasing the pharmacologic effects and adverse reactions.

Phenytoin serum concentrations may be reduced, decreasing the efficacy.

The effects of these agents may be impaired.

Cyclosporine concentrations may be decreased.

Disopyramide concentrations and bioavailability may be decreased, while anticholinergic actions may be enhanced.

May increase or decrease phenytoin concentrations and effects.

May cause folic acid deficiency.

Effects of itraconazole may be decreased, while those of phenytoin may be increased.

Phenytoin may cause subnormal response to metyrapone.

May cause these agents to have shorter duration or decreased effects.

May increase concentrations of primidone and metabolites, increasing the effects.

May cause profound hypotension and possibly cardiac arrest.

Tacrolimus serum concentrations may be reduced, decreasing the efficacy, while phenytoin concentrations may be elevated, increasing the pharmacologic effects and adverse reactions.

Effects of either agents may be decreased.

May precipitate seizures, necessitating fosphenytoin dosage adjustments.

Laboratory Test Interactions

Fosphenytoin may interfere with metapyrone and dexamethasone tests, causing inaccurate results because of increased metabolism of these agents. Drug may cause decrease in serum levels of protein-bound iodine. It may cause increased levels of glucose, alkaline phosphatase, and gamma glutamyl-transpeptidase.

Adverse Reactions

Cardiovascular

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

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%); CNS depression.

Dermatologic

Pruritus (49%); face edema, rash (at least 1%); burning/itching/tingling.

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%).

Metabolic-Nutritional

Hypokalemia (at least 1%).

Musculoskeletal

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

Respiratory

Pneumonia (at least 1%).

Miscellaneous

Pelvic pain (4%); accidental injury (3%); chills, fever, infection (at least 1%).

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Special Risk Patients

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

Age

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

CV depression

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.

Hematopoietic system

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

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 months and includes fever, skin eruptions, and lymphadenopathy.

Hyperglycemia

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

Phosphate load

Phosphate load due to content of phosphates in fosphenytoin should be considered in patients who have phosphate restriction (eg, severe renal function impairment).

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

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.

Withdrawal

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

Overdosage

Symptoms

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

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 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; may lead to status epilepticus.
• Instruct patient what to do in case of a missed dose.

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