Fosphenytoin

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

• Fosphenytoin sodium injection is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium injection can also be substituted, short-term, for oral phenytoin.ICD-10: G40.909

• Fosphenytoin sodium is contraindicated in patients with: A history of hypersensitivity to fosphenytoin sodium injection or its inactive ingredients, or to phenytoin or other hydantoins [see Warnings and Precautions (5.6) ] . Reactions have included angioedema.contraindicated

The dose, concentration, and infusion rate of fosphenytoin sodium injection should always be expressed as phenytoin sodium equivalents (PE) ( 2.1 ) For Status Epilepticus: Adult loading dose is 15 to 20 mg PE/kg at a rate of 100 to 150 mg PE/min ( 2.3 ) Pediatric loading dose is 15 to 20 mg PE/kg at a rate of 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) ( 2.3 ) For Non-emergent Loading and Maintenance Dosing: Adult loading dose is 10 to 20 mg PE/kg given IV or IM; initial maintenance dose is 4 to 6 mg PE/kg/day in divided doses ( 2.4 ) Pediatric loading dose is 10 to 15 mg PE/kg at a rate of 1 to 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower); initial maintenance dose is 2 to 4 mg PE/kg every 12 hours at a rate of 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower) ( 2.4 ) Intramuscular Administration: Fosphenytoin sodium injection should ordinarily not be given intramuscularly ( 2.3 , 2.4 ) 2.1 Important Administration Instructions to Avoid Dosing Errors Use caution when administering fosphenytoin sodium injection because of the risk of dosing errors [see Warnings and Precautions (5.1) ]. Phenytoin Sodium Equivalents (PE) The dose, concentration, and infusion rate of fosphenytoin sodium injection should always be expressed as phenytoin sodium equivalents (PE). There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin sodium injection should always be prescribed and dispensed in phenytoin sodium equivalent units (PE).

• Dosing Errors: Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial. Ensure the appropriate volume is withdrawn from the vial when preparing for administration. ( 5.1 ) • Withdrawal Precipitated Seizure: May precipitate status epilepticus. Dose reductions or discontinuation should be done gradually. ( 5.3 ) • Serious Dermatologic Reactions: Discontinue at the first sign of a rash, unless clearly not drug-related. If signs or symptoms suggest SJS/TEN, fosphenytoin sodium should not be resumed; consider alternative therapy. ( 5.4 ) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: If signs or symptoms of hypersensitivity are present, evaluate the patient immediately. Discontinue if an alternative etiology cannot be established. ( 5.5 ) • Angioedema: Discontinue immediately if symptoms of angioedema such as facial, perioral, or upper airway swelling occur. ( 5.7 ) • Hematopoietic Complications: If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used. ( 5.9 ) 5.1 Dosing Errors Phenytoin Sodium Equivalents (PE) Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial. Doses of fosphenytoin sodium are always expressed in terms of milligrams of phenytoin sodium equivalents (mg PE). 1 mg PE is equivalent to 1 mg phenytoin sodium. Do not, therefore, make any adjustment in the recommended doses when substituting fosphenytoin sodium for phenytoin sodium or vice versa.

The following serious adverse reactions are described elsewhere in the labeling: Cardiovascular Risk Associated with Rapid Infusion [see Warnings and Precautions (5.2) ] Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.3) ] Serious Dermatologic Reactions [see Warnings and Precautions (5.4) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.5) ] Hypersensitivity [see Warnings and Precautions (5.6) ] Angioedema [see Warnings and Precautions (5.7) ] Hepatic Injury [see Warnings and Precautions (5.8) ] Hematopoietic Complications [see Warnings and Precautions (5.9) ] Sensory Disturbances [see Warnings and Precautions (5.10) ] Local Toxicity (Including Purple Glove Syndrome) [see Warnings and Precautions (5.11) ] Exacerbation of Porphyria [see Warnings and Precautions (5.14) ] Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.15) ] Hyperglycemia [see Warnings and Precautions (5.16) ] Most common adverse reactions (incidence ≥10%) are: • Adults: pruritus, nystagmus, dizziness, somnolence, and ataxia • Pediatrics: vomiting, nystagmus, and ataxia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma Limited at 864-879-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

• Pregnancy: Phenytoin (the active metabolite of fosphenytoin sodium injection) prenatal exposure may increase risks for congenital malformations and other adverse developmental outcomes ( 5.15 , 8.1 ) • Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients ( 8.6 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as fosphenytoin sodium, during pregnancy. Physicians are advised to recommend that pregnant patients taking fosphenytoin sodium enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Risk Summary In humans, prenatal exposure to phenytoin (the active metabolite of fosphenytoin sodium) may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects.

Metabolism

Fosphenytoin Absorption Intravenous: When fosphenytoin sodium is administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion. Intramuscular : Fosphenytoin is completely bioavailable following IM administration of fosphenytoin sodium.

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin sodium. Because fosphenytoin sodium is a prodrug of phenytoin, the following information about phenytoin overdosage may be helpful. Initial symptoms of acute phenytoin toxicity are nystagmus, ataxia, and dysarthria. Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma, and hypotension. Death is caused by respiratory and circulatory depression. The lethal dose of phenytoin in adults is estimated to be 2 to 5 grams. The lethal dose in pediatrics is not known. There are marked variations among individuals with respect to serum phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 20 μg/mL, ataxia at 30 μg/mL, and dysarthria and lethargy appear when the serum concentration is over 40 μg/mL. However, phenytoin concentrations as high as 50 μg/mL have been reported without evidence of toxicity.

• Aug 5, 1996NDANDA020450Parke Davis
• Aug 6, 2007ANDAANDA077989Hikma
• Aug 6, 2007ANDAANDA078052Fresenius Kabi Usa
• Mar 18, 2008ANDAANDA078476Amneal
• Dec 2, 2009ANDAANDA078765Hikma Farmaceutica
• Oct 13, 2023ANDAANDA214926Gland

1. 1Drug Ineffective53321%
2. 2Off Label Use26911%
3. 3Status Epilepticus1566.2%
4. 4Seizure1485.9%
5. 5Cardiac Arrest1184.7%
6. 6Hypotension1144.5%
7. 7Drug Ineffective For Unapproved Indication983.9%
8. 8Multiple-drug Resistance943.7%
9. 9Drug Interaction933.7%
10. 10Toxicity To Various Agents843.3%
11. 11Pyrexia763.0%
12. 12Stevens-johnson Syndrome622.5%
13. 13Convulsion612.4%
14. 14Bradycardia602.4%
15. 15Rash542.1%

The 10 most recently updated of 16 ClinicalTrials.gov registrations naming Fosphenytoin as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• A Platform Protocol to Investigate Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis in Patients With Hematologic Malignancies Undergoing Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation
  Recruiting · Phase 2 · Interventional · 358 enrolled · Center for International Blood and Marrow Transplant Research
  NCT06859424updated 2026-03-17
• Antiseizure Medication in Seizure Networks at Early Acute Brain Injury
  Terminated · Phase 4 · Interventional · 5 enrolled · University of North Carolina, Chapel Hill
  NCT06081283updated 2025-11-14
• The Efficacy and Safety of Levetiracetam Versus Fosphenytoin in Convulsive Status Epilepticus
  Unknown · Phase 4 · Interventional · 62 enrolled · Dhaka Medical College
  NCT06403150updated 2024-05-07
• NPC-06 to Pain Associated With Acute Herpes Zoster
  Completed · Phase 3 · Interventional · 51 enrolled · Nobelpharma
  NCT05480553updated 2023-09-28
• Phenytoin as Treatment for Acute Exacerbations of Trigeminal Neuralgia - a Prospective Systematic Study of 20 Patients
  Completed · Observational · 15 enrolled · Danish Headache Center
  NCT03712254updated 2022-03-24
• Established Status Epilepticus Treatment Trial
  Completed · Phase 3 · Interventional · 478 enrolled · University of Virginia
  NCT01960075updated 2021-06-14
• Double Cord Blood Transplant for Patients With Malignant and Non-malignant Disorders
  Terminated · Phase 1 · Phase 2 · Interventional · 1 enrolled · Columbia University
  NCT00801931updated 2019-03-27
• Comparison Between Lorazepam, Clonazepam and Clonazepam + Fosphenytoin for the Treatment of Out-of-hospital Generalized Status Epilepticus
  Completed · Phase 3 · Interventional · 434 enrolled · Assistance Publique - Hôpitaux de Paris
  NCT01870024updated 2018-10-11
• Intravenous Lacosamide Compared With Fosphenytoin in the Treatment of Patients With Frequent Nonconvulsive Seizures
  Completed · Phase 2 · Interventional · 74 enrolled · Aatif Husain
  NCT01458522updated 2018-06-11
• Antiepileptic Drugs and Vascular Risk Markers
  Terminated · Interventional · 52 enrolled · Thomas Jefferson University
  NCT00774306updated 2017-12-18

CPIC-curated drug–gene pairs for Fosphenytoin. Levels describe the strength of curated evidence and guideline status — never a recommendation to test or to adjust therapy.

• CYP2C9CPIC AFDA label: Actionable PGx
  CYP2C9, HLA-B and Phenytoin
• HLA-BCPIC AFDA label: Actionable PGx
  CYP2C9, HLA-B and Phenytoin

Frequently asked questions

How does Fosphenytoin work?

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

What is Fosphenytoin used for?

According to FDA labeling, Fosphenytoin carries indications including: Fosphenytoin sodium injection is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium injection can also be substituted, short-term, for oral phenytoin.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Fosphenytoin?

Fosphenytoin is classified as Hydantoin derivatives, Sodium Channel Interactions, Decreased Disorganized Electrical Activity, Decreased Organized Electrical Activity.

What are the brand names for Fosphenytoin?

Fosphenytoin is marketed under brand names including Cerebyx.

What are the contraindications for Fosphenytoin?

Fosphenytoin labeling lists contraindications including: Fosphenytoin sodium is contraindicated in patients with: A history of hypersensitivity to fosphenytoin sodium injection or its inactive ingredients, or to phenytoin or other hydantoins [see Warnings and Precautions (5.6) ] . Reactions have included angioedema.. Always consult the full prescribing information and a clinician.