PHENYTOIN SODIUM 
Pronounciation
- (FEN-ih-toyn SO-dee-um)
Trade Name(s)
- Dilantin
See Maternal/Child.
In all situations, transfer to oral therapy as soon as practical. See Precautions and Monitor. Treatment with phenytoin can be initiated either with a loading dose or an infusion.
Status epilepticus, anticonvulsant:
A loading dose of 10 to 15 mg/kg. One source recommends not exceeding a total dose of 1.5 Gm in 24 hours. Lethal dose estimated at 2 to 5 Gm. Another source suggests that 15 to 20 mg/kg is generally recommended. Follow with maintenance doses of 100 mg every 6 to 8 hours. Adjust dose based on phenytoin levels; see Monitor. Other measures, including concomitant administration of an IV benzodiazepine (such as diazepam) or an IV short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of phenytoin. If seizure is not terminated, consider other anticonvulsants, barbiturates, or anesthesia.
Non-emergent loading and maintenance dosing:
10 to 15 mg/kg as a loading dose followed by a maintenance dose of oral or IV phenytoin every 6 to 8 hours.
Status epilepticus, anticonvulsant:
15 to 20 mg/kg as a loading dose. Follow with a maintenance dose for age (listed below):
Begin with 5 mg/kg/24 hr in equally divided doses every 12 hours. Range is 4 to 8 mg/kg/24 hr in divided doses every 8 or 12 hours (2 to 4 mg/kg every 12 hours or 1.33 to 2.67 mg/kg every 8 hours).
Infants and other pediatric patients:
Begin with 5 mg/kg/24 hr in equally divided doses every 8 to 12 hours (2.5 mg/kg every 12 hours or 1.67 mg/kg every 8 hours). Range varies according to age:
8 to 10 mg/kg/24 hr (4 to 5 mg/kg every 12 hours or 2.67 to 3.33 mg/kg every 8 hours).
7.5 to 9 mg/kg/24 hr (3.75 to 4.5 mg/kg every 12 hours or 2.5 to 3 mg/kg every 8 hours).
7 to 8 mg/kg/24 hr (3.5 to 4 mg/kg every 12 hours or 2.3 to 2.6 mg/kg every 8 hours).
6 to 7 mg/kg/24 hr (3 to 3.5 mg/kg every 12 hours or 2 to 2.3 mg/kg every 8 hours).
After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum levels of phenytoin to achieve a target therapeutic concentration. ■ Lower or less frequent dosing and a slower rate of administration may be required in elderly patients. ■ Use caution, lower dose, and slower rate of administration in seriously ill patients and cachectic patients. ■ Lower doses may also be required in patients with renal or hepatic disease or in those with hypoalbuminemia. Monitoring of unbound (free) phenytoin concentrations may be a better dosing guide. ■ Dose adjustment may be needed when switching between the sodium salt formulations (e.g., injection and capsules) and the free acid forms (e.g., suspension and infatabs). The free acid form contains approximately 8% more drug than the sodium salt form. ■ See Drug/Lab Interactions.
Available in 100- or 250-mg single-dose ampules or vials and in 100-mg single-dose syringes. After verifying patency, may be administered directly into a large peripheral or central vein through a large-gauge catheter. Alternately, may be further diluted in NS to a concentration of no less than 5 mg/mL and administered as an infusion. Use solution only when completely dissolved and clear.
Manufacturer recommends use of an in-line filter (0.22 to 0.55 microns) when administered as an infusion.
Store between 15° and 30° C (59° and 86° F). Infusion solutions should be administered immediately after preparation and must be completed within 1 to 4 hours. Do not refrigerate infusion solutions.
Manufacturer recommends not adding to IV solutions other than NS or mixing with other medications and states that “the addition of phenytoin to dextrose or dextrose-containing solutions will result in precipitation.” Always flush line with NS before and after administration of any other drug through the same IV line. See Dilution.
Other sources suggest a few specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.
Because of the risk of local toxicity, IV phenytoin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Before administration, the patency of the IV should be tested with a sterile saline flush. Follow the administration of phenytoin with a saline flush to avoid local venous irritation due to the alkalinity of the solution. In nonemergent situations, slower rates of administration should be used.
Administer slowly at a rate of 25 to 50 mg or fraction thereof over 1 minute. Do not exceed 50 mg/min.
Do not exceed 1 to 3 mg/kg/min (or 50 mg/min, whichever is slower). Another source suggests 0.5 mg/kg/min in neonates or 1 mg/kg/min in infants and other pediatric patients not to exceed 50 mg/min.
Limit rate to 25 mg/min.
Should be completed within 1 to 4 hours. Do not exceed 25 to 50 mg/min rate. Best if piggybacked to a compatible primary IV so phenytoin can be discontinued if side effects occur, but IV can be kept open.
An anticonvulsant, chemically related to barbiturates. Selectively stabilizes seizure threshold and depresses seizure activity in the motor cortex. Mechanism of action may be due to increasing efflux or decreasing influx of sodium ions across the cell membrane during generation of the action potential. Effective control in emergency treatment of seizures may take 15 to 20 minutes because of rate of injection required. Highly protein bound. Metabolized by cytochrome P450 enzymes CYP2C9 and CYP2C19. Most of the drug is excreted in the bile as inactive metabolites. Urinary excretion of phenytoin and its metabolites occurs by glomerular filtration and tubular secretion. Half-life ranges from 10 to 15 hours. Crosses the placental barrier. Secreted in breast milk.
Treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures during neurosurgery. Parenteral phenytoin should be used only when oral phenytoin administration is not possible.
Known hypersensitivity to phenytoin or other hydantoin products. ■ Bradycardia; sinoatrial, second-, or third-degree AV heart block; Adams-Stokes syndrome. ■ A history of prior acute hepatotoxicity attributable to phenytoin. ■ Coadministration with delavirdine (Rescriptor); see Drug/Lab Interactions.
Discontinue immediately for hypersensitivity reactions; with caution, substitute a nonhydantoin anticonvulsant. When substituting a new anticonvulsant, consideration should be given to avoiding structurally related drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione). ■ Angioedema has been reported. ■ Abrupt withdrawal may cause increased seizure activity. Gradually reduce dose, discontinue, or substitute alternative antiepileptic agents if possible. ■ Severe hypotension and cardiac arrhythmias have occurred with rapid infusion. Risk increases with increased rates, but adverse cardiac events have been reported at or below the recommended infusion rates. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation and have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. Careful cardiac monitoring is required during and after IV administration. Because of the risks of cardiac and local toxicity associated with IV phenytoin, oral phenytoin should be used whenever possible. ■ Use caution with low serum albumin level, and adjust dose as indicated. Phenytoin is highly bound to serum protein (approximately 80% to 90% or more), and a reduced albumin causes an increase in free drug availability. ■ Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported. Usually presents with fever, rash, lymphadenopathy, and/or facial swelling in association with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Deaths have been reported. Discontinue therapy if an alternative etiology for S/S cannot be established. ■ Severe cutaneous adverse reactions (SCARs) have been reported, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and DRESS. Deaths have occurred. Onset of symptoms is usually within 28 days but may occur later. Discontinue phenytoin at the first sign of a rash unless the rash is clearly not drug related. If a rash develops, the patient should be evaluated for S/S of SCARs. ■ Selected patients of Asian ancestry with a specific human leukocyte antigen allele (HLA-B*1502) may have an increased risk of serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) from phenytoin therapy. ■ Cases of acute hepatotoxicity, including hepatic failure, have been reported. These events may be part of the spectrum of DRESS or may occur in isolation. Reactions have included elevated liver function tests, eosinophilia, hepatomegaly, jaundice, and leukocytosis. Discontinue immediately and substitute alternative anticonvulsant therapy. ■ Hematopoietic complications, some fatal, have been reported (e.g., agranulocytosis, granulocytopenia, leukopenia, thrombocytopenia, or pancytopenia with or without bone marrow suppression). ■ Some reports suggest a relationship between phenytoin and the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin disease. Lymph node involvement may occur with or without S/S resembling DRESS; see Monitor. ■ Local toxicity, including purple glove syndrome (edema, discoloration, and pain distal to the injection site), has occurred and may or may not be associated with extravasation. Irritation may range from slight tenderness to extensive necrosis and sloughing. ■ Inhibits insulin release and may increase serum glucose; monitoring indicated in patients with diabetes. ■ A small percentage of patients may be slow metabolizers of phenytoin. This appears to be genetically determined. If early signs of dose-related CNS toxicity develop, obtain serum levels immediately. ■ Not effective for absence seizures; combined therapy is required if both conditions are present. ■ Not indicated for seizures due to hypoglycemia or other metabolic causes. ■ Use with caution in patients with porphyria. Phenytoin may exacerbate this disease. ■ Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Some psychotic symptoms and/or behavioral changes resolved without intervention. Others required dose reduction or discontinuation of the antiepileptic agent.
Narrow margin of error between therapeutic and toxic dose. Plasma levels above 10 mcg/mL usually control seizure activity. The acceptable range is 10 to 20 mcg/mL. ■ Consider monitoring free phenytoin levels in patients with hypoalbuminemia or renal or hepatic insufficiency (therapeutic range is 1 to 2 mcg/mL); fraction of unbound phenytoin is increased. ■ Toxicity usually begins with nystagmus and may be seen at levels less than 20 mcg/mL. Serum levels sustained above the optimum range may produce confusional states referred to as delirium, psychosis, encephalopathy or, rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy. Observe patient closely for signs of CNS side effects. At the first sign of acute toxicity, plasma levels are recommended. Reduce dose if levels are elevated. If symptoms persist, discontinuation of therapy is recommended. ■ Periodic monitoring of CBC, platelets, albumin, urinalysis, and hepatic and renal function is recommended. ■ Monitor ECG, BP, and respiratory status carefully during and after administration.■ Closely monitor patients who are gravely ill, have impaired liver function, or are elderly. May show early signs of toxicity. ■ In all cases of lymphadenopathy, follow-up observation for an extended period is indicated, and alternative anticonvulsant therapy should be strongly considered. ■ Observation of patient symptoms and evaluation of effectiveness of all medications is imperative. ■ Monitor for S/S of hypersensitivity reactions. ■ Observe for rash and discontinue if one appears; see Precautions. ■ Monitor for symptoms of angioedema (e.g., facial, perioral or upper airway swelling). ■ Determine absolute patency of vein. Avoid extravasation. Very alkaline; follow each injection with sterile NS to reduce local venous irritation; see Rate of Administration. ■ Patients maintained with phenytoin should be given a dose the morning of surgery to maintain adequate serum levels. ■ See Precautions and Drug/Lab Interactions.
May increase the risk of suicidal thoughts and behavior. Promptly report emergence or worsening of S/S of depression, any unusual changes in mood or behavior, or thoughts about self-harm. ■ Effective birth control required for women of childbearing potential who are not planning a pregnancy. Hormonal contraceptive efficacy may be decreased; see Maternal/Child. ■ Women who are pregnant or who become pregnant should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. ■ Do not discontinue phenytoin without consulting health care provider. ■ Report S/S of dermatologic, hematologic, hepatic, or hypersensitivity reactions (e.g., anorexia, easy bruising, facial swelling, fever, jaundice, lymphadenopathy, mouth ulcers, nausea and vomiting, petechial or purpuric hemorrhage, rash, sore throat) or angioedema (e.g., facial, perioral, or upper airway swelling). ■ Numerous drug interactions possible. Review all medications and alcohol use with provider. ■ May cause increase in blood sugar. ■ Good dental hygiene required to minimize development of gingival hyperplasia. ■ May cause decreased coordination, dizziness, gait disturbance, and somnolence. Use caution when performing tasks that require alertness.
Avoid pregnancy. May cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risk for congenital malformations and other adverse developmental outcomes; see manufacturer’s prescribing information. Consider risks versus benefit. ■ An increase in seizure frequency may occur because of alterations in phenytoin kinetics and decreased serum concentrations in pregnant women; may necessitate periodic monitoring of serum levels. Because of potential changes in protein binding, monitoring of phenytoin serum levels should be based on the unbound fraction. ■ Newborns whose mothers received phenytoin during pregnancy may develop a life-threatening bleeding disorder that can be prevented by giving vitamin K to the mother before delivery and to the neonate after birth. ■ Phenytoin is secreted in breast milk. Consider risk of infant exposure versus benefit of breast-feeding to the infant and benefit of treatment to the mother.
See Dose Adjustments and Rate of Administration. ■ Clearance tends to decrease with increasing age; lower or less frequent dosing may be required. ■ Low serum albumin causing a decrease in protein binding may result in increased sensitivity to phenytoin.
Interactions are numerous and potentially life threatening. Review of drug profile by pharmacist imperative.■ Phenytoin is highly protein bound and is prone to competitive displacement. ■ Phenytoin is metabolized by CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations, increasing the risk of toxicity. ■ Coadministration with delavirdine is contraindicated. Has potential for loss of virologic response and possible resistance to delavirdine or to the class of nonnucleoside reverse transcriptase inhibitors. ■ Serum levels may be increased by alcohol (acute ingestion), amiodarone, antiepileptic agents, azole antifungals, capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2 antagonists, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, sulfonamides, trazodone, and warfarin. ■ Serum levels and effectiveness may be decreased by antineoplastics, carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s wort, theophylline, and vigabatrin. ■ Phenytoin serum levels may be increased or decreased by phenobarbital, valproate sodium, and valproic acid. Similarly, phenytoin may unpredictably affect the levels and efficacy of these drugs. ■ The addition of withdrawal of drugs while patients are undergoing phenytoin therapy may require an adjustment of the phenytoin dose. ■ Phenytoin will inhibit the effects of azole antifungals, corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D. Dose adjustment of these agents may be indicated. ■ Because phenytoin is a potent enzyme inducer, it decreases plasma concentrations of albendazole, HIV antivirals, antiepileptic agents, atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, quetiapine, simvastatin, and verapamil. Adjust doses of these agents as indicated. ■ Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir. ■ May increase or decrease PT/INR responses when coadministered with warfarin. ■ Alters some clinical laboratory tests (e.g., may decrease T3 and T4; may increase glucose, alkaline phosphatase, GGT, and TSH; and may produce low results in dexamethasone or metyrapone tests).
The most common adverse reactions are nervous system reactions, including ataxia, decreased coordination, mental confusion, nystagmus, slurred speech, and somnolence. Other reported reactions include altered taste sensation, constipation, dizziness, drowsiness, dyskinesias, fever, headache, hyperplasia of gums, insomnia, local irritation/toxicity, nausea, nervousness, paresthesia, skin eruptions, tremors, vertigo, visual disturbances, and vomiting.
Serious adverse reactions, including acute hepatic failure, bradycardia, cardiac arrest, cardiovascular collapse, CNS depression, dermatologic reactions (including local toxicity, Stevens-Johnson syndrome, and toxic epidermal necrolysis), DRESS, heart block, hematopoietic complications, hypersensitivity reactions (including anaphylaxis [rare]), hypotension, lymphadenopathy, Peyronie’s disease, respiratory arrest, tonic seizures, toxic hepatitis, and ventricular fibrillation, have been reported. Psychotic symptoms, including aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hallucinations, hostility, irritability, and suicidal tendencies, have occurred with antiepileptic agents. Cerebellar atrophy has been reported and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use.
Ataxia, blurred vision, coma, dysarthria, hyperreflexia, hypotension, irreversible cerebellar dysfunction and atrophy, lethargy, nausea, nystagmus, slurred speech, tremor, and vomiting. Death is caused by respiratory and circulatory depression.
Notify the physician of any side effects. If minor symptoms progress or any major side effect occurs, discontinue the drug and notify the physician; see Precautions. Obtain serum plasma levels at first signs of toxicity. If serum levels are excessive, symptoms persist, or major side effects appear, discontinue phenytoin and notify physician. Treat symptomatically, maintain a patent airway, and resuscitate as necessary. Discontinue phenytoin at the first sign of a rash unless the rash is clearly not drug related. If TEN or SJS is suspected, do not rechallenge; consider alternate therapy. Discontinue immediately if symptoms of angioedema develop. Evaluate for multiorgan hypersensitivity reactions (DRESS). Cardiovascular toxicity, including hypotension or cardiac arrhythmias, may respond to a decrease in infusion rate. Decrease rate or discontinue infusion for severe hypotension or cardiac arrhythmias. Local toxicity (purple glove syndrome) may resolve spontaneously. Hemodialysis may be useful in overdose.