NEODOSE

INDICATIONS

Anticonvulsant often used to treat seizures refractory to phenobarbital.

Contraindications / Precautions :

CONTRAINDICATIONS

• Coadministration with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or the class of NNRTI.
• History of prior acute hepatotoxicity attributable to phenytoin.
• History of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins.

PRECAUTIONS

• Cardiovascular:
  • Bradycardia and cardiac arrest, including cases at recommended doses and phenytoin levels and those associated with toxicity, have been reported; cardiac arrest has occurred mostly in patients with underlying cardiac disease.
• Concomitant Use:
  • Concomitant use of oral phenytoin with enteral feeding preparations not recommended.
• Dermatologic:
  • Soft tissue irritation and inflammation varying from slight injection site tenderness to extensive necrosis and sloughing, including “purple glove syndrome” with edema, discoloration, and pain distal to injection site, have been reported (even without extravasation); fasciotomies, skin grafting, or amputation may be necessary.
  • 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.
• Endocrine & Metabolic:
  • Hyperglycemia has been reported.
  • Serum glucose levels may increase in patients with diabetes.
• Hematologic:
  • Thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression, including fatal cases, have been reported.
  • Use caution in patients with porphyria as exacerbation has been reported.
• Hepatic:
  • hyperbilirubinemia; bilirubin displaces phenytoin from protein-binding sites, resulting in increased serum free phenytoin concentration.
  • Patients with hepatic disease have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution.
  • Acute hepatotoxicity, including hepatic failure and fatalities, has been reported; discontinue and do not re-administer.
  • Phenytoin toxicity may occur in patients with impaired liver function or those who are gravely ill.
• Immunologic:
  • Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, including fatal cases, has been reported; evaluate patient if signs and symptoms are present and discontinue phenytoin if alternative etiology cannot be established.
  • Angioedema has been reported; discontinue immediately for presence of symptoms (facial, perioral, or upper airway swelling).
  • Consider alternatives to structurally similar drugs such as carboxamides, barbiturates, succinimides, and oxazolidinediones in patients with a history of hypersensitivity to phenytoin.
  • Consider alternative to phenytoin in patients with personal or immediate family history of hypersensitivity to structurally similar drugs.
  • Local and generalized lymphadenopathy may occur; extended follow-up is recommended in all cases and alternative antiepileptic therapy should be utilized if possible.
• Musculoskeletal:
  • Decreased bone density and bone fractures have been reported, possibly due to increased metabolism of vitamin D and vitamin D deficiency; consider screening and initiating treatment if detected.
• Neurologic:
  • Dose-related CNS toxicity may occur in slow metabolizers; check plasma levels immediately if signs of toxicity develop
  • Delirium, psychosis, encephalopathy, or rarely irreversible cerebellar dysfunction may occur with concentrations above the therapeutic range; recommend plasma phenytoin levels at first sign of toxicity and dose reduction if excessive.
• Pregnancy:
  • A potentially life-threatening bleeding disorder may occur in neonates exposed to phenytoin in utero; administer vitamin K to mother prior to delivery and to neonate after birth.
• Renal:
  • Patients with renal disease have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution.
• Special Populations:
  • Avoid use in HLA-B*1502 carriers if patient is phenytoin/fosphenytoin-naive. HLA-B*15:02-positive patients (most common in Asian patients) may have an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis.
  • Dose reduction and monitoring recommended in HLA-B*1502 noncarriers with intermediate or poor CYP2C9 metabolizer status.
• Withdrawal:
  • Abrupt withdrawal may precipitate increased seizure activity, status epilepticus. Dose reduction, discontinuation, or substitution of anticonvulsant therapy should be done gradually; if rapid withdrawal is necessary due to an allergic or hypersensitivity reaction, alternative therapy should not be in hydantoin class.

ADVERSE EFFECTS

• Extravasation causes tissue inflammation and necrosis due to high pH and osmolality. Propylene glycol content of the intravenous formulation has been associated with seizures and may potentiate the cardiovascular effects of phenytoin.Hypotension and cardiac arrhythmias have been reported.High serum concentrations are associated with seizures. 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.Hypersensitivity reactions have been reported in infants.Long – term effects of phenytoin include gingival hyperplasia, coarsening of the facies, hirsutism, hyperglycemia, and hypoinsulinemia.Cutaneous side effects include maculopapular exanthema, drug – induced lupus, and pigmentary alterations.Phenytoin interacts with carbamazepine, cimetidine, corticosteroids, digoxin, furosemide, phenobarbital, and valproate.
• Supplementation with folic acid 0.5 mg/day orally was associated with a significantly lower rate of gingival hyperplasia (21% vs. 87.9% for placebo) in children 6 to 15 years of age taking phenytoin in a 6 – month, randomized, double – blind, placebo controlled study(N = 120)

ADMINISTRATION

• Intravenous: Administer directly into a large peripheral or central vein through a largegauge catheter. Administer 50 mg/mL (undiluted) at a rate of 1 mg/kg/minute (over approximately 15 to 20 minutes for loading dose and 10 minutes for maintenance dose). May dilute in normal saline at a concentration of no less than 5 mg/mL and infuse within 1 to 4 hours (60 to 240 minutes). If diluted in normal saline, then use an in-line filter (0.22 to 0.55 microns). Flush IV with saline before and after administration. Always inspect for particulate matter and discoloration before administration. SubQ or perivascular injection should be avoided. IM route not acceptable: poorly absorbed with drug crystallization in muscle; may cause necrosis of soft tissues at the injection site.
• National Institute for Occupational Safety and Health (NIOSH) Recommendations:
  • 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.
  • In the preparation of tablets or capsules, including cutting, crushing, or manipulating, or the handling of uncoated tablets, NIOSH recommends the use of double gloves and a protective gown. Prepare in a ventilated control device, if possible. Use respiratory protection if not prepared in a control device. During administration, wear single gloves, and wear eye/face protection if the formulation is hard to swallow or if the patient may resist, vomit, or spit up .
  • NIOSH recommends the use of double gloves and a protective gown by anyone handling a hazardous oral liquid or any hazardous drug via a feeding tube. Prepare in a control device, if possible. Use respiratory, eye, and face protection if not done in a control device. During administration, eye/face protection is needed if the patient may resist, or if there is potential to vomit or spit up.
• Extravasation Management: ManagementNeonatal data are limited to pooled data from 10 case reports/case series (n=237) and are not specific to phenytoin extravasation; subcutaneous saline irrigation with or without hyaluronidase infiltration was commonly used. No standardized management was established. An option for more severe injuries (stages 3 and 4) is subcutaneous irrigation with saline, but this is not advocated as standard treatment. Conservative management is appropriate for mild extravasation (stages 1 and 2). Although not neonatal-specific, the following are recommendations for extravasation of acidic or alkaline agents (phenytoin is alkaline with a pH of 10 to 12, greater than 700 mOsm/L):
  • General:
    • Stop and disconnect infusion; do not remove the cannula or needle.
    • Attempt to gently aspirate as much extravasated agent as possible; avoid manual pressure.
    • Remove cannula or needle.
    • Dry heat and elevation.
    • Closely monitor for signs of coagulation and ischemia.
    • Avoid attempt at pH neutralization (phenytoin – pH 10 to 12).
    • Alternate treatment, topical nitroglycerin 2% apply up to 1-inch strip to affected area every 8 hours as needed. Hypotension may occur as dosage may exceed those typically used for angina.
    • Monitor and consider the need for surgical management such as surgical flushing with normal saline or debridement and excision of necrotic tissue (especially if pain persists for 1 to 2.
  • Refractory Events:
    • Hyaluronidase 15 units intradermally along injection site and edematous area. Give as five, 0.2-mL intradermal injections along extravasation site and edematous tissue.
  • Inadvertent Intraarterial Administration:
    • Leave inadvertent intraarterial line in place for diagnostics.
    • Systemic heparin titrated to therapeutic anticoagulant effect.
    • Stellate ganglion block.

BLACK BOX WARNING

The rate of intravenous phenytoin administration should not exceed 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous phenytoin. 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.

MONITORING

Monitor electrocardiogram, blood pressure, and respiratory function continuously during infusion, and for 15 minutes to 1 hour after infusion. Observe IV site for extravasation. Follow serum concentration closely: therapeutic range is 6 to 15 mcg/mL in the first weeks, then 10 to 20 mcg/mL due to changes in protein binding. Obtain initial trough level 48 hours after IV loading dose.