Fosphenytoin

362.27400

362.27

B4SF212641

DTXSID9044299

C65766

White crystals from acetone

N - Nervous system

2933990090

125.98000

1.81550

Solid

1.495g/cm3

173-176.5°

1.63

1.45e-01 g/L

6.1X10+11 mm Hg at 25 deg C (est)

Henry's Law constant = 8.3X10-14 atm-cu m/mol at 25 °C (est)

pKa = 1.20 (est)

Hydroxyl radical reaction rate constant = 8.9X10-11 cu cm/molec-sec at 25 °C (est)

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.

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.

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.

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.

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.

A small fraction of patients metabolize phenytoin slowly and /resulted in/ higher than expected plasma concentrations of phenytoin may occur in such individuals.|Following equal doses of phenytoin, total plasma phenytoin concentrations are lower in chronic uremic patients than in non-uremic patients which suggests an altered metabolic disposition of the drug in patients with uremia. /Phenytoin/

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.

While data specific to fosphenytoin were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Fosphenytoin is indicated for the treatment of generalized tonic-clonic status epilepticus and for the prevention and treatment of seizures occurring during neurosurgery in adult patients. It can also be substituted, short-term, for oral phenytoin in patients aged two years and older when oral phenytoin administration is not possible.|FDA Label

Fosphenytoin is a prodrug of phenytoin available in parenteral forms only. While not specifically associated with cases of drug induced liver injury, fosphenytoin is converted to phenytoin which is a well known cause of acute idiosyncratic drug induced liver disease.

Anticonvulsants

Parenteral fosphenytoin and phenytoin are both indicated for the control of tonic-clonic type status epilepticus. Although parenteral benzodiazepines are often used initially for rapid control of status epilepticus, both fosphenytoin and phenytoin are indicated for sustained control of seizure activity. /Included in US product label/|Fosphenytoin and phenytoin are both indicated for the prevention and treatment of seizures during and following neurosurgery. /Included in US product label/|Hydantoin anticonvulsants are indicated in the suppression and control of tonic-clonic (grand mal) and simple or complex partial (psychomotor or temporal lobe) seizures. /Hydantoin anticonvulsants; Included in US product labeling./|The objective of this case report is to emphasize the analgesic effect of antiepileptic drugs in those with neuropathic pain, confirm that fosphenytoin possesses these analgesic properties, and to highlight that intravenous administration of fosphenytoin for 24 hours can produce good quality pain relief that lasts for many weeks. A 37-year-old woman with a neuroma (caused by surgical intervention for an endometrial sarcoma) producing neuropathic pain unresponsive to opiates was successfully treated with intravenous infusion of 1,500 phenytoin equivalent units fosphenytoin for 24 hours. The pain relief after this and subsequent infusions persisted for between 3 and 14 weeks and was associated with a reduced opiate requirement and an increase in activities of daily living. Fosphenytoin infusion can give good quality pain relief in the patient with neuropathic pain.

Known hypersensitivity to fosphenytoin or any ingredient in the formulation, phenytoin, or other hydantoins.|Sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular (AV) block, Adams-Stokes syndrome (Stokes-Adams disease).|Doses of fosphenytoin sodium should always be expressed in terms of phenytoin sodium equivalents (PE). Therefore, adjustment to the recommended dosage should not be made when switching from phenytoin sodium to fosphenytoin sodium or vice versa.|Abrupt withdrawal of any anticonvulsant drug may result in increased seizure frequency or status epilepticus; therefore, if in the clinician's judgment there is a need for dosage reduction, discontinuance, or substitution of an anticonvulsant, this should be done gradually. However, if an allergic or hypersensitivity reaction occurs during fosphenytoin therapy, discontinuance of the drug and institution of alternative anticonvulsant therapy (with a drug structurally unrelated to hydantoin derivatives) may be necessary depending on the severity of the symptoms.|For more Drug Warnings (Complete) data for FOSPHENYTOIN (20 total), please visit the HSDB record page.

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.

Drugs used to prevent SEIZURES or reduce their severity. (See all compounds classified as Anticonvulsants.)|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. (See all compounds classified as Sodium Channel Blockers.)

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.|Protein binding is very high (95 to 99%); degree of binding is saturable, with the result that the percent bound decreases as the total plasma fosphenytoin concentration increases.|For more Absorption, Distribution and Excretion (Complete) data for FOSPHENYTOIN (10 total), please visit the HSDB record page.

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.

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 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.

Since there is no specific antidote for overdose with hydantoin anticonvulsants, treatment is symptomatic and supportive and may include the following. ... Multiple oral doses of charcoal and cathartic may shorten the duration of symptoms. Supportive care - oxygen, vasopressors, and assisted ventilation may be necessary for CNS, respiratory, or cardiovascular depression. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation. Following recovery, careful evaluation of blood-forming organs is advisable. /Hydantoin anticonvulsants/|Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat stupor and coma if they occur. Protect the patient from self-injury caused by ataxia. If seizures occur, consider an alternate diagnosis and treat with other usual anticonvulsants. If hypotension occurs with intravenous phenytoin administration, immediately stop the infusion and administer intravenous fluids and pressors if necessary. There are no specific antidotes. Decontamination: administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Elimination: Repeat-dose activated charcoal may enhance phenytoin elimination but is not necessary and may increase the risk of aspiration pneumonitis in drowsy patients. There is no role for diuresis, dialysis, or hemoperfusion.|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/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.

3-(hydroxymethyl)phenytoin disodium phosphate

Cerebyx

Marketing status: None (Tentative approval) /Sodium/

Analyte: fosphenytoin sodium; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /fosphenytoin sodium/|Analyte: fosphenytoin sodium; matrix: chemical identification; procedure: retention time of the major peak of the liquid chromatogram with comparison to standards /fosphenytoin sodium/|Analyte: fosphenytoin sodium; matrix: chemical purity; procedure: liquid chromatography with detection at 214 nm and comparison to standards /fosphenytoin sodium/|Analyte: fosphenytoin sodium; matrix: pharmaceutical preparation (injection solution); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification) /fosphenytoin sodium/|For more Analytic Laboratory Methods (Complete) data for FOSPHENYTOIN (6 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients