NEODOSE

INDICATIONS

Anticonvulsant. Generally used to treat seizures that are refractory to phenobarbital. Can be administered with lorazepam for rapid onset of seizure control.

FDA APPROVED INDICATION

Indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery in all pediatric age groups. May be used as a short-term substitute for oral phenytoin in patients with seizure disorders and should only be used when oral phenytoin administration is not possible.

CONTRAINDICATIONS

Contraindicated in patients with sinus bradycardia, sino-atrial block, second or third degree AV block, or Adams-Stokes syndrome. Contraindicated in patients with a history of prior acute hepatotoxicity attributable to fosphenytoin or phenytoin. Use is also contraindicated in patients with hypersensitivity to fosphenytoin, any component of the product, phenytoin, or other hydantoins; and with concomitant delavirdine due to a potential loss of virologic response and resistance to delavirdine.

PRECAUTIONS

• Administration:
  • Increased risk of cardiovascular reactions, including severe hypotension and cardiac arrhythmias, have been associated with rapid administration; increased risk in critically ill, elderly and patients with hypotension and severe myocardial insufficiency; monitoring and possible discontinuation recommended and use oral therapy whenever possible.
• Alcohol Use:
  • Acute alcohol use may increase phenytoin concentrations while chronic alcohol use may decrease concentrations.
• Cardiovascular:
  • Cardiovascular events, including severe hypotension and cardiac arrhythmias (bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation resulting in asystole, cardiac arrest, and death) have been reported. Increased risk in the critically ill and those with hypotension or severe myocardial insufficiency.
• Dermatologic:
  • Severe cutaneous reactions, including fatalities (eg, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)) have been reported; discontinue use at the first sign of rash, unless clearly not drug-related, and evaluate patients for severe cutaneous reaction; do not reinitiate therapy if signs or symptoms suggest severe cutaneous reaction.
  • Presence of HLA-B*1502 allele (more common in patients of Asian ancestry) may increase risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis in patients taking antiepileptic drugs, including phenytoin; consider avoiding phenytoin as a carbamazepine alternative in patients positive for HLA-B*1502.
  • Edema, discoloration, and pain distal to injection site (known as “purple glove syndrome”) have been reported following peripheral IV injection, which may or may not be associated with extravasation.
• Endocrine & Metabolic:
  • Hypoalbuminemia may increase fosphenytoin clearance to phenytoin without corresponding phenytoin clearance increase, which may potentiate frequency and severity of adverse effects.
  • yperglycemia has been reported.
  • May lower serum folate levels.
• Hematologic:
  • Hematopoietic events (eg, thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression), including fatal cases, have been reported.
  • May be associated with exacerbation of porphyria.
• Hepatic:
  • Hepatic disease may increase fosphenytoin clearance to phenytoin without corresponding phenytoin clearance increase, which may potentiate frequency and severity of adverse effects.
  • Hepatotoxicity (eg, jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, eosinophilia, and acute hepatic failure), some cases fatal, has been reported. Discontinue use and do not readminister.
• Immunologic:
  • Angioedema has been reported; discontinue immediately for presence of symptoms (facial, perioral, or upper airway swelling).
  • Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, including fatal cases, has been reported. Discontinue use if confirmed.
  • Consider alternative therapy in patients with personal or family history of hypersensitivity to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione).
  • Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin disease, has been reported.
• Medication Safety:
  • Medication errors, some resulting in death, have occurred. The amount of drug to be given in phenytoin equivalents (mg PE) should not be confused with the concentration of the drug in the vial. Carefully examine and confirm correct dose before administering.
• Phenytoin Toxicity:
  • Serum levels sustained above optimal ranges may result in confusional states (eg, delirium, encephalopathy, psychosis, irreversible cerebellar dysfunction). Increased risk with impaired liver function or critical illness. Dose reduction or discontinuation may be needed.
• Phosphate Intake:
  • Consider phosphate load (0.0037 mmol phosphate/mg PE fosphenytoin sodium) in patients requiring phosphate restriction, including severe renal impairment.
• Neurologic:
  • Abrupt discontinuation may increase seizure frequency or precipitate status epilepticus. Discontinue gradually when possible.
  • Not approved for absence seizures or seizures due to hypoglycemic or other metabolic causes.
• Renal:
  • Renal disease may increase fosphenytoin clearance to phenytoin without corresponding phenytoin clearance increase, which may potentiate frequency and severity of adverse effects.
• Reproductive:
  • May cause fetal harm.
• Special Populations:
  • Avoid use in HLA-B*15:02 carriers if patient is phenytoin/fosphenytoin-naive. HLA-B*1502-positive patients (most common in Asian patients) may have an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis.
  • Avoid using as an alternative for carbamazepine in HLA-B*1502- positive patients.
  • Dose reduction and monitoring recommended in HLA-B*15:02 noncarriers with intermediate or poor CYP2C9 metabolizer status.

ADVERSE EFFECTS

Fewer infusion-related reactions and tissue damage (eg, purple glove syndrome) compared with phenytoin. Hypotension and cardiac arrhythmias have been reported. Dose related adverse events include nystagmus (total level, 15 to 25 mg/L) and ataxia and mental status changes (total level greater than 30 mg/L). Movement disorders (bradykinesia and choreoathetosis) may also occur rarely. Minor venous irritation upon IV administration. Vomiting is common in children. Long-term effects of therapy include gingival hyperplasia, coarsening of the facies, hirsutism, hyperglycemia, and hypoinsulinemia. Fosphenytoin drug interactions are similar to phenytoin (ie, carbamazepine, cimetidine, corticosteroids, digoxin, furosemide, phenobarbital, and valproate). Use with caution in infants and children with hyperbilirubinemia: both fosphenytoin and bilirubin displace phenytoin from protein-binding sites, resulting in increased serum free phenytoin concentration. Serious and sometimes fatal skin reactions, including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis, have been reported with phenytoin therapy. Onset of symptoms is typically within 28 days, but can occur later. Limited data suggests that a particular human leukocyte antigen (HLA) allele, HLA-B*1502, found in patients of Asian ancestry may be a risk factor for the development of SJS/TEN in patients taking phenytoin. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502. Because fosphenytoin is a prodrug and is converted to phenytoin after administration, any concern regarding this association is also applicable to fosphenytoin.

BLACK BOX WARNING

The rate of intravenous fosphenytoin administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous fosphenytoin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed

ADMINISTRATION

Do not confuse concentration of fosphenytoin with the total amount of drug in the vial. Dosing errors have occurred, with patients receiving 2- or 10- fold overdoses of fosphenytoin, including fatal outcomes.

• Intravenous: Administer 1 to 2 mg PE/kg per minute (maximum 150 mg PE/minute for loading dose and 100 mg PE / minute for maintenance dose) at a concentration of 1.5 to 25 mg PE/mL. Some institutions use standard concentrations of 10 mg PE/mL and 25 mg PE/mL< /li>
• Intramuscular: Administer undiluted. May divide dose and give in more than one site. IM administration of fosphenytoin should not ordinarily be used for status epilepticus due to delays in achieving a therapeutic concentration compared with IV administration

In the preparation and administration of injections, the National Institute for Occupational Safety and Health (NIOSH) recommends the use of double gloves and a protective gown. Prepare in a biological safety cabinet or a compounding aseptic containment isolator; eye/face and respiratory protection may be needed. Prepare compounds in a closed system drug transfer device. During administration, if there is a potential that the substance could splash or if the patient may resist, use eye/face protection. Administer certain dosage forms via a closed system drug transfer device.

MONITORING

Monitor electrocardiogram, blood pressure, and respiratory function continuously during infusion and for 10 to 20 minutes after end of infusion. Measure serum phenytoin (not fosphenytoin) concentration 2 hours after IV dose and 4 hours after IM dose. For maintenance therapy, a trough measurement is suggested. Therapeutic serum phenytoin concentration is 10 to 20 mg/L for total phenytoin and 1 to 2 mg/L for unbound phenytoin. Collect blood samples in EDTA tubes to minimize fosphenytoin to phenytoin conversion in the tube.