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Seizure Disorders

Phenytoin is used mainly in the prophylactic management of tonic-clonic (grand mal) seizures and partial seizures with complex symptomatology (psychomotor and temporal lobe seizures). The drug is also effective in controlling autonomic seizures. The drug is often administered concomitantly with phenobarbital or other anticonvulsants. Phenytoin is not recommended for the treatment of pure absence (petit mal) seizures since the drug may increase the frequency of these seizures; however, phenytoin may be useful in conjunction with succinimide or oxazolidinedione anticonvulsants in the management of combined absence and tonic-clonic seizures.

Phenytoin and phenytoin sodium may be used for the prevention and treatment of seizures occurring during neurosurgery. Phenytoin sodium also may be used parenterally for the treatment of status epilepticus; however, the usefulness of the drug in this condition is limited by the need for slow administration and its slow onset of action. IV benzodiazepines (e.g., diazepam, lorazepam) generally are considered the drugs of choice for rapid termination of status epilepticus; phenytoin or fosphenytoin (a prodrug of phenytoin) usually is indicated as a second-line agent if seizures continue or recur. Because of the required slow rate of IV phenytoin administration, concurrent use of an IV benzodiazepine or a short-acting barbiturate may be necessary for rapid control of status epilepticus. If administration of IV phenytoin does not terminate seizures, the use of other anticonvulsants, IV barbiturates, general anesthesia, and/or other measures should be considered.

Cardiac Arrhythmias

IV phenytoin sodium may be useful in the treatment of ventricular tachycardia and paroxysmal atrial tachycardia, particularly in those patients who do not respond to conventional antiarrhythmic agents or to cardioversion. Most clinicians consider IV phenytoin sodium to be the drug of choice in the treatment of arrhythmias caused by digitalis intoxication. Oral phenytoin and phenytoin sodium have been used for maintenance therapy in the management of cardiac arrhythmias.

Other Uses

Phenytoin may have beneficial effects in the treatment of trigeminal neuralgia in some patients.

Dosage and Administration


Phenytoin and phenytoin sodium are administered orally. Phenytoin sodium also may be administered by slow IV injection for the treatment of status epilepticus and by slow IV or IM injection for the prophylaxis and treatment of seizures during neurosurgery. Because parenteral administration of phenytoin is associated with more frequent and severe complications, the oral route is preferred for maintaining therapeutic concentrations of the drug during nonemergency situations; patients receiving the drug parenterally should routinely be assessed for feasibility of oral therapy.

IV injections of phenytoin sodium should be made directly into a large vein through a large-gauge needle or IV catheter.The drug must be injected slowly at rates not exceeding 50 mg/minute in adults and 1-3 mg/kg per minute in pediatric patients. Each injection of phenytoin sodium should be followed by administration of sodium chloride injection through the same needle or IV catheter to reduce local venous irritation caused by the alkalinity of the injection solution. Subcutaneous and perivascular injection of phenytoin sodium should be avoided.(See Cautions: Adverse Effects.)The manufacturer states that continuous ECG, blood pressure, and respiratory monitoring is essential when phenytoin is administered IV.

Phenytoin sodium generally has not been recommended for use in IV infusions because of its lack of solubility and the possibility that precipitation may occur. However, some clinicians suggest that IV infusions are feasible provided that appropriate precautions are taken, such as using a suitable infusion fluid (e.g., 0.9% sodium chloride injection), using a sufficiently diluted solution (e.g., less than 6.7 mg/mL), starting the infusion immediately after preparation and completing administration within a relatively short period, using a 0.22-mcm inline filter, and carefully observing the admixture. Specialized references should be consulted for specific compatibility information. Alternatively, fosphenytoin sodium, a prodrug of phenytoin, can be used for IV infusion.

Because phenytoin sodium is erratically absorbed from IM injection sites and can cause local adverse effects (e.g., pain, necrosis, abscess formation), the drug should be administered IM only as a last resort. However, phenytoin sodium should not be administered IM for the treatment of status epilepticus because of the delay in reaching therapeutic serum concentrations of the drug. While some experts state that phenytoin should not be administered by the IM route under any circumstances, IM administration of phenytoin sodium may be of some value for sustaining established therapeutic plasma concentrations when the patient is unable to take the drug orally (e.g., during neurosurgery). Information regarding IM administration for longer than 1 week is lacking; therefore, for patients unable to take oral medication after 1 week, alternate routes for administering phenytoin (e.g., gastric intubation) should be considered. Alternatively, fosphenytoin sodium can be administered IM for short-term replacement of oral phenytoin.

Only extended phenytoin sodium capsules should be used for once-daily dosing regimens. When refilling a prescription for a preparation previously labeled as phenytoin sodium capsules, the pharmacist should determine whether the brand has been reformulated, whether the brand is now extended phenytoin sodium capsules or prompt phenytoin sodium capsules, and which one the clinician intends that the patient continue to receive. When a patient is changed from extended phenytoin sodium capsules to prompt phenytoin sodium capsules, serum phenytoin concentrations should be monitored. Oral formulations of phenytoin as the base (e.g., suspensions, chewable tablets) should not be used for once-daily dosing regimens.

To minimize loss of phenytoin oral suspension during oral administration via a nasogastric tube (secondary to adherence to PVC tubing), the suspension can be diluted (e.g., threefold) with a compatible diluent (e.g., sterile water, 5% dextrose, 0.9% sodium chloride) prior to administration, combined with flushing the tube with at least 20 mL of diluent after administration.

Patients who are currently receiving or beginning therapy with phenytoin, phenytoin sodium, and/or any other anticonvulsant should be closely monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.(See Cautions: Precautions and Contraindications.)


Each 100 mg of phenytoin sodium contains approximately 92 mg of phenytoin; the difference should be considered if a patient is switched from the drug to its sodium salt or vice versa.

Determination of serum phenytoin concentrations may be necessary to achieve optimal dosage adjustments. Concurrent administration of many drugs can increase or decrease serum concentrations of phenytoin. Acute alcohol intake may increase serum phenytoin concentrations and chronic alcohol use may decrease serum concentrations of the drug.

Seizure Disorders

Dosage of phenytoin and phenytoin sodium must be carefully and slowly adjusted according to individual requirements and response. When a patient is transferred from phenytoin to another anticonvulsant, the dosage of phenytoin should be gradually reduced over a period of about 1 week while at the same time therapy is instituted with a low dose of the replacement drug. The dosage of phenytoin is not altered when phenobarbital is added to the treatment regimen. When phenytoin replaces phenobarbital or any other barbiturate anticonvulsant, the dose of the barbiturate should be gradually reduced over a period of 1 week to prevent withdrawal symptoms. Phenytoin should be withdrawn slowly to avoid precipitating seizures or status epilepticus.

The usual initial adult oral dosage of phenytoin is 100 mg 3 times daily. A period of 5-10 days may be required to achieve anticonvulsant effects. Increases in dosage to greater than 300 mg daily may lead to markedly increased serum phenytoin concentrations, and therefore dosage above this level should be carefully and slowly adjusted. If necessary, daily dosage may be gradually increased in increments of 100 mg every 2-4 weeks until the desired response is obtained. Some patients may benefit from dosing at 100 mg 4 times daily, and others may require dosages up to 200 mg 3 times daily. The optimum daily dose varies considerably from one patient to another but is usually in the range of 6-7 mg/kg (300-600 mg daily for most adults).

For patients receiving extended phenytoin sodium capsules who are stabilized on a dosage of 100 mg 3 times daily, once-daily dosing with 300 mg as extended phenytoin sodium capsules may be considered. Prompt phenytoin sodium capsules should not be used for once-daily dosing nor should oral suspensions or chewable tablets of phenytoin as the base.

For children, the usual initial oral dosage of phenytoin is 5 mg/kg or 250 mg/m daily administered in 2 or 3 equally divided doses. Total dosage should not exceed 300 mg daily. Subsequent dosage should be adjusted carefully and slowly according to the patient's requirements. Maintenance dosage for children usually ranges from 4-8 mg/kg daily.

Therapeutic serum phenytoin concentrations can be achieved more rapidly (in 2-24 hours) by the use of an oral loading-dose regimen. There are few published studies evaluating oral loading-dose regimens. Various regimens have been suggested, and clinicians should consult published protocols for information on specific regimens. It is recommended that oral loading-dose regimens be reserved for patients in a clinic or hospital setting where serum phenytoin concentrations can be closely monitored. The manufacturer also recommends that patients with a history of renal or liver disease not receive an oral loading-dose regimen. In one regimen, an initial oral loading dose of 1 g in adults or 500-600 mg in children is administered in divided doses, followed by the usual maintenance dosage, beginning 24 hours after the loading dose. The 1-g oral loading dose for adults is usually administered in doses of 400, 300, and 300 mg at 2-hour intervals to minimize adverse GI effects. Alternatively, to achieve therapeutic plasma concentrations within 1-2 hours, phenytoin sodium may be given IV in a dose of approximately 10-15 mg/kg at a rate not exceeding 50 mg/minute.

The adult dosage of phenytoin sodium recommended by the manufacturers for prophylactic control of seizures during neurosurgery is 100-200 mg administered parenterally at approximately 4-hour intervals during surgery and the immediate postoperative period.

If phenytoin is administered IM to neurosurgical patients unable to take the drug orally, the IM dosage should be increased by 50% over the previously established oral dosage. To avoid drug accumulation resulting from eventual absorption from IM injection sites, it is recommended that for the first week back on oral therapy, the oral dosage be reduced to one-half the original oral dosage. Monitoring of serum concentrations is also recommended. IM therapy should generally be limited to 1 week. (See Dosage and Administration: Administration.)

For the treatment of status epilepticus, the manufacturers recommend an initial adult dose of phenytoin sodium of 10-15 mg/kg, preferably by direct IV administration at a rate not exceeding 50 mg/minute; the initial dose should be followed by IV or oral maintenance doses of 100 mg every 6-8 hours. In geriatric patients with heart disease, it has been recommended that the drug be given at a rate of 50 mg over 2-3 minutes. Children may be given 15-20 mg/kg IV, at a rate not exceeding 1-3 mg/kg per minute. Most clinicians recommend that adults be given 15-18 mg/kg of phenytoin sodium IV at a rate not greater than 25-50 mg/minute (maximum total dose of 1.5 g in 24 hours) and that children be given 10-15 mg/kg IV at a usual rate of 0.5-1.5 mg/kg per minute (maximum total dose of 20 mg/kg in 24 hours). Oral therapy should replace parenteral administration as soon as possible. Determination of serum phenytoin concentrations is recommended when IV phenytoin is used for the management of status epilepticus.

Cardiac Arrhythmias

For the treatment of ventricular tachycardia or paroxysmal atrial tachycardia, or arrhythmias caused by digitalis intoxication, 100 mg of phenytoin sodium has been administered by direct IV injection at 5-minute intervals until the arrhythmia was abolished or undesirable effects appeared or until a total of 1 g was given. Orally, 100 mg of phenytoin or phenytoin sodium has been given 2-4 times daily in the management of cardiac arrhythmias.


Adverse Effects

Adverse effects produced by phenytoin are frequent, of a wide variety, and may occasionally be serious in nature, particularly when the drug is administered IV; rarely, fatalities have been reported. In some instances, adverse effects may subside as therapy is continued. Most patients tolerate phenytoin blood concentrations less than 25 mcg/mL. In some patients, blood concentrations of 25 mcg/mL are associated with nystagmus, ataxia, and diplopia. As the blood concentration exceeds 30 mcg/mL, drowsiness and lethargy, and rarely asterixis, may result; extreme lethargy and, occasionally, comatose states occur with greater than 50 mcg/mL. Some patients metabolize phenytoin slowly and thus exhibit signs of toxicity even with low to moderate dosage. This effect is believed to result from congenital enzyme deficiency.

Adverse GI effects of phenytoin include nausea and vomiting, constipation, epigastric pain, dysphagia, loss of taste, anorexia, and weight loss. Adverse CNS effects include mental confusion, nystagmus, ataxia, blurred vision, diplopia, toxic amblyopia, dizziness, insomnia, transient nervousness, motor twitching, and headache. Rarely, phenytoin-induced dyskinesias, including chorea, dystonia, tremor, and asterixis, have been reported. Serum phenytoin concentrations sustained above the optimal range may produce confusional states such as delirium, psychosis, or encephalopathy; rarely, irreversible cerebellar dysfunction may develop. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Phenytoin frequently produces gingival hyperplasia, especially in children, and it is occasionally so severe that it may require surgical removal. Gingival hyperplasia does not occur in edentulous areas of gums. Secondary inflammatory changes which result in an edematous enlargement of the primary gingival lesion can be minimized by good oral hygiene and gum massage.

Phenytoin produces hypertrichosis in some patients. Hypertrichosis is usually confined to the extremities but can also occur on the trunk and face and may be irreversible. Coarsening of the facial features in one sister in each of 2 pairs of identical twins has been attributed to phenytoin.

Scarlatiniform or morbilliform rash, sometimes accompanied by fever, may occur in patients receiving phenytoin; a morbilliform rash occurs most commonly. Rarely, phenytoin has produced severe dermatologic reactions such as bullous, exfoliative, or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis, and a few fatalities have resulted. Most serious dermatologic reactions occur within the first few months of therapy. Occasionally, severe cutaneous reactions have been accompanied by fever, lymphadenopathy, eosinophilia, arthralgias, and hepatic dysfunction, including jaundice, producing a syndrome resembling mononucleosis. Limited data suggest an increased risk of serious dermatologic reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) with phenytoin therapy in individuals of Asian ancestry who carry the human leukocyte antigen (HLA)-B*1502 allele. A retrospective case-controlled study in patients of Thai ancestry demonstrated an association between the risk of developing Stevens-Johnson syndrome and presence of the HLA-B*1502 allele. The HLA-B*1502 allele was present in all phenytoin-treated patients who experienced Stevens-Johnson syndrome; the allele was present in about 18% of the phenytoin-tolerant group. Marked variation exists in the prevalence of the HLA-B*1502 allele among various Asian populations. More than 15% of the population reportedly is HLA-B*1502-positive in parts of China, Thailand, Malaysia, the Philippines, and Taiwan. South Asians, including Indians, appear to have an intermediate prevalence of HLA-B*1502, which averages about 2-4% but may be higher in some groups. HLA-B*1502 is present in less than 1% of the population in Japan and Korea.(See Cautions: Precautions and Contraindications.)

Phenytoin administration has been associated with the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. (See Cautions: Precautions and Contraindications.) Lymph node involvement may occur with or without serum sickness-like signs or symptoms (e.g., fever, rash, liver involvement); however, lymphadenopathy and severe cutaneous reactions rarely have preceded the development of phenytoin-induced systemic lupus erythematosus. Phenytoin has also been associated with a small number of fatalities caused by liver damage. Toxic hepatitis, periarteritis nodosa, immunoglobulin abnormalities, and Peyronie's disease have also occurred.

Adverse hematologic effects, sometimes fatal, have been associated with phenytoin, including thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia (with or without bone marrow suppression). Macrocytosis and megaloblastic anemia, which usually respond to folic acid therapy, may also occur.

Osteomalacia has been associated with phenytoin therapy and is thought to be caused by phenytoin's interference with vitamin D metabolism. Phenytoin, especially in large doses, may increase blood glucose concentrations resulting in hyperglycemia and glycosuria. Patients with impaired renal function may be most susceptible to this effect. Average doses do not regularly elevate blood glucose or increase insulin requirements in diabetic patients, but a few patients have experienced fatal, hyperosmolar, nonketotic coma in which phenytoin may have played at least an accessory etiologic role.

The most important signs of toxicity associated with the IV use of phenytoin sodium are cardiovascular collapse and/or CNS depression; hypotension occurs if the drug is administered too rapidly by the IV route. Therefore, it is extremely important that the drug be administered slowly, at a rate not exceeding 50 mg/minute in adults and not exceeding 1-3 mg/kg per minute in pediatric patients to minimize toxicity. In geriatric patients with heart disease, it has been recommended that the drug be given at a rate of 50 mg over 2-3 minutes. Personnel and equipment should be readily available for administration of artificial respiration. (See Dosage and Administration.) Severe cardiotoxic reactions with reduced cardiac output, atrial or ventricular conduction depression, and ventricular fibrillation have occurred, sometimes resulting in death. Periarteritis nodosa also has been reported. Severe complications are most common in geriatric or debilitated patients.

IV administration of phenytoin has been associated with local soft-tissue reactions ranging from mild irritation and inflammation to extensive tissue damage (necrosis and sloughing) at the site of injection; amputation has been required rarely.(See Cautions: Precautions and Contraindications.) Severe tissue injury can occur in the presence or absence of extravasation. Purple glove syndrome (PGS), a delayed soft-tissue injury of the hand and forearm, has been reported in patients receiving peripheral IV injections of phenytoin; in at least one case, the condition was reported following oral administration of the drug. PGS is characterized by progressive pain, discoloration, and edema of the distal limb, and may or may not be associated with extravasation. The clinical course of the syndrome typically follows 3 stages. In the initial stage, a distinctive blue or purple skin discoloration appears around the injection site 2-12 hours after phenytoin is administered. This is followed by increasing edema and progression of discoloration distally and proximally over the next 12-24 hours; local skin blistering, sloughing, and ulceration also may occur during this second stage. In the last stage, gradual healing occurs over several days to weeks. PGS generally is a mild and self-limiting condition that can be managed primarily with supportive measures (e.g., limb elevation, application of dry heat); however, in severe cases, tissue necrosis and limb ischemia have occurred requiring surgical intervention such as fasciotomy, skin grafting, or amputation. From initial marketing of the drug in 1956 until June 8, 2010, 43 cases of phenytoin-associated PGS have been reported to the US Food and Drug Administration (FDA); a few of these cases resulted in serious outcomes, including hospitalization and amputation. The specific cause of phenytoin-induced soft-tissue injury is not known, but may be related at least in part to the high alkalinity or presence of vehicles (propylene glycol and ethanol) in the parenteral formulation. Possible risk factors for PGS and other types of severe soft-tissue injury include young or advanced age, female gender, use of small-bore IV catheters, preexisting cardiovascular disease, administration of multiple or large doses, and rapid rates of infusion.

Precautions and Contraindications

Phenytoin shares the toxic potentials of the hydantoin-derivative anticonvulsants, and the usual precautions of anticonvulsant therapy should be observed.

Clinicians should inform patients, their families, and caregivers about the potential for an increased risk of suicidal thinking and behavior (suicidality) associated with anticonvulsant therapy. For a complete discussion,

Phenytoin may exacerbate porphyria, and the drug should be used with caution in patients with this disease. Phenytoin is contraindicated in patients who are hypersensitive to the drug or other hydantoins. In addition, caution should be exercised if using structurally similar compounds (e.g., barbiturates, succinimides, oxazolidinediones) in patients who have experienced phenytoin hypersensitivity.

If a rash appears during phenytoin therapy, the drug should be discontinued. If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected, phenytoin therapy should not be resumed. If the rash is morbilliform or scarlatiniform, therapy may be restarted after the rash has completely disappeared; if the rash recurs when phenytoin is restarted, further phenytoin therapy is contraindicated.

Limited data suggest an increased risk of serious dermatologic reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) with phenytoin therapy in individuals of Asian ancestry who carry the human leukocyte antigen (HLA)-B*1502 allele. FDA is continuing to evaluate the relationship between use of phenytoin and serious dermatologic reactions in individuals with the HLA-B*1502 allele. An association between presence of the HLA-B*1502 allele and increased risk of Stevens-Johnson syndrome or toxic epidermal necrosis has been established in patients receiving carbamazepine. FDA recommends that patients with ancestry in genetically at-risk populations be screened for the presence of the HLA-B*1502 allele prior to initiating carbamazepine therapy; FDA currently does not recommend screening for the presence of the HLA-B*1502 allele prior to initiating therapy with phenytoin. Phenytoin should not be used as an alternative to carbamazepine in HLA-B*1502-positive patients.

If lymphadenopathy occurs during phenytoin therapy, the condition should be differentiated from other types of lymph node pathology and the patient should be closely observed for an extended period; alternative anticonvulsants should be used, if possible, for seizure control.

To minimize the risk of purple glove syndrome (PGS) and other types of soft-tissue injury, appropriate procedures and precautions for IV phenytoin sodium should be followed. Improper administration resulting in subcutaneous and perivascular injection of phenytoin sodium should be avoided. In addition, administration of IV injections of the drug should be followed by administration of sodium chloride injection through the same needle or IV catheter to reduce the risk of local irritation of the vein (see Cautions: Adverse Effects). Injection sites should be monitored frequently during and for 72 hours following administration of the drug. If PGS occurs, phenytoin should be discontinued immediately and the IV catheter removed. Appropriate supportive measures (e.g., elevation of the affected extremity, application of dry heat) should also be employed.(See Dosage and Administration: Administration.)

IV administration of phenytoin must be made slowly to minimize risk of adverse cardiovascular effects (see Dosage and Administration: Administration). Phenytoin should be administered IV only with extreme caution to patients with respiratory depression, myocardial infarction, frank or impending congestive failure, or otherwise damaged myocardium, and in patients in whom a sudden change in blood pressure may lead to serious complications. IV use of the drug is contraindicated in patients with sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular block, or Adams-Stokes syndrome.



Safe use of phenytoin during pregnancy has not been established. The drug should be used during pregnancy only when clearly needed. In addition to reports of a fetal hydantoin syndrome, there have been rare reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

Coagulation defects have been reported within the first 24 hours of birth in neonates born to epileptic women receiving phenobarbital and/or phenytoin during pregnancy; administration of vitamin K to the mother prior to delivery and to the neonate after birth is recommended to prevent or correct these defects.

To provide information regarding the effect of in utero exposure to phenytoin, clinicians are advised to recommend that pregnant patients receiving oral phenytoin or phenytoin sodium enroll themselves in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334; registry information also is available on the website at

Because of altered absorption or metabolism of phenytoin during pregnancy, an increased frequency of seizures may occur in pregnant women receiving the drug. If the drug is administered during pregnancy, serum phenytoin concentrations should be monitored and dosage adjusted accordingly; however, restoration of the patient's usual dosage will probably be necessary postpartum.



Studies using Dilantin have shown that phenytoin and its sodium salt are usually completely absorbed from the GI tract. Bioavailability may vary enough among oral phenytoin sodium preparations of different manufacturers to result in toxic serum concentrations or a loss of seizure control (subtherapeutic serum concentrations), and this should be considered before dispensing a brand or dosage form which differs from that currently taken by a patient. The current edition of FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book; should be consulted to determine which specific manufacturers' phenytoin sodium preparations the FDA has evaluated and deemed as being therapeutically equivalent (i.e., as bioequivalent and expected to have the same clinical effect and safety profile when administered appropriately). Prompt phenytoin capsules are rapidly absorbed and generally produce peak serum concentrations in 1.5-3 hours, while extended phenytoin sodium capsules are more slowly absorbed and generally produce peak serum concentrations in 4-12 hours. When phenytoin sodium is administered IM, absorption may be erratic; this may result from crystallization of the drug at the injection site because of the change in pH.

Therapeutic plasma concentrations of phenytoin are usually 7.5-20 mcg/mL and depend on the assay method used. In some patients, seizure control is not achieved when plasma concentrations are maintained in this range, and therefore clinical response of the patient is more meaningful than plasma concentrations. When serum concentration determinations are necessary, they should be obtained at least 5-7 half-lives after treatment initiation, change in dosage, or addition or subtraction of another drug to the regimen, so that steady-state drug levels may be achieved. Trough phenytoin concentrations provide information on clinically effective serum concentration range and confirm patient compliance; trough concentrations should be obtained just before the patient's next scheduled dose. Peak concentrations indicate an individual's threshold for emergence of dose-related adverse effects and are obtained at the time of expected peak concentration. In general, therapeutic plasma phenytoin concentrations are achieved after about 1 week of therapy with an oral dosage of 300 mg daily in adults. Alternatively, therapeutic plasma concentrations can be obtained more rapidly (in 2-24 hours) and maintained by administering an initial oral loading dose of 1 g in adults or 500-600 mg in children, followed by 300-500 mg daily in adults or 200 mg daily in children. Following IV administration of 1-1.5 g of phenytoin sodium at a rate not exceeding 50 mg/minute, therapeutic plasma concentrations can be attained within 1-2 hours.


In patients with normal renal function, phenytoin is approximately 95% protein bound. In vitro studies of plasma from patients with renal and/or hepatic disease show substantially less protein binding of phenytoin. Since customary plasma assay procedures measure total phenytoin concentration, these measurements may be misleading in patients whose protein binding characteristics differ from normal (e.g., patients with renal and/or hepatic disease), and phenytoin intoxication may occur at lower total phenytoin concentrations than usual.

Phenytoin appears to be distributed into milk in small amounts.


Following oral administration, the plasma half-life of phenytoin averages about 22 hours, although the half-life has ranged from 7-42 hours in individual patients. The plasma half-life of phenytoin in humans following IV administration ranges from 10-15 hours.

The major route of metabolism of phenytoin is oxidation by the liver to the inactive metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Because this metabolism is a saturable process, small increases in dosage may produce substantial increases in plasma phenytoin concentrations; the steady-state plasma concentration may double or triple from a 10% or more increase in dosage, possibly resulting in toxicity. HPPH undergoes enterohepatic circulation and is excreted in urine via glomerular filtration and tubular secretion, mainly as the glucuronide. Approximately 60-75% of the daily dose of the drug is excreted in this form. Other minor metabolites also appear in urine. In therapeutic doses, approximately 1% is excreted unchanged in urine; in toxic doses, up to 10% of the ingested drug may be excreted unchanged by the kidneys.

Following equal doses of phenytoin, total plasma phenytoin concentrations are lower in chronic uremic patients than in non-uremic patients which suggests an altered metabolic disposition of the drug in patients with uremia.

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