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Pharmaceuticals -> Antiepileptics

Pharmaceuticals -> Listed in ZINC15

Mol wt: 406.24. White crystals as the dihydrate from water-ethanol-acetone, mp 220 °C (softens). pH of a saturated aqueous solution: approx 9. Solubility at 25 °C (mg/mL): 142 in water /Disodium salt/

1.45e-01 g/L

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fosphenytoin approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Treatment is nonspecific since there is no known antidote to Fosphenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children. (L1712)

Risk of hepatotoxicity from a single toxic dose or prolonged use of acetaminophen may be increased and therapeutic efficacy may be decreased in patients regularly taking other hepatic enzyme-inducing agents such as phenytoin. /Hydantoin anticonvulsants/

Concurrent use of alcohol or CNS depression-producing medications with hydantoin anticonvulsants may enhance CNS depression. Chronic use of alcohol may decrease serum concentrations and effectiveness of hydantoins; concurrent use of hydantoin anticonvulsants with acute alcohol intake may increase serum hydantoin concentrations. /Hydantoin anticonvulsants/

Concurrent use of amiodarone with phenytoin and possibly with other hydantoin anticonvulsants may increase plasma concentrations of the hydantoin, resulting in increased effects and/or toxicity. /Hydantoin anticonvulsants/

Concurrent use with coumarin- or indandione-derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamide may increase serum concentrations of hydantoin anticonvulsants because of decreased metabolism, thereby increasing the /hydantoins'/ effects and/or toxicity. Dosage adjustments of the anticonvulsant may be necessary. In addition, the anticoagulant effect of coumarin- or indandione-derivative anticoagulants may be increased initially, but decrease with continued concurrent use. /Hydantoin anticonvulsants/

For more Interactions (Complete) data for FOSPHENYTOIN (23 total), please visit the HSDB record page.

Hepatic injury has not been specifically ascribed to use of fosphenytoin, but because it is metabolized to phenytoin, it is likely to cause similar hepatic injury. Cases of typical immunoallergic hepatitis and DRESS syndrome have been reported in patients initially treated with fosphenytoin and then converted to the oral form.

Fosphenytoin has a black box warning due to its activated form of phenytoin. In adults, exceeding 150 mg phenytoin equivalents per minute may lead to severe cardiac outcomes, particularly hypotension and cardiac arrhythmias. Therefore, clinicians should perform cardiac monitoring up to 30 minutes after IV infusion. In the case of cardiac abnormalities, the discontinuation or reduction of the drug dosage may be necessary.

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.

/CASE REPORTS/ Following surgery for a chronic subdural hematoma, a 74-year-old patient received fosphenytoin as prophylaxis for epilepsy. The patient received 10 times the prescribed dose. This error in the administration of fosphenytoin was facilitated by a confusing labeling of the product. The phenytoin blood level was 79 micrograms.mL-1. The main adverse effect was a coma requiring 5 days of mechanical ventilation. No adverse cardiovascular event was noted. The phenytoin blood levels returned toward the therapeutic range in 8 days. At discharge from the hospital 20 days after surgery, the patient did not have any sequela from the fosphenytoin intoxication.

/CASE REPORTS/ .../The authors/ report the case of a 23-year-old man, weight 73 kg, with a known but untreated seizure disorder who was given prophylactic fosphenytoin, 1500-mg phenytoin equivalents over 85 minutes by intravenous infusion. The patient was normocalcemic before drug infusion. Fosphenytoin produced electrocardiographic changes (prolongation of the ST segment and the QT interval and merging of the T and P waves) consistent with hypocalcemia, and these changes were associated with new-onset reductions in both total and ionized serum calcium concentrations. Plasma phenytoin concentrations were within the therapeutic range during the electrocardiographic changes, and the patient's blood pressure was stable. /Investigators/ interpret these findings as fosphenytoin-related electrocardiographic changes likely attributable to inorganic phosphate-induced hypocalcemia.

/SURVEILLANCE/ To better characterize cardiac toxicity associated with fosphenytoin (FOS) administration, /investigators/ performed a review of the Food and Drug Administration's Adverse Event Reporting System databank for reports of possible FOS toxicity from 1997-2002. There were 29 applicable reports of adverse cardiac events likely related to FOS infusion, including 10 cardiac deaths. Among survivors, there were four cases of high-grade atrioventricular block, and five cases of transient sinus arrest. /The/ data suggest that FOS may produce more cardiac toxicity than previously thought. Clinicians should consider administering intravenous FOS in a monitored setting for selected high-risk patients.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

fosphenytoin

DILI Positive

Intramuscular

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher, which produced peak maternal plasma phenytoin concentrations of approximately 20 ug/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at non-maternotoxic dose of 17 mg PE/kg /SRP: phenytoin sodium equivalents/ was also considered drug-induced. the developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats.

/GENOTOXICITY/ Structural chromosome aberration frequency in cultured V79 Chinese hamster lung cells was increased by exposure to fosphenytoin in the presence of metabolic activation. No evidence of mutagenicity of fosphenytoin was observed in bacteria (Ames test) or Chinese hamster lung cells in vitro. No evidence of clastogenic activity of fosphenytoin was observed in the in vivo mouse bone marrow micronucleus test.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fosphenytoin approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N - Nervous system

QN - Nervous system

Fosphenytoin is extensively bound (95-99%) to human plasma proteins, primarily albumin, and displays saturable binding kinetics over a physiologically relevant range of fosphenytoin concentrations. Like fosphenytoin, phenytoin is extensively bound, again mainly to albumin, but can be displaced by fosphenytoin itself. Phenytoin is typically about 88% bound in the absence of fosphenytoin, but this drops to around 60% 0.5-1 hour following fosphenytoin infusion while fosphenytoin is being converted to phenytoin.

Fosphenytoin is a water-soluble phenytoin prodrug used for the treatment of epileptic seizures. Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin by endogenous phosphatases. Each 1.5 mg of fosphenytoin sodium is equivalent to 1.0mg of phenytoin sodium (PE equivalents); care should be taken to calculate the dose required in PE equivalents properly. Serious adverse effects such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and hematopoietic complications may occur and indicate an alternate antiepileptic should be used. Withdrawal of fosphenytoin sodium may precipitate seizures and should be done gradually.

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. In neurons, phenytoin decreases sodium and calcium ion influx by prolonging channel inactivation time during generation of nerve impulses. Phenytoin blocks the voltage-dependant sodium channels of neurons and inhibits the calcium flux across neuronal membranes, thus helping to stabilize neurons. It also decreases synaptic transmission, and decreases post-tetanic potentiation at the synapse. Phenytoin enhances the sodium ATPase activity of neurons and/or glial cells. It also influences second messenger systems by inhibiting calcium-calmodulin protein phosphorylation and possibly altering cyclic nucleotide production or metabolism.

Fosphenytoin has a conversion half-life of approximately 15 minutes. The resulting phenytoin has a wide range of mean total half-life values (12 to 28.9 hours), with longer half-life times at higher administered doses.

A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). The half-life of fosphenytoin was 4.5, 9.2, and 9.5 min for the three groups, respectively.

The conversion half-life /of fosphenytoin/ to phenytoin ranges from 8 to 15 minutes. This value is independent of dose, infusion rate, or plasma concentration of either fosphenytoin or phenytoin. The elimination half-life of fosphenytoin after intravenous or intramuscular injection is also independent of dose.

Fosphenytoin is metabolized, likely by phosphatases, to phenytoin, phosphate, and formaldehyde; the formaldehyde is subsequently converted into formate. The phenytoin produced is metabolized hepatically by CYP2C9 and, to a lesser extent, by CYP2C19.

Fosphenytoin undergoes rapid hydrolysis to phenytoin. ... Conversion of fosphenytoin also yields two additional metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which in turn is metabolized via a folate-dependent mechanism. ... Phosphatase enzymes probably play a major role in the conversion of fosphenytoin to phenytoin.

This investigation was undertaken to identify the structure of a novel immunoreactive metabolite derived from fosphenytoin that has been hypothesized previously as present in sera from renally impaired patients receiving this prodrug. The metabolite was isolated from uremic sera using solid-phase extraction and HPLC. Structural analysis was performed using HPLC-tandem mass spectrometry, nuclear magnetic resonance (NMR), deuterium exchange, and chemical derivatization. Immunoreactivity was evaluated using a fluorescence polarization immunoassay. The metabolite had a parent ion at m/z 457 in the negative-ion mode and fragmented to yield the m/z 251 of phenytoin, as well as other mass fragments of phenytoin. Mass fragments associated with glucuronic acid were also present. The chromatographic peak corresponding to this metabolite demonstrated immunoreactivity sufficient to lead to falsely increased reported values for phenytoin immunoassays. The observed immunoreactivity was also proportional to the relative concentration of the metabolite in collected fractions. Analysis by NMR indicated the presence of phenyl groups with chemical shifts identical to those of phenytoin, as well as the presence of a methylene bridge, which was consistent with the same methylene bridge present on the phosphate ester of fosphenytoin. Comparative analysis of serum samples from renally impaired patients receiving phenytoin vs fosphenytoin using multiple reaction monitoring quantification demonstrated that this metabolite was associated with fosphenytoin administration. A unique immunoreactive oxymethylglucuronide metabolite derived from fosphenytoin has been isolated from sera from uremic patients receiving this prodrug.

Fosphenytoin sodium is a hydantoin-derivative anticonvulsant. 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. Pharmacologic effects of fosphenytoin include those of phenytoin.

Hepatic. Route of Elimination: Phenytoin derived from administration of Cerebyx is extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1%-5% of the Cerebyx dose) is recovered in urine. Half Life: Fosphenytoin has a half-life of approximately 15 minutes.

B4SF212641

FOSPHENYTOIN

Established Pharmacologic Class [EPC] - Anti-epileptic Agent

Physiologic Effects [PE] - Decreased Central Nervous System Disorganized Electrical Activity

Fosphenytoin is an Anti-epileptic Agent. The physiologic effect of fosphenytoin is by means of Decreased Central Nervous System Disorganized Electrical Activity.

Drugs used to prevent SEIZURES or reduce their severity.

A class of drugs that act by inhibition of sodium influx through cell membranes. Blockade of sodium channels slows the rate and amplitude of initial rapid depolarization, reduces cell excitability, and reduces conduction velocity.

Fosphenytoin at 15 to 20 mg PE/kg infused at 100 to 150 mg PE/min intravenously yields free plasma phenytoin concentrations similar to an equivalent dose of phenytoin sodium administered at 50 mg/min. Single intravenous administration of fosphenytoin shows a linear increase in mean maximum total phenytoin concentration while the mean maximum unbound phenytoin concentrations increase with both dose and infusion rate. Fosphenytoin is rapidly converted to phenytoin following intravenous administration with a half-life of 15 minutes; if administered intramuscularly, the peak plasma phenytoin concentration is not reached until three hours.

Phenytoin derived from fosphenytoin administration is excreted in the urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide. There is little unchanged phenytoin (1%–5% of the administered dose), and essentially no fosphenytoin recovered in urine.

The volume of distribution of fosphenytoin increases with dose and rate, ranging between 4.3 and 10.8 L.

Bioavailability from either intravenous or intramuscular route is essentially 100%.

/Fosphenytoin is/ most likely distributed in humans to heart, kidneys, small intestine, liver, lungs, spleen, where it is hydrolyzed by phosphatases to phenytoin. Predominately distributed in the central (plasma) compartment.

The volume of distribution ranges from 4.3 to 10.8 liters, and increases with increasing dose and administration rate of fosphenytoin.

MEDICATION

THERAP CAT: Anticonvulsive

Use (kg) in USA (2002): 278

For the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery. It can also be substituted, short-term, for oral phenytoin.