PHENYTOIN (Generic for DILANTIN)

General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-INJECTABLES: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
-ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

Route-Specific Administration

Oral Administration
-Different oral dosage forms are not directly interchangeable. Phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin. Dosage adjustments may be needed when switching products, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.
-In general, phenytoin should be administered at the same time with regard to meals to ensure consistent absorption.
Oral Solid Formulations
-Chewable tablets: Administer at a consistent time with an adequate amount of fluid. Crush or chew tablet well before swallowing; tablets may be swallowed whole if preferable.
-Immediate-release capsules: Administer at a consistent time with an adequate amount of fluid. For patients with difficulty swallowing, the capsules may be opened and the contents mixed with food or fluids.
-Extended-release capsules: Administer intact; do not crush, cut, or chew. Administer at a consistent time with an adequate amount of fluid. While food does not affect the absorption of Dilantin Kapseals, some generic products exhibit reduced absorption in the presence of a high-fat meal. Administer in a consistent manner in relation to food.

Oral Liquid Formulations
-Oral suspension: Shake well prior to each dose. Administer with an oral syringe or calibrated measuring device. Enteral nutrition through feeding tubes may decrease the absorption of phenytoin suspension by up to 80%. Hold enteral nutrition at least 1 hour before and 1 hour after administration of phenytoin; flush the tubing with 0.9% Sodium Chloride or Sterile Water before and after drug administration. It may be preferable to divide total daily dose into 2 doses to minimize enteral nutrition interruption; however, this may not be possible for young children with fast phenytoin metabolism. Monitor therapeutic concentrations and clinical response as dosage may need to be adjusted with feeding status changes.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Parenteral phenytoin is generally for intravenous (IV) administration only. Although intramuscular (IM) is a labeled route of administration, it is generally avoided due to injection site pain, tissue damage, and erratic absorption. If IM administration is needed, fosphenytoin is preferred over phenytoin.
-Storage: Vials are for single-dose only. Discard any unused product.
Intravenous Administration
Intermittent IV Infusion
-May be given undiluted or diluted with 0.9% Sodium Chloride Injection to a concentration of no less than 5 mg/mL. Do not dilute with a dextrose-containing solution; precipitation can occur.
-Administer immediately after preparation and complete the infusion within 1 to 4 hours. Do not refrigerate the diluted infusion mixture.
-If undiluted parenteral phenytoin is refrigerated or frozen, precipitation is possible; however, this will dissolve during exposure to room temperature and the product is still suitable for use. A faint yellow coloration may develop, but this has no effect on the potency of the solution.

Intermittent IV Administration
-Phenytoin is irritating to the veins and can result in local tissue damage; good IV access is recommended prior to administration. Acceptable access includes a) peripheral vein that is at least as large as the antecubital fossa vein, preferably accessed with a catheter size 20 gauge or larger; or b) pre-existing central venous access. The vein utilized should be free from injury or thrombophlebitis. Avoid the use of scalp veins for infusion in neonates and infants. In emergency situations, the treatment of the emergency dictates the importance of these IV access recommendations.
-Administer phenytoin through a free-flowing IV of 0.9% Sodium Chloride Injection or other non-dextrose containing saline solution. Prior to administration, test the patency of the IV catheter with a flush of sterile saline. Follow each dose by a flush of sterile saline through the same catheter to reduce the risk of local vein irritation.
-Use an in-line filter of 0.22 to 0.55 microns.
-Avoid extravasation; phenytoin is irritating to tissues and may cause injury.
-The rate of administration is critically important. Do not exceed the following infusion rates:-Neonates and Infants: Infuse at a rate of 0.5 to 1 mg/kg/minute. Max rate: 50 mg/minute. Due to their small veins, infants may be more at risk of thrombophlebitis or other tissue injuries from IV phenytoin; do not infuse via scalp veins. While rates of administration of up to 3 mg/kg/minute are recommended in the product labeling, they are associated with an increased frequency of infusion-related adverse reactions and generally not recommended in pediatric patients.
-Children and Adolescents: Infuse at a rate of 0.5 to 1 mg/kg/minute. Max rate: 50 mg/minute. While rates of administration of up to 3 mg/kg/minute are recommended in the product labeling, they are associated with an increased frequency of infusion-related adverse reactions and generally not recommended in pediatric patients.

-Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 1-hour post-infusion.

Intramuscular Administration
-Do not use IM phenytoin for the treatment of status epilepticus or other emergent conditions; absorption is erratic and peak plasma concentrations may not be achieved for up to 24 hours.
-Avoid IM administration if possible. IM administration is painful and may cause tissue injury, necrosis, or abscess formation at the injection site.
-If IM administration is the only available option and the patient is currently stable on an oral regimen with plasma concentrations within the therapeutic range, an intramuscular dose of 50% greater than the oral dose is necessary to maintain these plasma concentrations. Experience for periods greater than 1 week is lacking and plasma concentration monitoring is recommended. When returning to oral administration, the dose should be reduced by 50% of the original oral dose for 1 week to prevent excessive plasma concentrations caused by sustained release from muscle tissue sites.
-Inject deeply into a large muscle (e.g., lateral part of the thigh). Aspirate prior to injection to avoid injection into a blood vessel.

Antiepileptic drugs (AEDs) such as phenytoin increase the risk of suicidal ideation and behavior. Monitor all patients beginning treatment with AEDs or currently receiving such treatment closely for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. A pooled analysis of 199 placebo-controlled trials including 11 different AEDs showed that patients (>= 5 years of age) receiving AEDs had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), with an adjusted relative risk of 1.8 (95% CI 1.2-2.7). Four completed suicides occurred in patients treated with AEDs compared to none among controls. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor and risk was generally consistent among all AEDs examined. Suicidal ideation or behavior have occurred as early as 1 week after AED initiation and may occur any time during treatment.

Central nervous system (CNS) reactions are common and often dose-related. The most common dose-related CNS effects are nystagmus, ataxia, slurred speech (dysarthria), decreased coordination, somnolence, and mental confusion. Other CNS effects include insomnia, nervousness, vertigo, and motor twitching. During comparative trials of fosphenytoin and phenytoin in adult patients with epilepsy, the following CNS effects were reported in the in the phenytoin group: headache (4.5% to 4.9%), asthenia (3.3%), nystagmus (8.2% oral, 59.1% IV), ataxia (8.2% oral, 18.2% IV), incoordination (4.5% to 4.9%), drowsiness/somnolence (9.8% oral, 27.3% IV), dizziness (3.3% oral, 27.3% IV), paresthesias (3.3%), hyporeflexia (4.9%), stupor (4.5% IV only), cerebral edema (4.5% IV only) and hypoesthesia (9.1%). Nystagmus is an early manifestation of phenytoin toxicity (more than 20 mcg/mL), while ataxia and confusion generally occur when plasma concentrations exceed 30 mcg/mL. Phenytoin concentrations of 50 mcg/mL or greater may result in coma; concentrations of 95 mcg/mL can be fatal as a result of circulatory or respiratory depression. In a small study, phenytoin-induced seizures occurred most often in patients with serum phenytoin concentrations of 50 mcg/mL or higher. Peripheral neuropathy (sensory peripheral polyneuropathy), usually occurring weeks to months after drug initiation, has also been reported in patients receiving phenytoin; however, a case report describes the onset of neuropathy within a few hours of drug administration. Cerebellar atrophy has been reported with phenytoin use and appears to be more likely in the setting of elevated phenytoin concentrations and/or long-term use.

Adverse gastrointestinal (GI) effects of phenytoin therapy include nausea, vomiting, constipation, and abdominal pain. During a comparative trial of intravenous fosphenytoin and phenytoin, nausea (13.6%), vomiting (9.1%), and xerostomia (4.5%) were reported in the intravenous phenytoin group who received maximum doses and rates of administration. Taking the oral dosage with food may reduce some symptoms; however, clinicians should keep in mind that oral administration with continuous nasogastric feedings can significantly impair phenytoin bioavailability.

Gingival hyperplasia is frequently associated with chronic phenytoin therapy. While the exact incidence is unclear, some data indicate that up to 50% of patients taking phenytoin chronically will experience some degree of gingival overgrowth, often within 1 month after drug initiation. While some literature indicates correlation with dosage and duration of use, other studies emphasize the role of poor oral hygiene. Emphasis should be placed on good personal oral hygiene and gum massage, as the presence of dental plaque may contribute to hyperplasia. Patients on chronic therapy should be encouraged to see a dental professional regularly for removal of plaque and for oral monitoring. In some cases, referral to an oral medicine specialist may be considered.

Dermatological reactions to phenytoin can present as scarlatiniform exanthema or morbilliform (measles-like) rash, maculopapular rash, or a more serious response such as bullous rash, exfoliative dermatitis, purpura, lupus erythematosus (lupus-like symptoms), erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), or acute generalized exanthematous pustulosis (AGEP). Severe hypersensitivity reactions usually occur within 1 month of treatment; however, a prolonged duration of therapy should not preclude the possibility of an association to the drug. If a rash develops, evaluate the patient for signs and symptoms of DRESS. Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations such as pyrexia and lymph node involvement may be present without evidence of a rash. Discontinue phenytoin in patients presenting with a rash or symptoms indicative of a hypersensitivity reaction in whom an unrelated etiology cannot be identified. Subsequent resumption of therapy should not occur in those with signs or symptoms suggestive of a severe reaction such as SJS, TEN, or DRESS. Although treatment may be resumed after milder rashes (e.g., morbilliform or scarlatiniform) have resolved, further use of phenytoin is contraindicated if the rash recurs. Patients who test positive for a specific human leukocyte antigen allele (HLA-B 1502) may have an increased risk of developing SJS or TEN while receiving phenytoin or fosphenytoin; this variant allele is most common in Oceana, East Asian, and South/Central Asian populations. Immediate hypersensitivity, anaphylactoid reactions including angioedema have also been reported with phenytoin use. Other less severe but bothersome dermatologic effects of phenytoin include coarsening of facial features, lip enlargement, and hypertrichosis or hirsutism. Skin hyperpigmentation caused by an increase in melanin of the basal layer and dispersion of melanin granules has been seen and is more common in women than in men.

Lymphadenopathy has been associated with phenytoin therapy. Specific disorders observed have included benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Lymph node involvement may or may not be accompanied by pyrexia, rash, and liver involvement. Although these disorders appear infrequent, all cases of lymph node involvement necessitate follow-up, and phenytoin should be substituted with alternative antiepileptic agents. Periarteritis nodosa has also been reported with phenytoin use.

Hyperglycemia and diabetic ketoacidosis (DKA) secondary to phenytoin administration have been reported. Closely monitor blood glucose when phenytoin is administered to patients with diabetes. The actions of phenytoin on control of blood sugar are complex. Phenytoin can interfere with glucose metabolism. Phenytoin can stimulate glucagon secretion and can impair insulin secretion. Either of these effects could cause serum glucose to rise.

Phenytoin is potentially hepatotoxic, although acute hepatic failure is an uncommon occurrence. It can cause benign elevated hepatic enzymes or more serious manifestations of hepatitis such as focal hepatic necrosis and hepatomegaly. Cholestasis with jaundice can occur. Hepatotoxicity may be associated with Drug Reaction with Eosinophilia and Systemic Symptoms syndrome that includes such symptoms as pyrexia, skin reactions, and lymphadenopathy. Hepatic manifestations seen include jaundice, hepatomegaly, elevated hepatic enzymes (e.g., alkaline phosphatase, gamma glutamyl transpeptidase [GGT]), leukocytosis, and eosinophilia. Phenytoin should be immediately discontinued in the case of acute hepatotoxicity and not be readministered. Clinical outcomes for acute hepatotoxicity with phenytoin therapy are variable, ranging from acute recovery to fatality.

Phenytoin has been reported to cause thrombocytopenia, leukopenia, neutropenia, pancytopenia, macrocytosis, megaloblastic anemia, or more severe reactions like agranulocytosis, aplastic anemia, and hemolytic anemia. Pure red cell aplasia has also been reported with phenytoin use. The risk of serious blood dyscrasias is rare. A cohort study of patients age 10 to 74 years reported 2.7 out of 100,000 prescriptions (95% CI 0.9 to 6.3) for phenytoin resulted in blood dyscrasia. Cumulative risk increased as length of antiepileptic treatment increased. Baseline and periodic hematologic counts should be obtained; if a patient develops neutropenia or thrombocytopenia the patient should be closely monitored. Discontinuation of phenytoin should be considered if significant bone marrow suppression develops. Although macrocytosis and megaloblastic anemia usually respond to therapy with folic acid, folic acid should not be administered indiscriminately to patients receiving phenytoin due to its potential detrimental effects on phenytoin efficacy. Isolated reports have associated exacerbation of porphyria with phenytoin use. Immunoglobulin abnormalities have also been reported with phenytoin use. There has been a single case report of methemoglobinemia in a breast-fed infant whose mother was receiving phenytoin.

Long-term therapy with phenytoin in epileptic patients has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures, effects that are particularly concerning in pediatric patient because childhood and adolescence are critical periods of bone development. Induction of hepatic enzymes by phenytoin may enhance vitamin D metabolism, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Monitor bone health and vitamin D/calcium/phosphorous status in all patients receiving chronic phenytoin. Osteomalacia has been readily observed in institutionalized children who have received a combination of phenytoin and phenobarbital for long periods of time. It is difficult to determine the true incidence of this problem from phenytoin since prolonged immobilization and lack of sunlight exposure are likely contributing factors.

Phenytoin rarely causes genitourinary complications. Cases of Peyronie's disease, priapism, glomerulonephritis, acute interstitial nephritis, acute renal failure (unspecified), nephrolithiasis (phenytoin metabolite urinary stone), and nephrotic syndrome have been reported.

Pain and inflammation (vasculitis) with or without extravasation are examples of an injection site reaction that can occur with intravenous (IV) phenytoin administration. Purple glove syndrome (PGS) is a potentially serious adverse effect of phenytoin IV administration, resulting in soft tissue injury, limb edema, skin discoloration, and pain distal to the injection site. In severe cases, PGS may progress to skin necrosis, limb ischemia, skin grafting, or amputation. PGS may or may not be associated with extravasation; it may not become evident for several days after the injection. Because of the risk of localized toxicity, recommended IV administration guidelines should be followed. Generally, phenytoin should not be administered via intramuscular (IM) injection because it precipitates at the injection site, producing delayed and erratic absorption. IM administration may also cause pain, necrosis, and abscess formation at the injection site.

Severe cardiovascular reactions have occurred in association with intravenous phenytoin, including bradycardia, AV block, ventricular tachycardia, and ventricular fibrillation, which have resulted in asystole, cardiac arrest, and death in some cases. Cases of bradycardia and cardiac arrest have also been reported in patients treated with enteral phenytoin, at recommended doses and concentrations and in association with toxicity. The rate of intravenous administration is critically important to avoid or limit infusion-related reactions, specifically cardiovascular events; do not exceed recommended infusion rates. Reactions to phenytoin occur more often in children (particularly infants), those who are critically ill or have preexisting hypotension or severe myocardial insufficiency. Though the FDA-approved labeling recommends a pediatric infusion rate of 1 to 3 mg/kg/minute (not to exceed 50 mg/minute), most experts recommend not exceeding a rate of 1 mg/kg/minute in any pediatric patient. Although the risk of cardiovascular toxicity is increased with rapid administration, adverse cardiac reactions have also been reported at or below the recommended infusion rates. In a comparative trial of IV fosphenytoin and phenytoin given at maximum dose and rate, hypotension and peripheral vasodilation occurred in 9.1% and 4.5% of phenytoin-treated patients, respectively. Phenytoin injection contains 40% propylene glycol, a substance that may contribute to the cardiac effects of the drug. Careful cardiac monitoring is needed during and after phenytoin administration. A reduction in the rate of administration or discontinuation of therapy may be necessary if cardiac reactions occur.

Patients with thyroid disease, especially hypothyroidism, should be monitored for signs of underactive thyroid. A significant decline in total T4 and free T4 serum concentrations have occurred in both epileptic and healthy subjects receiving phenytoin. In some cases, significant decreases in total T3 concentrations have been reported. Elevations in TSH have not been a consistent finding. The mechanism(s) by which phenytoin alters thyroid hormone functioning have not been clearly established; however, it has been postulated that these changes may occur secondary to protein-binding displacement, increased peripheral conversion of T4 to T3, inhibition of thyrotropin-releasing hormone, weak T3 agonism by phenytoin, or a combination of these factors. Despite reductions in T4 and/or T3 concentrations, most patients are clinically euthymic.

There have been rare reports of dyskinesia occurring during phenytoin therapy. Choreoathetosis, tremor, asterixis, and dystonic reaction have also been reported. During comparative trials of fosphenytoin and phenytoin, tremor was reported in 9.1-13.1% of patients receiving phenytoin.

Altered taste sensations (dysgeusia), including metallic taste, have been reported during phenytoin therapy. During a comparative trial of intravenous fosphenytoin and phenytoin, tinnitus and amblyopia were both reported in 9.1% of adult phenytoin-treated patients. Cataracts have been rarely reported after long-term therapy.

Anticonvulsants may enhance the hepatic breakdown of vitamin D into inactive polar metabolites. Patients receiving phenytoin for greater than 6 months should be monitored for vitamin D deficiency and receive supplementation when indicated by low serum concentrations. Anticonvulsants may also impair folate metabolism; patients should be monitored for folate deficiency and supplemented when necessary.

Phenytoin is contraindicated in patients with a hydantoin hypersensitivity (e.g., phenytoin, fosphenytoin, ethotoin). Hypersensitivity reactions to anticonvulsants may be severe and sometimes fatal. Consider an alternative to phenytoin if the patient or an immediate family member has a carbamazepine hypersensitivity, barbiturate hypersensitivity, succinimide hypersensitivity, or oxazolidinedione hypersensitivity. Hypersensitivity reactions may include, but are not limited to, fever, sore throat, skin rash, periorbital or facial edema, angioedema, myalgia, arthralgia, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or yellowing of the eyes or skin. These signs and symptoms should be reported even if mild or occurring after extended use. Discontinue phenytoin immediately if a severe hypersensitivity reaction occurs. Hypersensitivity reactions to phenytoin have been reported in patients who previously experienced hypersensitivity to fosphenytoin, barbiturates, or carbamazepine. Estimates of cross-sensitivity vary but may range from 30% to 80%. Phenytoin, carbamazepine, and phenobarbital are all metabolized to hydroxylated aromatic compounds via the cytochrome P450 hepatic oxidative enzymes; arene oxide intermediates are formed during metabolism and are thought to be responsible for cross-sensitivity among these anticonvulsants in susceptible individuals. Some individuals may have a reduced ability to detoxify the intermediate toxic metabolites (e.g., arene oxides) of these anticonvulsants, which may be genetically mediated. However, studies of familial reactions have also shown that allergies to 1 anticonvulsant may not translate to allergies to others. There is no way to predict with certainty which patients will exhibit cross-sensitivity.

Phenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Avoid phenytoin in patients positive for HLA-B 1502 or in CYP2C9 3 carriers. If used in patients who are CYP2C9 2 or 3 carriers (intermediate or poor metabolizers), consider an initial dosage reduction of 25% in patients who are intermediate metabolizers and at least a 50% in those who are poor metabolizers; guide further dosage adjustments by phenytoin concentration monitoring and clinical response. Studies have found a strong association between the risk of developing SCARs and the presence of HLA-B 1502, an inherited variant allele of the HLA-B gene, in patients taking carbamazepine. Limited evidence suggests HLA-B 1502 is a risk factor for the development of SCARs in patient taking other drugs associated with SCARs, including phenytoin and fosphenytoin. HLA-B 1502, the variant allele of human leukocyte antigen B, is most prevalent in Asian patients; prevalence ranges from 1% to over 10% in Oceania, East Asian, and South/Central Asian populations. It is less frequent in European populations (0 to 1%) and largely absent in African, Hispanic, and Native American populations. Retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9 3 variant, which has also been associated with decreased clearance of phenytoin. Additionally, patients who are intermediate or poor metabolizers of CYP2C9 (e.g., 1/3, 2/2, 3/3) may exhibit increased phenytoin concentrations compared to normal metabolizers (e.g., 1/1). The prevalence of CYP2C9 poor and intermediate metabolizer phenotype is about 2% to 3% and 35% in the White population, 0.5% to 4% and 15% to 36% in the Asian population, and less than 1% and 24% in the African American population, respectively.

There is an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur any time during treatment. All patients beginning treatment with phenytoin should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A pooled analysis of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age) was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2-2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor.

Phenytoin is not effective for, and may worsen, petit mal (absence) seizures. If grand-mal (tonic-clonic) and petit mal (absence) seizures are present, combined drug therapy is needed. Phenytoin and other hydantoins are not indicated for seizures due to hypoglycemia or other metabolic causes (e.g., hyponatremia). Appropriate diagnostic procedures should be performed as indicated.

Like other antiepileptic drugs, the abrupt discontinuation of phenytoin therapy can lead to increased seizure activity, including status epilepticus. Dosage reduction, substitution in therapy, or drug discontinuation should be done gradually. Allergic or hypersensitivity reactions may require rapid substitutions. In these cases, change therapy to an antiepileptic agent not belonging to the hydantoin class.

Phenytoin should be used with caution in patients with hematological disease or blood dyscrasias. Although uncommon, phenytoin can cause hematological toxicity, which may exacerbate or worsen other hematological abnormalities. Baseline and periodic hematologic counts should be obtained; if a patient develops abnormalities, the patient should be closely monitored. Discontinuation of phenytoin should be considered if significant bone marrow suppression develops. In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using phenytoin in patients suffering from this disease.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness (e.g., fever, rash, and liver involvement). Follow-up observation for an extended period is indicated for cases of lymphadenopathy and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Phenytoin injection is contraindicated in patients with sinus bradycardia, sino-atrial block, second or third degree AV block, and Adams-Stokes syndrome because of the effects of the drug on ventricular automaticity. Intravenous phenytoin should not be used in patients with other cardiac conduction abnormalities (e.g., bundle-branch block) and should be used with caution in any patient with cardiac disease, such as cardiac arrhythmias, congestive heart failure, or coronary artery disease, because symptoms may be potentiated or exacerbated. Cases of bradycardia and cardiac arrest have been reported in patients treated with enteral phenytoin, at recommended doses and concentrations and in association with toxicity. Most cases of cardiac arrest occurred in patients with underlying cardiac disease. FDA-approved labeling for parenteral phenytoin contains a boxed warning that highlights infusion-related reactions, specifically cardiovascular risks associated with rapid intravenous administration rates. Severe cardiovascular reactions have occurred, including bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation, which have resulted in asystole, cardiac arrest, and death in some cases. The rate of intravenous administration is critically important to avoid or limit adverse reactions; do not exceed recommended infusion rates. Though the FDA-approved labeling recommends a pediatric infusion rate of 1 to 3 mg/kg/minute (not to exceed 50 mg/minute), most experts recommend not exceeding a rate of 1 mg/kg/minute in any pediatric patient. Hypotension may occur, especially after high doses are given at high rates of administration. Although the risk of cardiovascular toxicity is increased with rapid administration, cardiac events have also been reported at or below the recommended infusion rates. Reactions to parenteral phenytoin occur more often in children (particularly infants), those who are critically ill, and those with preexisting hypotension or severe myocardial insufficiency. Careful cardiac and respiratory monitoring is required during and after intravenous phenytoin administration. A reduction in the rate of administration or discontinuation of the drug may be necessary if cardiac reactions occur. Some cardiac effects are thought to be secondary to the propylene glycol (PEG) diluent of the parenteral product.

Local soft tissue irritation, ranging from tenderness to extensive necrosis, and inflammation can occur at the site of administration with and without extravasation of intravenous phenytoin. Edema, discoloration and pain distal to the injection site ("purple glove syndrome") have been reported. To minimize the risk for these adverse effects, administer phenytoin directly into a large peripheral or central vein through a large-gauge catheter. Confirm the patency of the catheter prior to each dose using a sterile saline flush. Because of the limited venous access and the small vein size of infants and young children, many clinicians prefer the use of fosphenytoin in these populations.

In general, intramuscular administration of phenytoin is not recommended because of the risk of necrosis, abscess formation, and erratic absorption. Due to delayed and erratic absorption, intramuscular administration should never be used in the treatment of status epilepticus. Parenteral phenytoin has an alkaline pH (pH = 10-12) and causes a high degree of local irritation and pain.

Phenytoin is contraindicated in patients with a history of prior acute hepatotoxicity attributable to phenytoin. Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These hepatic events may be part of the spectrum of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase concentrations, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered. Use phenytoin cautiously in patients with hyperbilirubinemia, which may manifest clinically as jaundice. Bilirubin displaces phenytoin from protein-binding sites, resulting in increased free phenytoin concentrations. Hypoalbuminemia also results in increased free phenytoin concentrations, which may increase the likelihood of drug toxicity. Hypoalbuminemia is common in the critically ill, as well as in patients with malnutrition, burns, and renal or hepatic disease. In these patients, the monitoring of serum phenytoin concentrations should be based on the unbound fraction of the drug. Phenytoin is eliminated via hepatic metabolism and should be used with caution in any patient with hepatic dysfunction. A small percentage of individuals metabolize phenytoin slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; slow metabolism appears to be genetically determined. Reduced phenytoin clearance may increase the frequency and severity of adverse events. Dose adjustments may be necessary in patients with hepatic disease or genetic polymorphism; if early signs of central nervous system toxicity develop, check serum concentrations immediately. Baseline and periodic evaluations of liver function, particularly in patients with a history of hepatic disease, must be performed during treatment. Phenytoin should be discontinued if there is evidence of new or worsening hepatotoxicity.

Phenytoin may cause vision disturbances, dizziness, drowsiness, and abnormal thinking. Advise patients and caregivers that caution should be used when participating in activities requiring coordination and concentration (e.g., getting in and out of bed, riding a bicycle, operating a vehicle) until they are aware of how the drug affects them. Serum concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as 'delirium,' 'psychosis,' or 'encephalopathy,' or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, measuring plasma concentrations is recommended. A dosage reduction is indicated if plasma concentrations are excessive; if symptoms persist, termination of phenytoin therapy is recommended.

Patients with renal failure or renal impairment leading to uremia should be monitored for phenytoin toxicity. High serum concentrations of urea displace phenytoin from protein-binding sites and may indicate a need to monitor free phenytoin concentrations. Dose adjustments may be necessary in patients with renal disease. Phenytoin may rarely cause interstitial nephritis or other renal disease; occasional monitoring of renal parameters or urinalysis has been suggested for all patients.

The chronic use of phenytoin may cause gingival hyperplasia. Proper oral hygiene should be maintained in order to minimize the development of gingival hyperplasia and its complications (e.g., dental disease). Adherence to scheduled dental work is encouraged to limit the risk of gum disease.

Monitor blood glucose closely when phenytoin is administered to patients with diabetes mellitus. Phenytoin has an inhibitory effect on insulin release and can cause hyperglycemia. There are case reports of hyperglycemia and even diabetic ketoacidosis (DKA) occurring as a result of phenytoin administration.

Patients with thyroid disease, especially hypothyroidism, should be monitored for signs of underactive thyroid. Phenytoin stimulates hepatic enzyme activity, which may cause an increased degradation of circulating concentrations of thyroid hormone (T3 and T4), with an accompanying increase in thyroid-stimulating hormone (TSH). Phenytoin reduces serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%; however, most patients are clinically euthyroid.

Osteomalacia has been associated with chronic phenytoin therapy and is considered to be due to phenytoin's interference with vitamin D metabolism. There may be an increased risk of rickets, osteopenia, and/or osteoporosis in patients on chronic phenytoin therapy. These adverse effects may be particularly concerning in pediatric patients because bone development is critical; monitor bone health of patients receiving chronic phenytoin therapy.

Cranial irradiation administered to patients receiving phenytoin has been associated with erythema multiforme and/or Stevens-Johnson syndrome. Phenytoin should be used cautiously in patients receiving radiation therapy.

Phenytoin has been reported to decrease acetylcholine receptor sensitivity; this action may exacerbate symptoms of myasthenia gravis.

Acute alcoholic intake may increase phenytoin serum concentrations while chronic ethanol ingestion can induce hepatic oxidative enzymes, decreasing serum concentrations. Such parameters may need to be considered when treating patients with a history of alcoholism or acute intermittent binge drinking.

Neonatal coagulation defects have been reported in neonates with in utero exposure to phenytoin and appear to result from drug-induced vitamin K deficiency in the fetus. Administration of vitamin K to the mother before obstetric delivery and to the neonate at birth can prevent this defect. Prenatal exposure to phenytoin may also increase the risks for congenital malformations (e.g., orofacial clefts, cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (e.g., dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities, cognitive deficits). Several reported cases of malignancies, including neuroblastoma, have been reported in children whose mothers received phenytoin during pregnancy.

Description: Phenytoin is an oral and parenteral hydantoin anticonvulsant approved for the management of tonic-clonic (grand mal) and complex partial seizures, as well as the prevention and treatment of seizures associated with neurosurgery. Though often used as a second therapy choice (after a benzodiazepine) to control status epilepticus in children and adolescents, phenytoin is traditionally considered a therapy of choice after phenobarbital in the neonate. In children and adolescents, fosphenytoin/phenytoin, levetiracetam, and valproate are equally effective in benzodiazepine-refractory status epilepticus. Due to phenytoin's poor solubility, the parenteral solution is formulated with propylene glycol and alcohol and has a basic pH (12); these formulation characteristics can cause the cardiovascular adverse reactions and injection site reactions that are commonly associated with parenteral phenytoin use. Development of its parenteral prodrug, fosphenytoin, has made phenytoin a less attractive option for some patients, particularly pediatric populations with small veins. When both are available, fosphenytoin is preferred based on tolerability. Because phenytoin exhibits nonlinear pharmacokinetics and is highly protein-bound, individualized dosing strategies are more complex than with many other anticonvulsant drugs. In addition, switching patients from one dosage form to another may produce significant changes in phenytoin bioavailability. Phenytoin is FDA-approved for use in pediatric patients with no defined age range and has been used in patients as young as neonates.

General Dosing Information
-Different phenytoin dosage forms are not directly interchangeable.-Intravenous phenytoin solutions contain phenytoin sodium, which is 92% phenytoin.
-Phenytoin capsules contain phenytoin sodium, which is 92% phenytoin.
-Chewable tablets and suspensions contain 100% phenytoin.


For the treatment of status epilepticus:
Intravenous dosage:
Neonates: 15 to 20 mg/kg/dose IV as a single dose. Persons who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.
Infants, Children, and Adolescents: 15 to 20 mg/kg/dose (Max: 1,500 mg/dose) IV as a single dose; may administer additional 5 to 10 mg/kg/dose IV as a single dose after 10 minutes if needed. Persons who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.

For the treatment of partial seizures or tonic-clonic seizures:
Oral dosage (suspension):
Neonates: 5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Some neonates, particularly after the first week of life, may have difficulty maintaining therapeutic concentrations within this dosage range and require higher maintenance doses (e.g., 10 mg/kg/day).
Infants, Children, and Adolescents: 5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. Infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.
Oral dosage (chewable tablets):
Children and Adolescents: 5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. If the daily dosage cannot be divided equally, give the larger dose before bedtime. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.
Oral dosage (extended-release capsules):
Children and Adolescents: 5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.
Intravenous dosage:
Neonates: 15 to 20 mg/kg/dose IV loading dose, then 5 mg/kg/day IV in 3 or 4 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Some neonates, particularly after the first week of life, may have difficulty maintaining therapeutic concentrations within this dosage range and require higher maintenance doses (e.g., 10 mg/kg/day).
Infants, Children, and Adolescents: 15 to 20 mg/kg/dose IV loading dose, then 5 mg/kg/day IV in 3 or 4 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.

For seizure prophylaxis due to specific neurologic conditions, including neurosurgery, head trauma* or traumatic brain injury*:
Intravenous dosage:
Infants: The loading dose is 10 to 20 mg/kg IV. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 1 hour post-infusion. The maintenance dose is 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day. Max IV administration rate: 0.5 to 1 mg/kg/minute. Infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. Due to fast clearance, a dosing frequency of at least every 8 hours may provide more consistent plasma concentrations. Limited studies are available for traumatic brain injury seizure prophylaxis; efficacy data are inconsistent. Clinical practice guidelines state that prophylactic phenytoin may be considered in pediatric patients with severe traumatic brain injury to reduce incidence of early post-traumatic seizures; however, the data do not suggest prophylaxis improves neurologic outcome or reduces the risk of seizures long-term. Monitor phenytoin concentrations.
Children and Adolescents: The loading dose is 10 to 20 mg/kg IV. Max initial IV load: 1,000 mg IV. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion and until 1 hour post-infusion. The maintenance dose is 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day. Max IV administration rate: 0.5 to 1 mg/kg/minute (Max rate: 50 mg/minute). Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. Due to faster clearance, dosing frequencies of at least every 8 hours may provide more consistent concentrations. Pharmacokinetic data from oral formulations (chewable tablets and capsules) suggest higher maintenance doses are typically required to maintain therapeutic concentrations for pediatric patients. Limited studies are available for traumatic brain injury seizure prophylaxis; efficacy data are inconsistent. Clinical practice guidelines state that prophylactic phenytoin may be considered in pediatric patients with severe traumatic brain injury to reduce incidence of early post-traumatic seizures; however, the data do not suggest prophylaxis improves neurologic outcome or reduces the risk of seizures long-term. Monitor phenytoin concentrations.

Therapeutic Drug Monitoring:
Usual therapeutic serum/plasma concentration: 10 to 20 mcg/mL
-Serum phenytoin concentrations should be used to monitor patients receiving phenytoin therapy. Therapeutic concentrations are generally considered to be 10 to 20 mcg/mL (equivalent to 1 to 2 mcg/mL unbound or 'free' phenytoin). Total phenytoin concentrations as high as 25 mcg/mL may be acceptable in some patients (e.g., in status epilepticus). Infrequently, some patients may be be controlled with lower maintenance levels of phenytoin (i.e., 8 to 10 mcg/mL).
-'Free' (i.e. unbound) phenytoin concentrations may be helpful in assessing patients with hypoalbuminemia or elevated blood urea nitrogen (BUN). Hypoalbuminemia is common in the critically ill, trauma or burn patients, with malnutrition, and severe hepatic disease. Hyperbilirubinemia as well as coadministration of other protein-bound medications decrease phenytoin protein binding, enhancing levels of free drug and making free concentrations a useful tool.
-To assess a loading dose, phenytoin concentrations may be measured immediately after the end of intravenous (IV) infusion. Several days may be required to reach steady-state with a given maintenance dose due to variable metabolism. Trough concentrations are typically used to assess maintenance doses and should be drawn 7 to 10 days after initiating or changing dosage.
-Seizure control signifies clinical efficacy in epileptic conditions. For other conditions, assess the patient for clinical improvement of the condition, as well as for drug tolerance.
-When evaluating phenytoin serum concentrations consider the potential for disease, drug, or food interactions.
-There are marked variations among individuals with respect to plasma phenytoin concentrations and when toxicity occurs. Lateral gaze nystagmus usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, and dysarthria and lethargy appear when the total phenytoin level is 40 mcg/mL or greater. However, total phenytoin concentrations as high as 50 mcg/mL have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in plasma phenytoin concentrations over 100 mcg/mL, with complete recovery.
-When switching route or formulation, note that different phenytoin dosage forms are not interchangeable. IV phenytoin solutions contain phenytoin sodium, which is 92% phenytoin. Phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin.

Maximum Dosage Limits:
Specific maximum dosage information not available. Individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters. Usual maximum initial IV load: 1,000 to 1,500 mg.

Patients with Hepatic Impairment Dosing
Dosage adjustments may be required based on serum phenytoin concentrations and clinical response. Phenytoin is primarily metabolized in the liver. Patients with hepatic disease may have an increased fraction of unbound ('free') phenytoin.

Patients with Renal Impairment Dosing
Dosage adjustments may be required based on serum phenytoin concentrations and clinical response. Patients with renal disease may have an increased fraction of unbound ('free') phenytoin.

Intermittent hemodialysis
Phenytoin is not significantly removed during a standard hemodialysis session; therefore, supplemental dosing after hemodialysis is not necessary.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Anticonvulsant drugs can elevate the seizure threshold and/or limit the spread of seizure discharge. Phenytoin exerts its anticonvulsant effect mainly by limiting the spread of seizure activity and reducing seizure propagation, unlike phenobarbital and carbamazepine, which elevate the seizure threshold. Because phenytoin does not elevate the seizure threshold, it is less effective against drug-induced or electroconvulsive-induced seizures.

The cellular mechanisms thought to be responsible for phenytoin's anticonvulsant activities include modulation of voltage-dependent sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and the enhancement of Na+/K+ ATPase activity of neurons and glial cells. The limitation of repetitive firing in neurons caused by slowing the rate of recovery in inactivated sodium channels is thought to be phenytoin's primary mechanism. Phenytoin exerts its anticonvulsant effects with less sedation than phenobarbital. In toxic concentrations, phenytoin is excitatory and can induce seizures. Phenytoin is also a weak antiarrhythmic. Antiarrhythmic actions are also mediated through effects on sodium channels, in this case, in Purkinje fibers.

Pharmacokinetics: Phenytoin is administered orally and parenterally. Phenytoin dosage forms are available as either phenytoin acid (chewable tablets and oral suspension) or phenytoin sodium (capsules and injection). While phenytoin acid is 100% phenytoin, phenytoin sodium is 92% phenytoin. Dosage adjustment may be necessary when switching from salt form to acid form (or vice versa) to account for this 8% difference; small changes may lead to significant serum phenytoin concentration fluctuation in some patients.

Phenytoin is extensively protein bound (90% to 95% in adults); protein binding is lower in neonates and approaches adult values during later infancy. Hyperbilirubinemia, hypoalbuminemia, renal dysfunction, and uremia all decrease protein binding and increase the free fraction of phenytoin available for therapeutic action. Phenytoin distributes into all fluids in its free acid form. The mean steady state Vd of phenytoin in children and adults is about 0.75 L/kg (range 0.7 to 0.8 L/kg); however, neonates have a larger volume of distribution.

Phenytoin is primarily metabolized via CYP2C9 and to a lesser extent via CYP2C19. It exhibits non-linear, Michaelis-Menten pharmacokinetics; hepatic metabolism of phenytoin is saturable, leading to AUC values that increase disproportionately with increasing dose. Metabolism of phenytoin is also highly variable. Phenytoin is 1 of only a few drugs in which metabolic capacity can be saturated at therapeutic concentrations. Below the saturation point, phenytoin is eliminated in a linear, first-order process. Beyond the saturation point, elimination is much slower and occurs via a zero-order process. Because of this saturable metabolism, it is inaccurate to report a fixed value for phenytoin half-life; it can range from 7 to 60 hours (mean: 22 hours) in most populations, depending on dosage and various patient factors. In addition, small increases in dose can produce large increases in plasma concentrations. Maximal elimination rate (Vmax) is higher and more variable in children than in adults; therefore, children require higher doses on a mg/kg basis than adults in order to achieve the same serum concentrations. Febrile illness may increase the clearance of phenytoin by enhancing biotransformation. Phenytoin is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and less than 5% is excreted unchanged in the urine.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2C19, CYP3A4, P-gp, UGT
Phenytoin is a potent inducer of hepatic cytochrome P450 microsomal enzymes including CYP3A4, CYP2C9, and CYP2C19 isoenzymes. However, a patient's susceptibility to enzyme-induction interactions may be influenced by factors such as age, cigarette smoking, or the presence of liver disease. Limited data suggest phenytoin is also a mild inducer of P-glycoprotein (P-gp) and induces UGT. Phenytoin is metabolized primarily by CYP2C9 (major) and CYP2C19 (minor), thus several drugs may inhibit or induce phenytoin's metabolism. Patients who are intermediate or poor metabolizers of CYP2C9 may exhibit increased phenytoin serum concentrations compared to normal metabolizers and, hence, may require reduction of the starting maintenance dose to reduce the risk of toxicity.


-Route-Specific Pharmacokinetics
Oral Route
Oral formulations of phenytoin are generally considered to be 90% to 100% bioavailable; however, absorption rates vary for different products. In general, absorption is slow due to the poor dissolution of phenytoin in aqueous fluids. Immediate release products reach peak concentrations in 1.5 to 3 hours, whereas extended-release capsules reach peak concentrations in 4 to 12 hours. The absorption rate is also dose-dependent. For example, time to achieve peak concentration (Tmax) may occur 1 to 2 hours after a 200 mg oral dose, whereas Tmax may not be observed for up to 18 hours after an 800 mg dose. Because the absorption rate of phenytoin is dose-dependent, oral loading doses should be administered in divided doses. Extent of absorption is also multifactorial. The amount of phenytoin absorbed (AUC) in infants is less than in children and adolescents. An absorption study of enteral phenytoin (exact formulation not defined) 75 mg/m2 reported an AUC of 194 mcg/mL, 409 mcg/mL, and 809 mcg/mL in patients younger than 12 months (mean 4 months), 1 to 6 years (mean 2.9 years), and 7 to 18 years (mean 9.2 years), respectively when given without food. When doses were administered with food, AUC increased to 285 mcg/mL, 517 mcg/mL, and 918 mcg/mL, respectively. When using phenytoin oral suspension, concomitant administration with enteral nutritional products will significantly reduce phenytoin bioavailability. While food does not affect the absorption of branded Dilantin Kapseals, generic extended-release phenytoin products exhibit reduced absorption in the presence of a high-fat meal. It may be best to administer generic extended-release capsules on an empty stomach or in a consistent manner in relation to food to avoid fluctuation in bioavailability.

Intravenous Route
Intravenous (IV) phenytoin rapidly penetrates the brain, reaching peak concentrations within 10 to 30 minutes. IV administration is the preferred route for rapidly achieving therapeutic concentrations.

Intramuscular Route
After intramuscular (IM) administration, phenytoin is more slowly absorbed compared to oral administration; phenytoin exhibits poor water solubility and forms a depot in the muscle. Peak plasma concentrations of IM phenytoin may not be attained for up to 24 hours. The intravenous (IV) route is preferable to the IM route for rapidly producing therapeutic serum concentrations. During interchange of oral and IM routes of administration, dosage adjustments are necessary to maintain therapeutic plasma concentrations and avoid toxicity.


-Special Populations
Pediatrics
Neonates
The impact of enteral feedings on the absorption of oral phenytoin is more pronounced in young infants, which presents an administration challenge in neonates requiring continuous or frequent feedings. Neonates have a more variable and lower level of protein binding (80%) compared to children and adolescents. Hyperbilirubinemia, which is often prevalent in critically ill neonates, further decreases protein binding. Full-term and premature neonates have a larger Vd (0.8 to 0.9 L/kg and 1 to 1.2 L/kg, respectively) compared to children and adolescents. Elimination is significantly slower in neonates, and it slows further with increasing serum concentrations. There is significant inter-patient and intra-patient variability in elimination during the first month of life, which can make interpretation of serum concentrations challenging. A 60% reduction in terminal elimination half-life between the first and fourth week of life has been reported.

Infants, Children, and Adolescents
Phenytoin bioavailability from oral dosage forms appears to be less in infants than in children and adolescents. Protein binding capacity in infants 3 months of age is approximately 85%, compared to 80% in neonates, and from there begins to approach adult values (90% to 95%). The mean steady state volume of distribution (Vd) of phenytoin in children and adolescents is approximately 0.75 L/kg (range 0.7 to 0.8 L/kg), which is consistent with adult values. Infants and young children have enhanced hepatic clearance, resulting in larger maintenance dose requirements.

Hepatic Impairment
Patients with hepatic disease may have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution.

Renal Impairment
Patients with renal disease may have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution.

Other
CYP2C9 Intermediate and Poor Metabolizers

CYP2C9 activity is decreased in individuals with CYP2C9 2 and 3 alleles. Patients who are intermediate (e.g., 1/3, 2/2) or poor (e.g., 2/3, 3/3) metabolizers of CYP2C9 have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles (e.g., 5, 6, 8, 11) may also result in decreased clearance of phenytoin.