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Medication Safety Issues
Sound-alike/look-alike issues:
Cerebyx® may be confused with Celebrex®, Celexa™, Cerezyme®
Overdoses have occurred due to confusion between the mg per mL concentration of fosphenytoin (50 mg PE/mL) and total drug content per vial (either 100 mg PE/2 mL vial or 500 mg PE/10 mL vial). ISMP recommends that the total drug content per container is identified instead of the concentration in mg per mL to avoid confusion and potential overdosages. Additionally, since most errors have occurred with overdoses in children, they recommend that pediatric hospitals should consider stocking only the 2 mL vial.
Pronunciation
(FOS fen i toyn)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Used for the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery; indicated for short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate, or deemed less advantageous (the safety and effectiveness of fosphenytoin in this use has not been systematically evaluated for more than 5 days)
Pregnancy Risk Factor
D
Pregnancy Considerations
Fosphenytoin is the prodrug of phenytoin. Refer to Phenytoin for additional information.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Fosphenytoin is the prodrug of phenytoin. It is not known if fosphenytoin is excreted in breast milk prior to conversion to phenytoin. Refer to Phenytoin monograph for additional information.
Contraindications
Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation; patients with sinus bradycardia, sinoatrial block, second- and third-degree AV block, or Adams-Stokes syndrome; occurrence of rash during treatment (should not be resumed if rash is exfoliative, purpuric, or bullous); treatment of absence seizures
Warnings/Precautions
Concerns related to adverse effects:
• Arrhythmias: Administration of phenytoin has been associated with atrial and ventricular conduction depression and ventricular fibrillation; careful cardiac monitoring is needed when administering I.V. loading doses of fosphenytoin.
• Blood dyscrasias: A spectrum of hematologic effects have been reported with use (eg, neutropenia, leukopenia, thrombocytopenia, pancytopenia, and anemias); patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage.
• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis and Stevens-Johnson syndromes, although rarely reported, have resulted in fatalities; drug should be discontinued if there are any signs of rash.
• Hypersensitivity syndrome: Acute hepatotoxicity associated with a hypersensitivity syndrome characterized by fever, skin eruptions, and lymphadenopathy has been reported to occur within the first 2 months of treatment; discontinue if skin rash or lymphadenopathy occurs.
• Hypotension: May occur, especially after I.V. administration at high doses and high rates of administration.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with hypotension and/or severe myocardial insufficiency.
• Diabetes: Use with caution in patients with diabetes mellitus.
• Fever: Use with caution in patients with fever.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Hypoalbuminemia: Use with caution in patients with hypoalbuminemia.
• Hypothyroidism: Use with caution in patients with hypothyroidism.
• Porphyria: Use with caution in patients with porphyria.
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Dosage form specific issues:
• Phenytoin sodium equivalent (PE): Doses of fosphenytoin are expressed as their phenytoin sodium equivalent (PE).
Other warnings/precautions:
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Adverse Reactions
The more important adverse clinical events caused by the I.V. use of fosphenytoin or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the I.V. route. Do not exceed a rate of 150 mg phenytoin equivalent/minute when administering fosphenytoin.
The adverse clinical events most commonly observed with the use of fosphenytoin in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. Paresthesia and pruritus were seen more often following fosphenytoin (versus phenytoin) administration and occurred more often with I.V. fosphenytoin than with I.M. administration. These events were dose and rate related (doses ?15 mg/kg at a rate of 150 mg/minute). These sensations, generally described as itching, burning, or tingling are usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of infusion.
Transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2-3 times more often at doses ?15 mg/kg and rates ?150 mg/minute.
I.V. administration (maximum dose/rate):
>10%:
Central nervous system: Nystagmus, dizziness, somnolence, ataxia
Dermatologic: Pruritus
1% to 10%:
Cardiovascular: Hypotension, vasodilation, tachycardia
Central nervous system: Stupor, incoordination, paresthesia, extrapyramidal syndrome, tremor, agitation, hypoesthesia, dysarthria, vertigo, brain edema, headache
Gastrointestinal: Nausea, tongue disorder, dry mouth, vomiting
Neuromuscular & skeletal: Pelvic pain, muscle weakness, back pain
Ocular: Diplopia, amblyopia
Otic: Tinnitus, deafness
Miscellaneous: Taste perversion
I.M. administration (substitute for oral phenytoin):
1% to 10%:
Central nervous system: Nystagmus, tremor, ataxia, headache, incoordination, somnolence, dizziness, paresthesia, reflexes decreased
Dermatologic: Pruritus
Gastrointestinal: Nausea, vomiting
Hematologic/lymphatic: Ecchymosis
Neuromuscular & skeletal: Muscle weakness
<1% (Limited to important or life-threatening): Acidosis, acute hepatic failure, acute hepatotoxicity, alkalosis, anemia, atrial flutter, bundle branch block, cardiac arrest, cardiomegaly, cerebral hemorrhage, cerebral infarct, CHF, cyanosis, dehydration, hyperglycemia, hyperkalemia, hypertension, hypochromic anemia, hypokalemia, hypophosphatemia, ketosis, leukocytosis, leukopenia, lymphadenopathy, palpitation, postural hypotension, pulmonary embolus, QT interval prolongation, sinus bradycardia, syncope, thrombocytopenia, thrombophlebitis, ventricular extrasystoles
Metabolism/Transport Effects
As phenytoin: Substrate of CYP2C9 (major), 2C19 (major), 3A4 (minor); Induces CYP2B6 (strong), 2C8 (strong), 2C9 (strong), 2C19 (strong), 3A4 (strong)
Drug Interactions
Acetaminophen: Anticonvulsants (Hydantoin) may increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Antacids: May decrease the serum concentration of Anticonvulsants (Hydantoin). Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Specifically, osteomalacia and rickets. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy
Chloramphenicol: May decrease the metabolism of Anticonvulsants (Hydantoin). Anticonvulsants (Hydantoin) may decrease the serum concentration of Chloramphenicol. Increased chloramphenicol concentrations have also been seen. Risk D: Consider therapy modification
Cimetidine: May decrease the metabolism of Anticonvulsants (Hydantoin). Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP2B6 Substrates: CYP2B6 Inducers (Strong) may increase the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification
CYP2C19 Substrates: CYP2C19 Inducers (Strong) may increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C8 Substrates (High risk with Highly Effective Inducers): CYP2C8 Inducers (Highly Effective) may increase the metabolism of CYP2C8 Substrates (High risk with Highly Effective Inducers). Risk C: Monitor therapy
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inducers). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). Risk D: Consider therapy modification
CYP2C9 Substrates (High risk with Highly Effective Inducers): CYP2C9 Inducers (Highly Effective) may increase the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inducers). Risk C: Monitor therapy
CYP3A4 Substrates: CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Maraviroc: CYP3A4 Inducers may decrease the serum concentration of Maraviroc. Risk D: Consider therapy modification
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated in persons with a history of convulsions. If anticonvulsant is being used for another indication monitor response to treatment closely, as concurrent mefloquine may decrease response to treatment. Risk D: Consider therapy modification
Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination
Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination
Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination
Sorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sorafenib. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol:
Acute use: Avoid or limit ethanol (inhibits metabolism of phenytoin); watch for sedation.
Chronic use: Avoid or limit ethanol (stimulates metabolism of phenytoin).
Storage
Refrigerate at 2°C to 8°C (36°F to 46°F). Do not store at room temperature for more than 48 hours. Do not use vials that develop particulate matter.
Reconstitution
Must be diluted to concentrations of 1.5-25 mg PE/mL, in normal saline or D5W, for I.V. infusion.
Compatibility
Stable in D5LR, D51/2NS, D5W, D10W, hetastarch 6% in NS, mannitol 20%, LR, NS.
Y-site administration: Compatible: Lorazepam. Incompatible: Midazolam.
Compatibility when admixed: Compatible: Potassium chloride.
Mechanism of Action
Diphosphate ester salt of phenytoin which acts as a water soluble prodrug of phenytoin; after administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin as the active moiety; phenytoin works by stabilizing neuronal membranes and decreasing seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses
Pharmacodynamics/Kinetics
Also refer to Phenytoin monograph for additional information.
Protein binding: Fosphenytoin: 95% to 99% to albumin; can displace phenytoin and increase free fraction (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin
Metabolism: Fosphenytoin is rapidly converted via hydrolysis to phenytoin; phenytoin is metabolized in the liver and forms metabolites
Bioavailability: I.M.: Fosphenytoin: 100%
Half-life elimination:
Fosphenytoin: 15 minutes
Phenytoin: Variable (mean: 12-29 hours); kinetics of phenytoin are saturable
Time to peak: Conversion to phenytoin: Following I.V. administration (maximum rate of administration): 15 minutes; following I.M. administration, peak phenytoin levels are reached in 3 hours
Excretion: Phenytoin: Urine (as inactive metabolites)
Dosage
The dose, concentration in solutions, and infusion rates for fosphenytoin are expressed as phenytoin sodium equivalents (PE); fosphenytoin should always be prescribed and dispensed in phenytoin sodium equivalents (PE)
Infants and Children (unlabeled use): I.V.:
Loading dose: 10-20 mg PE/kg for the treatment of generalized convulsive status epilepticus
Maintenance dosing: Phenytoin dosing guidelines in pediatric patients are used when dosing fosphenytoin using doses in PE equal to the phenytoin doses (ie, phenytoin 1 mg = fosphenytoin 1 PE); maintenance doses may be started 8-12 hours after a loading dose
Adults:
Status epilepticus: I.V.: Loading dose: 15-20 mg PE/kg I.V. administered at 100-150 mg PE/minute
Nonemergent loading and maintenance dosing: I.V. or I.M.:
Loading dose: 10-20 mg PE/kg I.V. or I.M. (maximum I.V. rate: 150 mg PE/minute)
Initial daily maintenance dose: 4-6 mg PE/kg/day I.V. or I.M.
I.M. or I.V. substitution for oral phenytoin therapy: May be substituted for oral phenytoin sodium at the same total daily dose; however, Dilantin® capsules are ?90% bioavailable by the oral route; phenytoin, supplied as fosphenytoin, is 100% bioavailable by both the I.M. and I.V. routes; for this reason, plasma phenytoin concentrations may increase when I.M. or I.V. fosphenytoin is substituted for oral phenytoin sodium therapy; in clinical trials, I.M. fosphenytoin was administered as a single daily dose utilizing either 1 or 2 injection sites; some patients may require more frequent dosing
Dosing adjustments in renal/hepatic impairment: Phenytoin clearance may be substantially reduced in cirrhosis and plasma level monitoring with dose adjustment advisable; free phenytoin levels should be monitored closely in patients with renal or hepatic disease or in those with hypoalbuminemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin in these patients leading to increased frequency and severity of adverse events
Administration: I.M.
I.M. may be administered as a single daily dose using either 1 or 2 injection sites.
Administration: I.V.
Rates of infusion:
Children: 1-3 mg PE/kg/minute
Adults: Should not exceed 150 mg PE/minute
Monitoring Parameters
Continuous blood pressure, ECG, and respiratory function monitoring with loading dose and for 10-20 minutes following infusion; vital signs, CBC, liver function tests, plasma level monitoring (plasma levels should not be measured until conversion to phenytoin is complete, ?2 hours after an I.V. infusion or ?4 hours after an I.M. injection)
Reference Range
Therapeutic: 10-20 mcg/mL (SI: 40-79 ?mol/L); toxicity is measured clinically, and some patients require levels outside the suggested therapeutic range
Toxic: 30-50 mcg/mL (SI: 120-200 ?mol/L)
Lethal: >100 mcg/mL (SI: >400 ?mol/L)
Manifestations of toxicity:
Nystagmus: 20 mcg/mL (SI: 79 ?mol/L)
Ataxia: 30 mcg/mL (SI: 118.9 ?mol/L)
Decreased mental status: 40 mcg/mL (SI: 159 ?mol/L)
Coma: 50 mcg/mL (SI: 200 ?mol/L)
Peak serum phenytoin level after a 375 mg I.M. fosphenytoin dose in healthy males: 5.7 mcg/mL
Peak serum fosphenytoin levels and phenytoin levels after a 1.2 g infusion (I.V.) in healthy subjects over 30 minutes were 129 mcg/mL and 17.2 mcg/mL, respectively
Test Interactions
Increased glucose, alkaline phosphatase (S); decreased thyroxine (S), calcium (S); serum sodium increased in overdose setting
Dietary Considerations
Provides phosphate 0.0037 mmol/mg PE fosphenytoin
Patient Education
Patients may not be in a position to evaluate their response. If conscious or alert, advise patient to report signs or symptoms of palpitations, racing or falling heartbeat, respiratory difficulty, acute faintness, or CNS disturbances (eg, somnolence, ataxia), and visual disturbances. Pregnancy precaution: Inform prescriber if you are pregnant.
Geriatric Considerations
No significant changes in fosphenytoin pharmacokinetics with age have been noted. Phenytoin clearance is decreased in the elderly and lower doses may be needed. Elderly may have reduced hepatic clearance due to age decline in Phase I metabolism. Elderly may have low albumin which will increase free fraction and, therefore, pharmacologic response. Monitor closely in those who are hypoalbuminemic. Free fraction measurements advised, also elderly may display a higher incidence of adverse effects (cardiovascular) when using the I.V. loading regimen; therefore, it is recommended to decrease loading I.V. dose to 25 mg/minute.
Additional Information
1.5 mg fosphenytoin is approximately equivalent to 1 mg phenytoin. Equimolar fosphenytoin dose is 375 mg (75 mg/mL solution) to phenytoin 250 mg (50 mg/mL).
Anesthesia and Critical Care Concerns/Other Considerations
Fosphenytoin 1.5 mg is approximately equivalent to phenytoin 1 mg.
Fosphenytoin is compatible with all diluents; does not require propylene glycol or ethanol for solubility. Since there is no precipitation problem with fosphenytoin, no I.V. filter is required. Formaldehyde production is not expected to be clinically consequential (about 200 mg) if used for 1 week. As with phenytoin, fosphenytoin, when given I.V., can cause marked and dramatic hypotension and reflex tachycardia. Fosphenytoin administration is safer, in that the risk of hypotension may be somewhat less, and there are no adverse effects of extravasation. Avoid rapid I.V. infusion of fosphenytoin (infusion rates >150 mg of phenytoin equivalent per minute). Pruritus can be severe, requiring discontinuation of infusion.
Cardiovascular Considerations
As with phenytoin, fosphenytoin, when given I.V., can cause marked and dramatic hypotension and reflex tachycardia. Avoid rapid I.V. infusion of fosphenytoin (infusion rates >150 mg of phenytoin equivalent per minute).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Tongue disorder and dry mouth.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness, drowsiness, or visual hallucinations
Mental Health: Effects on Psychiatric Treatment
May cause neutropenia; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Assess all other medications patient may be taking. Continuous monitoring is essential during infusion and for 30 minutes following infusion. Monitor closely for adverse or overdose reactions during and following infusion.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as sodium: 75 mg/mL (2 mL, 10 mL) [equivalent to phenytoin sodium 50 mg/mL]
Cerebyx®: 75 mg/mL (2 mL, 10 mL) [equivalent to phenytoin sodium 50 mg/mL]
References
Bebin M and Bleck TP, “New Anticonvulsant Drugs. Focus on Flunarizine, Fosphenytoin, Midazolam, and Stiripentol,” Drugs, 1994, 48(2):153-71.
Boucher BA, “Fosphenytoin: A Novel Phenytoin Prodrug,” Pharmacotherapy, 1996, 16(5):777-91.
Boucher BA, Feler CA, Dean JC, et al, “The Safety, Tolerability, and Pharmacokinetics of Fosphenytoin After Intramuscular and Intravenous Administration in Neurosurgery Patients,” Pharmacotherapy, 1996, 16(4):638-45.
Chapman MG, Smith M, and Hirsch NP, “Status Epilepticus,” Anaesthesia, 2001, 56(7):648-59.
Fischer JH, Cwik MS, Luer MS, et al, “Stability of Fosphenytoin Sodium With Intravenous Solutions in Glass Bottles, Polyvinyl Chloride Bags, and Polypropylene Syringes,” Ann Pharmacother, 1997, 31(5):553-9.
Jamerson BD, Dukes GE, Brouwer KL, et al, “Venous Irritation Related to Intravenous Administration of Phenytoin Versus Fosphenytoin,” Pharmacotherapy, 1994, 14(1):47-52.
Leppik IE, Boucher R, Wilder BJ, et al, “Phenytoin Prodrug: Preclinical and Clinical Studies,” Epilepsia, 1989, 30(Suppl 2):22-6.
Manno EM, “New Management Strategies in the Treatment of Status Epilepticus,” Mayo Clin Proc, 2003, 78(4):508-18.
Pellock JM, “Fosphenytoin Use in Children,” Neurology, 1996, 46(6 Suppl 1):14-6.
Wilder BJ, Campbell K, Ramsay RE, et al, “Safety and Tolerance of Multiple Doses of Intramuscular Fosphenytoin Substituted for Oral Phenytoin in Epilepsy or Neurosurgery,” Arch Neurol, 1996, 53(8):764-8.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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