Fenitoin (Epanutin)

Clinical Effects:

PHENYTOIN
  • This management includes phenytoin and ethotoin, both in the hydantoin class of anticonvulsants; however, phenytoin will be the primary drug discussed. Fosphenytoin is covered in a separate management. USES: Phenytoin is primarily used as an anticonvulsant, both for status epilepticus and for seizure prevention. PHARMACOLOGY: Phenytoin stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during nerve impulse generation. TOXICOLOGY: Phenytoin prolongs effective refractory period and suppresses ventricular pacemaker automaticity, thus shortening the action potential in the heart. The intravenous form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol at a pH of 12. This formulation can have its own toxicity secondary to cardiac toxicity of propylene glycol (mechanism unknown) and tissue necrosis from infiltration (secondary to the alkaline nature of the formulation). EPIDEMIOLOGY: There are thousands of exposures reported to poison centers every year, as it is a widely used anticonvulsant. However, deaths are extremely rare and severe manifestations occur in only a minority of cases. MILD TO MODERATE TOXICITY: Nausea and vomiting may develop early after overdose. Nystagmus, ataxia, and mild CNS depression are common. SEVERE TOXICITY: Large oral ingestions can cause more severe CNS depression, coma, and, rarely, respiratory depression. Rapid infusion of the parenteral formulation (faster than 50 mg/min) can cause hypotension, bradycardia, AV conduction delays, and ventricular dysrhythmias which may be fatal. It is felt that the cardiotoxicity of the intravenous formulation of phenytoin is secondary to the diluent, propylene glycol, and not the phenytoin itself. ADVERSE EFFECTS: Significant adverse effects seen from intravenous use of phenytoin include venous irritation and pain, and thrombophlebitis. Extravasation can cause tissue necrosis. Adverse effects unrelated to plasma phenytoin levels include hypertrichosis, gingival hypertrophy, thickening of facial features, carbohydrate intolerance, folic acid deficiency, peripheral neuropathy, vitamin D deficiency, osteomalacia, and systemic lupus erythematosus (SLE). Some rarely seen but important adverse reactions include blood dyscrasias, dyskinesias, hepatitis, lymphadenopathy, lymphoma, pseudolymphoma, SLE-like syndrome, Steven-Johnson Syndrome, and toxic epidermal necrolysis. Phenytoin is a known teratogen. Fetal hydantoin syndrome is characterized by microcephaly, mental retardation, craniofacial abnormalities, and digital hypoplasia. It occurs in 10% to 30% of exposed pregnancies.

Range of Toxicity:

PHENYTOIN
  • TOXICITY: The minimum acute toxic oral overdose is 20 mg/kg. However, since phenytoin has dose-dependent kinetics, inadvertent intoxication from drug interactions or small dose adjustments can easily occur in patients taking the medication chronically. Fatalities have most often been associated with the intravenous formulation being given too rapidly, and is thought to be secondary to the propylene glycol diluent rather than the phenytoin itself. THERAPEUTIC DOSE: SEIZURE DISORDER: ADULT: Usual maintenance dose is 100 mg orally 3 to 4 times daily, up to a maximum of 600 mg/day. PEDIATRIC: Children less than 6 years of age: 5 mg/kg/day divided into 2 or 3 doses up to a maximum of 300 mg/day; usual maintenance dose is 4 to 8 mg/kg/day. Children older than 6 years of age: May require the minimum adult dose of 300 mg/day. STATUS EPILEPTICUS: ADULT: Loading dose is between 10 to 15 mg/kg IV with a maximum rate of 50 mg/minute. PEDIATRIC: The recommended loading dose is 15 to 20 mg/kg IV at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min (whichever is slower).

Treatment:

PHENYTOIN
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: For mild and moderate toxicity, treat with supportive care, as the patient eventually metabolizes the phenytoin. If the patient is awake and alert, administer a dose of activated charcoal. Protect the patient from self-injury secondary to ataxia. MANAGEMENT OF SEVERE TOXICITY: For large phenytoin overdoses, treat with supportive care, which may include intubation for comatose patients. If seizures do occur, treat with benzodiazepines and evaluate for other causes of seizures. PARENTERAL EXPOSURE: In patients with parenteral overdoses, monitor mental status and intubate patients with significant CNS depression. Treat hypotension with intravenous fluids, add vasopressors if hypotension persists. Treat dysrhythmias with standard ACLS protocols. Thrombophlebitis and infiltrations should be treated supportively with pain medications such as NSAIDs and warm compresses.
  • Decontamination: PREHOSPITAL: Prehospital activated charcoal might be considered if the patient is awake, alert, and cooperative, and the exposure was relatively recent (within the last hour). HOSPITAL: Activated charcoal could be considered if the patient is awake, alert, and cooperative, and the ingestions is relatively recent. Gastric lavage should be avoided in most phenytoin overdoses as it is not life-threatening.
  • Airway management: Perform endotracheal intubation in patients with significant CNS depression.
  • Antidote: None
  • Extravasation injury: If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer hyaluronidase. Elevate the affected area. Apply a warm or cold compress as indicated. One study recommended applying a dry warm compress. However, another source recommended ice packs for 15 to 20 minutes at least 4 times daily. Administer analgesics for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy.
  • Monitoring of patient: Obtain a basic metabolic panel, aspirin concentration, and acetaminophen concentration after deliberate overdose. Monitor phenytoin concentrations every 4 hours until clearly declining. Monitor serial neurologic examinations. Obtain an ECG and institute continuous cardiac monitoring during and after rapid intravenous infusion or intravenous overdose. Obtain serum albumin concentration as phenytoin toxicity may occur in the setting of normal total serum phenytoin concentrations, but elevated free phenytoin concentrations. Some clinical effects reported in elevated phenytoin concentrations include: greater than 20 mcg/mL: far lateral nystagmus; greater than 30 mcg/mL: 45 degrees lateral gaze nystagmus and ataxia; greater than 40 mcg/mL: decreased mentation; greater than 100 mcg/mL: death.
  • Enhanced elimination procedure: There is some evidence that repeated doses of charcoal may enhance phenytoin elimination, but the evidence is weak that actually improves outcomes, and it should not be given in drowsy patients secondary to the risk of aspiration pneumonitis, so it is rarely indicated. Although there are some anecdotal reports of efficacy, there is no indication for hemodialysis, hemoperfusion, or urinary alkalinization.
  • Patient disposition: HOME CRITERIA: For unintentional ingestions where the patient is asymptomatic and the dose is less than 20 mg/kg, the patient can be observed at home. OBSERVATION CRITERIA: Any intentional overdose or inadvertent overdoses above 20 mg/kg, or if symptomatic, the patient should be sent to a healthcare facility for observation. Patients should be observed for at least 4 to 6 hours, and should not be sent home until symptoms are clearly improving, or they are asymptomatic and serum concentrations are clearly declining. ADMISSION CRITERIA: Patients who have worsening symptoms after 4 to 6 hours or with significant ataxia or CNS depression, and those with rising serum concentrations, should be admitted to the hospital. If the CNS depression is severe enough that there is respiratory depression or concern of airway protection, the patient should be admitted to an intensive care setting. Otherwise, most patients can be safely admitted to a hospital ward bed. Criteria for discharge from the hospital should include clinical symptomatic improvement, which should be reflected by declining phenytoin serum concentrations. CONSULT CRITERIA: In patients with cardiac toxicity secondary to the intravenous formulation of phenytoin, it might be reasonable to consult a cardiologist. Neurologists are often very familiar with both the acute and chronic toxicity of phenytoin. Consult a medical toxicologist or poison center for patients with severe toxicity.