Introduction ⬇
AHFS Class:
Generic Name(s):
Phenytoin is a hydantoin-derivative anticonvulsant.
Uses ⬆ ⬇
Seizure Disorders 
Phenytoin is used in the management of generalized tonic-clonic (grand mal) seizures and partial seizures with complex symptomatology (psychomotor and temporal lobe seizures).195,196,197,240,258 Although efficacy of phenytoin has been well established for the management of seizure disorders, particularly for partial (focal) seizures, use of the drug may be limited because of its complicated pharmacokinetics, adverse effects, and multiple drug interactions.240,258 Phenytoin is not recommended for the treatment of pure absence (petit mal) seizures since the drug may increase the frequency of these seizures, but may be used in conjunction with other anticonvulsants when mixed seizure types are present.
Phenytoin sodium also is used IV 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.184,186,194,233 Benzodiazepines (e.g., diazepam, lorazepam, midazolam) are considered the drugs of choice for initial treatment of status epilepticus; IV phenytoin or fosphenytoin (a prodrug of phenytoin) may be used as a second-line agent if seizures continue.186,187,188,189,191,192,233,235,236,262 IV fosphenytoin appears to be better tolerated than IV phenytoin, and some experts state that fosphenytoin is preferred when both drugs are available.233 Because the full antiepileptic effect of phenytoin is not immediate, concurrent use of an IV benzodiazepine usually is necessary for rapid control of status epilepticus.194 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.187,188,189,190,191,192 (See Status Epilepticus under Seizure Disorders: Principles of Anticonvulsant Drug Therapy, in the Anticonvulsants General Statement 28:12.)
Phenytoin and phenytoin sodium also may be used for the prevention and treatment of seizures occurring during or following neurosurgery.194,195
Cardiac Arrhythmias
Phenytoin is a class IB antiarrhythmic agent.266 Because of its potent antiarrhythmic properties,266 IV phenytoin sodium has been used in the treatment of cardiac arrhythmias†, particularly ventricular arrhythmias† in patients who do not respond to conventional antiarrhythmic agents or to cardioversion. However, current use of phenytoin as an antiarrhythmic agent is limited by its narrow therapeutic window, multiple drug interactions, and adverse effect profile.266
IV phenytoin sodium also has been used in the treatment of arrhythmias caused by cardiac glycoside intoxication†. (See Therapeutic Measures under Acute Toxicity: Treatment, in Digoxin 24:04.08.)
Other Uses
Phenytoin has been used in the treatment of some neuropathic pain conditions†.263,264 However, there is insufficient evidence from clinical studies to support this use.263,264
Dosage and Administration ⬆ ⬇
Administration
Phenytoin and phenytoin sodium usually are administered orally in the management of seizure disorders.195,196,197,198 Phenytoin sodium also may be administered parenterally as a short-term replacement for oral phenytoin when oral administration is not possible.194 Phenytoin sodium is administered by slow IV injection or IV infusion in the treatment of status epilepticus.194 IM administration of phenytoin generally is not recommended because of the risk of necrosis, abscess formation, and erratic absorption.194 (See IM Administration under Dosage and Administration: Administration.) Because parenteral administration of phenytoin is associated with more frequent and severe complications, the oral route is preferred for maintaining therapeutic drug concentrations during nonemergency situations; patients receiving the drug parenterally should routinely be assessed for feasibility of oral therapy.184,194
Phenytoin therapy should not be abruptly discontinued to avoid precipitating seizures or status epilepticus.195 (See Cautions: Precautions and Contraindications.) Dosage reduction, discontinuance of therapy, or substitution with another anticonvulsant should be done cautiously and slowly.195 When a patient is transferred from phenytoin to another anticonvulsant, 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 dosage of the replacement drug.
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.100,102,195 (See Cautions: Precautions and Contraindications.)
Therapeutic Drug Monitoring
Therapeutic drug monitoring of serum phenytoin concentrations usually is recommended to guide dosing of phenytoin.194,195,258,268 Trough concentrations (obtained just prior to the next scheduled dose) can be used to assess therapeutic effect and patient compliance, while peak concentrations (obtained at the time of expected peak concentration) can be used to assess toxicity.195 The usual therapeutic range for phenytoin is 10-20 mcg/mL (or 1-2 mcg/mL based on unbound [free] phenytoin concentrations); however, some patients may achieve adequate seizure control or experience toxicity with lower or higher concentrations.194,195,258,269
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 discontinuance of another drug to the regimen, so that steady-state drug concentrations may be achieved.195 Patients with renal or hepatic impairment and those with hypoalbuminemia have an increased fraction of free phenytoin due to altered protein binding; therefore, free phenytoin concentrations rather than total serum concentrations should be monitored in these patients.195,268
Oral Administration
Phenytoin is administered orally as chewable tablets, extended-release capsules, or an oral suspension;195,196,197,198 only the extended-release phenytoin sodium capsules should be used for once-daily dosing.195,198 The extended-release capsules have been specifically formulated to be given as a single daily dose, while other oral formulations (e.g., oral suspension, chewable tablets) have different dissolution characteristics and absorption rates that do not permit once-daily dosing.195,196,197,198 Careful monitoring of serum phenytoin concentrations is recommended whenever there is a change in dosage form or preparation.195,198
Phenytoin oral suspension should be administered using a calibrated measuring device; a household teaspoon or tablespoon is not an adequate measuring device.197 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.
IV Administration
Phenytoin sodium is administered by slow IV injection or IV infusion.194
Although some clinicians have not recommended IV infusions of phenytoin,185 such administration is 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, starting the infusion immediately after preparation and completing administration within a relatively short period, using a 0.22-0.55-µm inline filter, and carefully inspecting the admixture for any discoloration or particulate matter prior to administration.194 To prepare the IV infusion solution, the commercially available phenytoin sodium injection should be diluted with 0.9% sodium chloride injection to a final concentration of no less than 5 mg/mL; dextrose-containing solutions should not be used for dilution because of the possibility of precipitate formation.194 Specialized references should be consulted for specific compatibility information. Following dilution, the infusion should begin immediately and must be completed within 1-4 hours.194 (See Chemistry and Stability: Stability.)
IV administration of phenytoin sodium should be made directly into a large peripheral or central vein through a large-gauge IV catheter to minimize the risk of local toxicity.194 Prior to administration, the IV catheter should be flushed with sterile saline to check patency.194 Following administration, the IV catheter should be flushed again with saline to reduce local venous irritation caused by the alkalinity of the solution.194
The manufacturer states that continuous ECG, blood pressure, and respiratory monitoring is essential during IV administration of phenytoin.194
Rate of Administration
Because of the risk of cardiovascular complications, the manufacturer states that the rate of IV administration of phenytoin sodium should not exceed 50 mg/minute in adults and 1-3 mg/kg per minute (or 50 mg/minute, whichever is slower) in pediatric patients.194 Some clinicians recommend not exceeding a rate of 0.5 mg/kg per minute in neonates and a rate of 1 mg/kg per minute in infants, children, and adults.267 A slower rate of administration is recommended in nonemergent situations.194
IM Administration
IM administration of phenytoin sodium generally is not recommended since the drug is erratically absorbed from IM injection sites and can cause local adverse effects (e.g., pain, necrosis, abscess formation).184,195 The manufacturer states that phenytoin should not be administered IM for the treatment of status epilepticus because of the delay in reaching therapeutic concentrations.194 Some experts state that phenytoin should not be administered by the IM route under any circumstances.184 If IM administration is needed (e.g., when IV access is not possible), IM fosphenytoin rather than IM phenytoin is preferred since fosphenytoin is well absorbed from IM injection sites.184,270
Patients transitioning from oral to an equal dosage of IM phenytoin may experience a 50-60% decrease in peak plasma phenytoin concentrations due to slower IM absorption of the drug.194 If IM administration of phenytoin is necessary, dosage must be increased by 50% over the previously established oral dosage to maintain therapeutic serum phenytoin concentrations.194 To avoid drug accumulation caused by absorption from muscle depots, dosage should be reduced once oral phenytoin therapy is resumed.194 (See Dosage and Administration: Dosage.) Experience with IM administration for longer than 1 week is lacking; serum phenytoin concentrations should be monitored.194
Dosage
Phenytoin formulations containing the free acid form of the drug (oral suspension and chewable tablets) have approximately 8% greater drug content than phenytoin sodium formulations (extended-release capsules and injection); this difference should be considered if a patient is switched from the free acid form to the sodium salt form or vice versa.194,195,196,197,198,267
Determination of serum phenytoin concentrations may be necessary to achieve optimal dosage adjustments.195 (See Therapeutic Drug Monitoring under Dosage and Administration: Administration.) Concurrent administration of many drugs can increase or decrease serum concentrations of phenytoin.195 (See Drug Interactions.)
Seizure Disorders
Dosage of phenytoin and phenytoin sodium must be carefully and slowly adjusted according to individual requirements and response. Therapy is usually initiated with a low dosage and gradually titrated over several weeks.258
The recommended initial oral dosage of phenytoin for the management of seizure disorders in adults who have not previously received the drug is 100 mg 3 times daily (as chewable tablets or extended-release capsules).195,196,198 Subsequent dosage should be adjusted based on individual requirements up to a maximum of 200 mg 3 times daily.195,196,198 If the oral suspension is used, the recommended initial adult dosage is 125 mg (5 mL of the 125 mg per 5 mL suspension) 3 times daily; dosage should be adjusted based on individual requirements up to a maximum of 625 mg (25 mL) daily.197 For patients receiving extended-release phenytoin sodium capsules who are stabilized on a dosage of 100 mg 3 times daily, once-daily dosing with 300 mg as extended-release phenytoin sodium capsules may be considered.195,198 If necessary, daily dosage may be gradually increased in increments of 100 mg every 2-4 weeks until the desired response is obtained. A period of 7-10 days may be required to achieve steady-state concentrations of the drug, and therefore, any change in dosage should not be made sooner than this interval.195 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. Some experts recommend that dosage adjustments above 300 mg daily in adults be made in 25- or 30-mg increments.258 The optimum daily dosage varies considerably from one patient to another but is usually in the range of 300-400 mg daily for most adults.195,196,198,258 Lower doses or less frequent dosing may be required in geriatric patients.195
In pediatric patients, the recommended initial oral dosage of phenytoin is 5 mg/kg daily administered in 2 or 3 equally divided doses (as chewable tablets, extended-release capsules, or oral suspension).195,196,197,198,267 Subsequent dosage should be adjusted based on individual requirements up to a maximum of 300 mg daily in divided doses.195,196,197,198,258 Maintenance dosage for children usually ranges from 4-8 mg/kg daily (administered in 2 or 3 equally divided doses); however, usual dosages may vary depending on whether phenytoin is used alone or as adjunctive therapy.195,196,197,198,258 Children older than 6 years of age and adolescents may require the minimum adult dosage of 300 mg daily.195,196,197,198 Some clinicians state that the usual daily phenytoin dosage (administered in 2 or 3 divided doses) for maintenance of seizure control in pediatric patients is 8-10 mg/kg for those 6 months to 3 years of age, 7.5-9 mg/kg for those 4-6 years of age, 7-8 mg/kg for those 7-9 years of age, and 6-7 mg/kg for those 10-16 years of age.267
Therapeutic serum phenytoin concentrations can be achieved more rapidly (in 2-24 hours) with an oral loading-dose regimen. Some clinicians have recommended the use of oral loading doses of phenytoin in adults to achieve rapid steady-state concentrations when IV administration is not desirable.195 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.195 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.
When oral therapy is temporarily not feasible, phenytoin sodium may be given IV at the same total daily oral dosage (administered at a rate not exceeding 50 mg/minute in adults and 1-3 mg/kg per minute [or 50 mg/minute, whichever is slower] in pediatric patients).194 However, serum phenytoin concentrations may increase slightly when IV phenytoin is substituted for extended-release phenytoin sodium capsules since bioavailability of the capsules is about 90%.194
Because of the risks of adverse effects associated with parenteral phenytoin, oral phenytoin should be used whenever possible.194 However, if IV phenytoin sodium is used in a nonemergent situation (e.g., prevention of seizures during neurosurgery), the manufacturer states that a loading dose of 10-15 mg/kg should be administered slowly in adults.194 An IV loading dose of 15-20 mg/kg will usually produce serum phenytoin concentrations in the generally accepted therapeutic range of 10-20 mcg/mL in pediatric patients.194 The rate of IV administration should not exceed 50 mg/minute in adults and 1-3 mg/kg per minute (or 50 mg/minute, whichever is slower) in pediatric patients; however, slower rates are recommended to minimize the risk of cardiovascular toxicity.194 Following administration of the loading dose, maintenance IV or oral doses of phenytoin should be administered every 6-8 hours.194
If IM administration of phenytoin sodium is required, the IM dosage should be increased by 50% over the previously established oral dosage.194 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.194 Monitoring of serum concentrations is also recommended.194 Experience with IM therapy for periods longer than 1 week is lacking.194 (See Dosage and Administration: Administration.)
Status Epilepticus
For the treatment of status epilepticus in adults, the manufacturer recommends an IV phenytoin sodium loading dose of 10-15 mg/kg, administered slowly at a rate not exceeding 50 mg/minute.194 In pediatric patients, the manufacturer states that an IV phenytoin sodium loading dose of 15-20 mg/kg will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range of 10-20 mcg/mL; the drug should be administered slowly at a rate not exceeding 1-3 mg/kg per minute (or 50 mg/minute, whichever is slower).194 Some clinicians recommend an initial IV phenytoin sodium dose of 20 mg/kg (administered at a rate not exceeding 50 mg/minute in adults or not exceeding 1 mg/kg per minute in children) in adults and children with status epilepticus; an additional dose of 5-10 mg/kg may be given after 10 minutes if seizures continue.236,262 However, individual dosage requirements may vary, and as much as 30 mg/kg may be required to achieve adequate seizure control in some patients.233,262,271 A maximum of 1.5 g in 24 hours has been recommended for the loading dose of phenytoin sodium in patients with status epilepticus.267 Following administration of the loading dose, IV or oral maintenance doses should be administered every 6-8 hours.194 Lower doses or less frequent dosing may be required in geriatric patients.194
Because of the required slow rate of IV phenytoin administration, concurrent use of an IV benzodiazepine usually is necessary for rapid control of status epilepticus.194 (See Uses: Seizure Disorders.) Determination of serum phenytoin concentrations is recommended when IV phenytoin is used in the management of status epilepticus; however, treatment should not be delayed to measure serum concentrations.194,262
Cardiac Arrhythmias
For the treatment of ventricular tachycardia†, 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.
For the treatment of arrhythmias associated with cardiac glycoside intoxication†, IV phenytoin sodium loading doses of 1.25 mg/kg administered every 5 minutes up to a total of 15 mg/kg have been recommended in patients of all ages; maintenance IV or oral doses of 5-10 mg/kg daily given in divided doses every 8-12 hours are recommended in pediatric patients, and a maintenance oral dosing regimen consisting of 250 mg 4 times daily for 1 day, then 250 mg every 12 hours for 2 days, then 300-400 mg (in divided or once-daily doses) is recommended in adults.267
Cautions ⬆ ⬇
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. Clinical signs of toxicity are more likely to occur with serum phenytoin concentrations above 20 mcg/mL (unbound [free] phenytoin concentrations of 1-2 mcg/mL); however, there is marked variability and patients may experience toxicity with lower or higher concentrations.194,195,258,269 In some patients, serum phenytoin 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 concentrations 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.
Cardiovascular Effects
Rapid IV administration of phenytoin has caused severe hypotension and cardiac arrhythmias, including bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation, sometimes resulting in asystole, cardiac arrest, and death.194 (See Cautions: Precautions and Contraindications.) Severe complications appear to be most common in critically ill patients, elderly patients, and those with hypotension and severe myocardial insufficiency, although cardiac events also have been reported in patients without underlying cardiac disease or other comorbidities.194 Cardiovascular toxicity may be due in part to the propylene glycol (cardiac depressant) in the parenteral formulation.200
Dermatologic and Sensitivity Reactions
A scarlatiniform or morbilliform rash, sometimes accompanied by fever, has been reported in patients receiving phenytoin, usually in the first month of therapy.195,196,197,258 More serious dermatologic reactions that have occurred include bullous, exfoliative, or purpuric dermatitis; acute generalized exanthematous pustulosis (AGEP); Stevens-Johnson syndrome (SJS); and toxic epidermal necrolysis (TEN).195,196,197 (See Cautions: Precautions and Contraindications.)
Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with several anticonvulsant drugs including phenytoin.195,196,197 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.195,196,197 However, signs and symptoms associated with other organ systems also may occur.195,196,197
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.
Hypersensitivity reactions, including anaphylaxis and angioedema, also have been reported in patients receiving phenytoin.195
Pharmacogenomic Considerations in the Development of Cutaneous Reactions
Limited data suggest an increased risk of SJS and TEN with phenytoin in individuals of Asian ancestry who carry the human leukocyte antigen (HLA)-B*1502 allele.104,105,195,196,197,231,232 A strong association has been found between the presence of HLA-B*1502 and an increased risk of developing SJS and TEN in patients with Chinese ancestry receiving carbamazepine; although evidence is more limited, HLA-B*1502 also has been associated with SJS/TEN in such patients receiving structurally similar anticonvulsants such as phenytoin.195,196,197,231,232 These anticonvulsants (e.g., eslicarbazepine, lamotrigine, phenytoin, fosphenytoin, phenobarbital) generally should not be used as alternatives to carbamazepine in HLA-B*1502-positive patients.195,196,197,231 (See Cautions: Dermatologic and Sensitivity Reactions, in the Anticonvulsants General Statement 28:12.)
Hematologic Effects
Adverse hematologic effects (sometimes fatal) have been associated with the use of phenytoin, including thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia (with or without bone marrow suppression).195 Macrocytosis and megaloblastic anemia, which usually respond to folic acid therapy, also may occur.
Although a causal relationship has not been established, phenytoin administration may be associated with the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease.195,196,197 (See Cautions: Precautions and Contraindications.) Lymph node involvement may or may not occur in association with DRESS.195,196,197 (See Cautions: Dermatologic and Sensitivity Reactions.)
Hepatic Effects
Acute hepatotoxicity, including infrequent cases of acute hepatic failure, has been reported with phenytoin.195 Such events may or may not occur in association with DRESS.195 (See Cautions: Dermatologic and Sensitivity Reactions.) Toxic hepatitis also has occurred.
Nervous System Effects
Adverse CNS effects of phenytoin include mental confusion, nystagmus, ataxia, blurred vision, diplopia, toxic amblyopia, dizziness, insomnia, transient nervousness, motor twitching, and headache. Drowsiness, ataxia, and diplopia are more likely to occur at serum phenytoin concentrations greater than 20 mcg/mL, but can also occur at lower concentrations, particularly in patients with hypoalbuminemia and in geriatric patients.258 Rarely, phenytoin-induced dyskinesias, including chorea, dystonia, tremor, and asterixis, have been reported. Serum phenytoin concentrations sustained above the therapeutic range may produce confusional states such as delirium, psychosis, or encephalopathy; rarely, irreversible cerebellar dysfunction may develop.195 A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants compared with placebo.100,102,195,196 (See Suicidality under Cautions: CNS Effects, in the Anticonvulsants General Statement 28:12.) This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.100,102,195 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.100,102,195 (See Cautions: Precautions and Contraindications.)
GI Effects
Adverse GI effects of phenytoin include nausea and vomiting, constipation, epigastric pain, dysphagia, loss of taste, anorexia, and weight loss.
Other Adverse Effects
Phenytoin frequently produces gingival hyperplasia, especially in children, which 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 has been associated with changes in bone metabolism; decreased bone mineral density (BMD) and related bone effects (e.g., osteopenia, osteoporosis, osteomalacia, fractures) have occurred in epileptic patients receiving long-term therapy with the drug.195,259 The mechanism of this effect is thought to be due to phenytoin's interference with vitamin D metabolism.195,259
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.
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.172,173,174,175,176,177,178,179,180,181,182,184 (See Cautions: Precautions and Contraindications.) Severe tissue injury can occur in the presence or absence of extravasation.172,176 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.170,171,173,174,175,176,177,178,179,180,181,182,183,184 PGS is characterized by progressive pain, discoloration, and edema of the distal limb, and may or may not be associated with extravasation.173,174,175,176,177,178,179,180,181,182 The clinical course of the syndrome typically follows 3 stages.173,174,177,179,180 In the initial stage, a distinctive blue or purple skin discoloration appears around the injection site 2-12 hours after phenytoin is administered.173,174,177,179,180,181 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.173,174,177,179,180,181 In the last stage, gradual healing occurs over several days to weeks.173,174,177,179,180,181 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.174,175,176,177,178,179,180,181,182 From initial marketing of the drug in 1956 until June 8, 2010, 43 cases of phenytoin-associated PGS have been reported to FDA; a few of these cases resulted in serious outcomes, including hospitalization and amputation.170 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 formulations.172,173,174,175,176,177,178,179,180,181,182 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.172,173,174,175,177,178,179,180,181,182,184
Precautions and Contraindications
Phenytoin shares the toxic potentials of the hydantoin-derivative anticonvulsants, and the usual precautions of anticonvulsant therapy should be observed. (See Cautions in the Anticonvulsants General Statement 28:12.)
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.100 For a complete discussion, see Cautions: CNS Effects and Cautions: Precautions and Contraindications, in the Anticonvulsants General Statement 28:12. If any signs of CNS toxicity (e.g., delirium, psychosis, encephalopathy, cerebellar dysfunction or atrophy) occur during therapy, serum phenytoin concentrations should be measured immediately.195 If the serum concentration is found to be excessive, dosage of phenytoin should be decreased; if symptoms persist, therapy should be discontinued.195
Phenytoin may exacerbate porphyria, and the drug should be used with caution in patients with this disease.195,196,197 If lymphadenopathy occurs during phenytoin therapy, the patient should be closely observed and further evaluated to establish a differential diagnosis; alternative anticonvulsants should be used, if possible, for seizure control.195
To minimize the possibility of increasing seizure frequency and status epilepticus, phenytoin should not be abruptly discontinued; therapy should be withdrawn slowly and dosage reductions or drug substitutions should be done gradually.195 In the event of an allergic or hypersensitivity reaction, more rapid substitution with an alternative, non-hydantoin anticonvulsant may be considered.195
Because phenytoin can decrease vitamin D concentrations and cause associated bone-related effects, consideration should be given to monitoring vitamin D concentrations and other measures of bone health in patients receiving long-term therapy with the drug.195,259
Because of altered protein binding, the fraction of unbound (free) phenytoin may be increased in patients with renal or hepatic impairment and in those with hypoalbuminemia; total serum phenytoin concentrations should be interpreted with caution, and it is recommended that the unbound (free) phenytoin concentration be monitored in these patients.195,268 A small percentage of patients receiving phenytoin has been found to metabolize the drug slowly; this appears to be due to genetic variations in hepatic enzyme induction.195 Because serum concentrations of phenytoin may be higher than expected in such individuals, serum concentrations should be checked immediately if early signs of CNS toxicity occur.195
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.172,175,194 (See Cautions: Other Adverse Effects.) In addition, administration of IV injections of the drug should be followed by administration of sodium chloride injection through the same IV catheter to avoid the risk of local irritation of the vein.194 Injection sites should be monitored frequently during and for 72 hours following administration of the drug.177,182,184 If PGS occurs, phenytoin should be discontinued immediately and the IV catheter removed.175,176,177,178,180,184 Appropriate supportive measures (e.g., elevation of the affected extremity, application of dry heat) should also be employed.177,184 (See Dosage and Administration: Administration.)
IV phenytoin must be administered slowly to minimize the risk of cardiovascular toxicity (see Cautions: Cardiovascular Effects and also see Rate of Administration under Administration: IV Administration, in Dosage and Administration).194 While the risk of toxicity increases with infusion rates above the recommended rates, cardiac events also can occur at or below these rates.194 Cardiac and respiratory monitoring should be performed during and after IV administration of the drug.194 A reduction in the rate of administration or discontinuance of the drug may be necessary.194 Phenytoin should be administered IV only with extreme caution to patients with respiratory depression, myocardial infarction, frank or impending congestive heart 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 because of the drug's effects on ventricular automaticity.194
If a rash appears during phenytoin therapy, the drug should be discontinued unless the rash is clearly not drug related.195,196,197 If manifestations suggestive of SJS or TEN occur, phenytoin therapy should not be resumed and alternative therapy should be considered.195,196,197 Because of the risk of developing SJS and TEN, consideration should be given to avoiding the use of phenytoin as an alternative to carbamazepine in HLA-B*1502-positive patients.195,196,197 (See Pharmacogenomic Considerations in the Development of Cutaneous Reactions under Cautions: Dermatologic and Sensitivity Reactions.) If signs and symptoms of DRESS occur during phenytoin therapy, patients should be evaluated immediately; if an alternative etiology cannot be identified, the drug should be discontinued.195,196,197 (See Cautions: Dermatologic and Sensitivity Reactions.)
Phenytoin is contraindicated in patients with a history of hypersensitivity to the drug, any of its ingredients, or other hydantoins.195,196,197 Clinicians should consider alternatives to structurally similar compounds such as carboxamides, barbiturates, succinimides, and oxazolidinediones in patients who have experienced phenytoin hypersensitivity.195,196,197 Similarly, if there is a history of hypersensitivity to these structurally similar drugs in the patient or immediate family member, alternatives to phenytoin should be considered.195,196,197 If manifestations of angioedema (e.g., facial, perioral, or upper airway swelling) occur during phenytoin therapy, the drug should be discontinued immediately.195,196,197
Concomitant use of phenytoin and delavirdine is contraindicated because of possible loss of virologic response and resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.195 (See Drug Interactions: Delavirdine.) Phenytoin also is contraindicated in patients who have experienced previous acute hepatotoxicity with the drug.195
Pregnancy and Lactation
Pregnancy
Phenytoin may cause fetal harm (e.g., congenital malformations, adverse developmental outcomes) if used during pregnancy.195,201 However, the risk-to-benefit ratio generally favors continued use in pregnant women whose seizure control depends on the drug.201,258 (See Cautions: Pregnancy and Lactation, in the Anticonvulsants General Statement 28:12.) Phenytoin has been associated with a fetal hydantoin syndrome consisting of craniofacial abnormalities, nail and digital hypoplasia, prenatal growth deficiency, microcephaly, and cognitive deficiency; such effects have been observed in children born to epileptic women who received phenytoin alone or in combination with other anticonvulsant drugs during pregnancy.195 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.195 Fetal malformations (e.g., craniofacial, cardiovascular, neural, limb, and digit abnormalities) and other evidence of developmental toxicity (e.g., embryofetal death, growth impairment, behavioral abnormalities) have been observed in animal reproductive studies.195
Coagulation defects which have resulted in life-threatening bleeding disorders have been reported in neonates born to women receiving phenytoin during pregnancy; because these reactions are related to decreased concentrations of vitamin K-dependent clotting factors, administration of vitamin K to the mother prior to delivery and to the neonate after birth may prevent these complications.195
Women who are pregnant while receiving phenytoin should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334; registry information also is available at [Web].193,195
Because of altered pharmacokinetics of phenytoin during pregnancy, serum concentrations of phenytoin may decline, possibly increasing the frequency of seizures in pregnant women receiving the drug.195 If phenytoin is administered during pregnancy, serum phenytoin concentrations should be monitored and dosage of phenytoin should be adjusted accordingly; however, restoration of the patient's usual dosage will probably be necessary postpartum.195,201 Because of potential changes in protein binding of phenytoin during pregnancy, it is recommended that unbound (free) phenytoin concentrations be monitored in pregnant women.195
Lactation
Phenytoin is distributed into milk; however, use of phenytoin is generally considered compatible with breast-feeding.195,201 The known benefits of breast-feeding should be considered along with the woman's clinical need for phenytoin and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.195
Drug Interactions ⬆ ⬇
Phenytoin is involved in multiple drug interactions because of its extensive plasma protein binding, saturable metabolism, and potent hepatic enzyme-inducing properties.195
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Phenytoin is metabolized by cytochrome P-450 (CYP) isoenzymes 2C9 and 2C19; concomitant use of drugs that inhibit or induce these CYP isoenzymes can alter serum phenytoin concentrations.195,258 Phenytoin is particularly susceptible to inhibitory interactions because of its saturable metabolism.195 Inhibition of phenytoin metabolism may substantially increase serum concentrations of phenytoin and increase the risk of toxicity.195 If a drug interaction is suspected, serum phenytoin concentrations should be monitored and dosage of phenytoin should be adjusted as necessary.195
Drugs that can increase serum phenytoin concentrations include, but are not limited to, azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, miconazole, voriconazole), certain selective serotonin-reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, sertraline), cimetidine, omeprazole, sulfonamides, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, and warfarin.195,232 Drugs that can decrease serum phenytoin concentrations include, but are not limited to, certain HIV protease inhibitors (e.g., fosamprenavir, nelfinavir, ritonavir), diazepam, diazoxide, folic acid, rifampin, St. John's wort, sucralfate, and theophylline.195 Certain anticonvulsants (e.g., ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate) can increase serum phenytoin concentrations, while others (e.g., carbamazepine, vigabatrin) can decrease serum concentrations of phenytoin; phenobarbital and valproate can either increase or decrease serum phenytoin concentrations.195 Certain antineoplastic agents (e.g., capecitabine, fluorouracil) can increase serum phenytoin concentrations, while others (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate) can decrease serum concentrations of the drug.195
Phenytoin is a potent inducer of CYP isoenzymes and can therefore decrease plasma concentrations and possibly reduce efficacy of many drugs.195,241,258 Dosage adjustments of these drugs may be necessary when phenytoin is added to or withdrawn from concomitant therapy.195 Drugs whose efficacy may be impaired by phenytoin include, but are not limited to, azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), certain antineoplastic agents (e.g., irinotecan, paclitaxel, teniposide), delavirdine, neuromuscular blocking agents (e.g., cisatracurium, pancuronium, rocuronium, vecuronium), warfarin, corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D.195 Drugs whose plasma concentrations may be decreased by phenytoin include, but are not limited to, certain anticonvulsant agents (e.g., carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine), certain antilipemic agents (e.g., atorvastatin, fluvastatin, simvastatin), certain antiviral agents (e.g., efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), calcium channel-blocking agents (e.g., nifedipine, nimodipine, nisoldipine, verapamil), albendazole, chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, and quetiapine.195 The effect of phenytoin on phenobarbital and valproate concentrations is unpredictable.195 The effect of phenytoin on fosamprenavir varies depending on whether fosamprenavir is administered alone or in conjunction with ritonavir.195
Protein-bound Drugs
Phenytoin is extensively bound to plasma proteins and has the potential to displace or be displaced by other protein-bound drugs.195
Alcohol
Chronic alcohol abuse can decrease serum phenytoin concentrations, while acute alcohol intake can increase concentrations of the drug.195
Amiodarone
Concomitant administration of phenytoin and amiodarone has resulted in a twofold to threefold increase in steady-state serum concentrations of phenytoin and subsequent signs of phenytoin toxicity (e.g., nystagmus, ataxia, lethargy) in a limited number of patients. The increase in serum phenytoin concentrations occurred within 3-4 weeks of initiating amiodarone therapy. Patients receiving phenytoin should be monitored closely for signs of phenytoin toxicity when amiodarone is administered concomitantly; serum phenytoin concentrations should be monitored and dosage of phenytoin reduced as necessary.
Antacids
Antacids (e.g., calcium carbonate, aluminum hydroxide, magnesium hydroxide) may interfere with absorption and decrease serum concentrations of phenytoin.195 Antacids should not be taken at the same time of day as phenytoin.195
Delavirdine
Phenytoin can substantially reduce plasma concentrations of delavirdine and result in loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.195 Concomitant use of phenytoin and delavirdine is contraindicated.195
Folic Acid
In folate-deficient patients, folic acid therapy may increase phenytoin metabolism resulting in decreased serum phenytoin concentrations. Although this interaction is not usually clinically important, an increase in seizure frequency may occur in some patients.
Isoniazid
Isoniazid appears to inhibit metabolism of phenytoin, thereby increasing serum phenytoin concentrations, decreasing urinary excretion of 5-( p -hydroxyphenyl)-5-phenylhydantoin, and resulting in phenytoin toxicity in about 25% of patients receiving concomitant therapy. Phenytoin toxicity occurs mainly in slow isoniazid inactivators and in patients receiving both isoniazid and aminosalicylic acid or cycloserine.
Patients receiving isoniazid and phenytoin should be closely observed for signs of phenytoin intoxication. If clinical evidence of intoxication occurs, reduction of phenytoin dosage to 100 or 200 mg daily may decrease toxicity while maintaining adequate serum phenytoin concentrations. Serum phenytoin concentrations may be less stable in patients receiving isoniazid and aminosalicylic acid, and periodic dosage adjustment may be required.
Neuromuscular Blocking Agents
Resistance to the nondepolarizing neuromuscular blocking agents cisatracurium, pancuronium, rocuronium, and vecuronium has occurred in patients receiving long-term phenytoin therapy.195 Whether the same effect occurs with other nondepolarizing neuromuscular blocking agents is not known.195 Patients receiving neuromuscular blocking agents should be monitored closely for more rapid than expected recovery from neuromuscular blockade; increased dosage of the neuromuscular blocking agent may be necessary.195
Oral Contraceptives
Phenytoin can induce the metabolism of oral contraceptives and decrease serum concentrations of estrogens and/or progestins.232,258 The resulting decrease in concentrations of the oral contraceptive may lead to contraceptive failure.195,258
Warfarin
Several interactions are possible in patients receiving phenytoin and warfarin, and the net effects are difficult to predict.106,195 Warfarin may inhibit phenytoin metabolism and increase serum phenytoin concentrations; in addition, phenytoin may induce hepatic metabolism of warfarin and/or displace the anticoagulant from its protein-binding sites.106,195,232 Depending on the response, prothrombin time (PT) and international normalized ratios (INR) may be increased or decreased.106,195
If warfarin and phenytoin are used concomitantly, the patient should be closely monitored.106 Dosage adjustments may be required when phenytoin is added to or withdrawn from concomitant warfarin therapy.195
Other Information ⬆ ⬇
Laboratory Test Interferences
Patients receiving phenytoin have shown reduced protein-bound iodine (PBI) test values without lowered triiodothyronine (T3) values and without clinical symptoms of hypothyroidism; free thyroxine concentrations may also be decreased. The 24-hour I 131 thyroidal uptake is apparently not affected. Phenytoin may produce increased resin or red cell T3 uptake values. Lowered PBI values do not occur unless phenytoin is administered for 1 week or longer, and altered values persist for 7-10 days after phenytoin is discontinued.
Phenytoin administration may cause slight decreases in urinary 17-hydroxycorticosteroids and 17-ketosteroids while urinary 6-β-hydroxycortisol excretion is increased. The drug may produce lower than normal values for dexamethasone or metyrapone tests.
Phenytoin may produce increased serum alkaline phosphatase or γ-glutamyl transferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations.
Pharmacology
The principal pharmacologic effects of phenytoin are similar to those of other hydantoin-derivative anticonvulsants. The exact mechanism of action of phenytoin has not been established, but may be due to voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.195 In addition, phenytoin exhibits antiarrhythmic properties similar to those of quinidine or procainamide. Although the drug has little effect on the electrical excitability of cardiac muscle, it decreases the force of contraction, depresses pacemaker action, and improves atrioventricular conduction, particularly when it has been depressed by digitalis glycosides. Phenytoin, like quinidine, prolongs the effective refractory period relative to the action potential duration. The drug may produce hypotension following IV administration. Phenytoin has little hypnotic activity.
Pharmacokinetics
Absorption
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; [Web]) 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). 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 serum concentrations of phenytoin are usually 10-20 mcg/mL, but can be variable depending on the patient.194,105,258,269 In some patients, seizure control is not achieved when serum concentrations are maintained in this range, and therefore clinical response of the patient is more meaningful than serum 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 elimination 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 serum 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.
Distribution
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.
Elimination
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.
Phenytoin is metabolized by hepatic cytochrome P-450 (CYP) isoenzymes.195 The drug is principally oxidized 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.
Chemistry and Stability
Chemistry
Phenytoin is a hydantoin-derivative anticonvulsant. Phenytoin occurs as a white powder and is practically insoluble in water, soluble in hot alcohol, and slightly soluble in cold alcohol. The drug has an apparent pKa of 8.06-8.33. Phenytoin sodium occurs as a white, hygroscopic powder and is freely soluble in water, soluble in alcohol, and freely soluble in warm propylene glycol.
Aqueous solutions of phenytoin sodium gradually absorb carbon dioxide, and the drug undergoes partial hydrolysis to phenytoin, resulting in turbid solutions. The drug is more stable in propylene glycol. Commercially available phenytoin sodium injection is a sterile solution of the drug containing 40% propylene glycol and 10% alcohol in water for injection. Sodium hydroxide is added during manufacture of the injection to adjust the pH to 12. Each 100-mg phenytoin sodium capsule contains approximately 0.35 mEq of sodium, and phenytoin sodium injection contains about 0.2 mEq of sodium per mL.
Stability
Commercially available phenytoin oral suspension and tablets, and the extended-release phenytoin sodium capsules should be stored at room temperature (20-25°C); the tablets should be protected from moisture, the extended-release capsules should be protected from light and moisture, and the oral suspension should be protected from freezing and light.195,197,198 Phenytoin sodium injection should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.194 Diluted solutions of phenytoin sodium injection should not be refrigerated.194 A precipitate may form if the injection is refrigerated or frozen; however, this will dissolve after warming to room temperature and the injection may still be used.194 Slight yellowish discoloration of the injection will not affect potency, but the injection should not be used if the solution is not clear or if a precipitate is present.194 Precipitation of free phenytoin will occur at a pH of 11.5 or less.
Phenytoin sodium injection is physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Phenytoin
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Phenytoin Sodium
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions September 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References ⬆
Only references cited for selected revisions after 1984 are available electronically.
11. Millichap JG. Drug treatment of convulsive disorders. N Engl J Med . 1972; 286:464-9. [PubMed 4333276]
100. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.
102. Food and Drug Administration. FDA Alert: Suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.
104. Locharernkul C, Loplumlert J, Limotai C et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia . 2008; 49:2087-91. [PubMed 18637831]
105. Man CBL, Kwan P, Baum L et al. Association between HLA-B* 1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia . 2007: 48:1015-8.
106. Panegyres PK, Rischbieth RH. Fatal phenytoin warfarin interaction. Postgrad Med J . 1991; 67:98. [PubMed 2057444]
170. Food and Drug Administration. Joint Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Gaithersburg, MD; November 3, 2010. From FDA website [Web]/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM233399.pdf
171. Summary minutes: Joint meeting of the Peripheral and Central Nervous System Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, November 3, 2010. From FDA website [Web]/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM243258.pdf.
172. Spengler RF, Arrowsmith JB, Kilarski DJ et al. Severe soft-tissue injury following intravenous infusion of phenytoin. Patient and drug administration risk factors. Arch Intern Med . 1988; 148:1329-33. [PubMed 3377616]
173. O'Brien TJ, Cascino GD, So EL et al. Incidence and clinical consequence of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology . 1998; 51:1034-9. [PubMed 9781525]
174. Burneo JG, Anandan JV, Barkley GL. A prospective study of the incidence of the purple glove syndrome. Epilepsia . 2001; 42:1156-9. [PubMed 11580764]
175. Singh G, Cherian VT, Thomas BP. Low-concentration, continuous brachial plexus block in the management of Purple Glove Syndrome: a case report. J Med Case Reports . 2010; 4:48.
176. Edwards JJ, Bosek V. Extravasation injury of the upper extremity by intravenous phenytoin. Anesth Analg . 2002; 94:672-3; table of contents. [PubMed 11867395]
177. Hanna DR. Purple glove syndrome: a complication of intravenous phenytoin. J Neurosci Nurs . 1992; 24:340-5. [PubMed 1289432]
178. Mahajan RP, Batra YK, Rajeev S. Intravenous phenytoin and percutaneous arterial cannulation: the purple-glove syndrome. Eur J Anaesthesiol . 2007; 24:900-1. [PubMed 17977106]
179. Bhattacharjee P, Glusac EJ. Early histopathologic changes in purple glove syndrome. J Cutan Pathol . 2004; 31:513-5. [PubMed 15239684]
180. Santoshi JA, Justin AS, Jacob JI et al. Purple glove syndrome: a case report. Hand surgeons and physicians be aware. J Plast Reconstr Aesthet Surg . 2010; 63:e340-2. [PubMed 19596627]
181. Chokshi R, Openshaw J, Mehta NN et al. Purple glove syndrome following intravenous phenytoin administration. Vasc Med . 2007; 12:29-31. [PubMed 17451091]
182. Sonohata M, Asami A, Tsunoda K et al. Purple glove syndrome associated with intravenous phenytoin administration in a patient with severe mental and motor retardation. J Orthop Sci . 2006; 11:409-11. [PubMed 16897209]
183. Yoshikawa H, Abe T, Oda Y. Purple glove syndrome caused by oral administration of phenytoin. J Child Neurol . 2000; 15:762. [PubMed 11108512]
184. Meek PD, Davis SN, Collins DM et al. Guidelines for nonemergency use of parenteral phenytoin products: proceedings of an expert panel consensus process. Arch Intern Med . 1999; 159:2639-44. [PubMed 10597754]
185. ASHP's interactive handbook on injectable drugs. McEvoy, GK, ed. Bethesda, MD: American Society of Health-System Pharmacists, Inc; Updated December 13, 2018. From HID website. [Web]
186. Prasad K, Al-Roomi K, Krishnan PR et al. Anticonvulsant therapy for status epilepticus (review). Cochrane Database of Systematic Reviews. 2005, Issue 4. Article No: CD003723. DOI: 10.1002/14651858.CD003723.pub2.
187. Minicucci F, Muscas G, Perucca E et al. Treatment of status epilepticus in adults: guidelines of the Italian League against Epilepsy. Epilepsia . 2006; 47 Suppl 5:9-15. [PubMed 17239099]
188. Meierkord H, Boon P, Engelsen B et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol . 2010; 17:348-55. [PubMed 20050893]
189. Kälviäinen R. Status epilepticus treatment guidelines. Epilepsia . 2007; 48 Suppl 8:99-102. [PubMed 18330014]
190. Phelps SJ, Hovinga CA, Wheless JW. Status Epilepticus. In Dipiro, JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 7th ed. New York: McGraw-Hill; 2008: 953-63.
191. Marik PE, Varon J. The management of status epilepticus. Chest . 2004; 126:582-91. [PubMed 15302747]
192. . Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus. JAMA . 1993; 270:854-9. [PubMed 8340986]
193. Massachusetts General Hospital. Antiepileptic drug pregnancy registry. Boston, MA; Accessed 2011 Oct 7. From the Antiepileptic Drug Pregnancy Registry website. [Web]
194. West-ward Pharmaceuticals. Phenytoin sodium injection prescribing information. Eatontown, NJ; 2018 Dec.
195. Parke-Davis, Division of Pfizer Inc. Dilantin® (extended-release phenytoin sodium capsules) prescribing information. New York, NY; 2018 Dec.
196. Parke-Davis, Division of Pfizer Inc. Dilantin® Infatabs® (phenytoin chewable tablets) prescribing information. New York, NY; 2018 Dec.
197. Taro Pharmaceuticals. Phenytoin suspension prescribing information. Hawthorne, NY; 2017 Nov.
198. Mylan. Phenytek® (extended-release phenytoin sodium capsules) prescribing information. Morgantown, WV; 2018 Feb.
200. Winter ME. Phenytoin and Fosphenytoin. In: Murphy JE, ed. Clinical pharmacokinetics. 2nd ed. 2001:285-303.
201. Briggs GG, Freeman RK, Sumner YJ. Drugs in pregnancy and lactation. 6th ed. 2002:1116-1127.
231. Phillips EJ, Sukasem C, Whirl-Carrillo M et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther . 2018; 103:574-581. [PubMed 29392710]
232. Caudle KE, Rettie AE, Whirl-Carrillo M et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther . 2014; 96:542-8. [PubMed 25099164]
233. Glauser T, Shinnar S, Gloss D et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr . 2016 Jan-Feb; 16:48-61. [PubMed 26900382]
234. Prasad M, Krishnan PR, Sequeira R et al. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev . 2014; :CD003723. [PubMed 25207925]
235. Sánchez Fernández I, Loddenkemper T. Therapeutic choices in convulsive status epilepticus. Expert Opin Pharmacother . 2015; 16:487-500. [PubMed 25626010]
236. Brophy GM, Bell R, Claassen J et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care . 2012; 17:3-23. [PubMed 22528274]
240. Glauser T, Ben-Menachem E, Bourgeois B et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia . 2013; 54:551-63. [PubMed 23350722]
241. French JA, Kanner AM, Bautista J et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology . 2004; 62:1252-60. [PubMed 15111659]
254. Linnebank M, Moskau S, Semmler A et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol . 2011; 69:352-9. [PubMed 21246600]
258. . Drugs for epilepsy. Med Lett Drugs Ther . 2017; 59:121-130. [PubMed 28746301]
259. Lee RH, Lyles KW, Colón-Emeric C. A review of the effect of anticonvulsant medications on bone mineral density and fracture risk. Am J Geriatr Pharmacother . 2010; 8:34-46. [PubMed 20226391]
262. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med . 1998; 338:970-6. [PubMed 9521986]
263. Wiffen PJ, Derry S, Moore RA et al. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev . 2013; :CD010567. [PubMed 24217986]
264. Birse F, Derry S, Moore RA. Phenytoin for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev . 2012; :CD009485. [PubMed 22592741]
265. Johannessen SI, Landmark CJ. Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol . 2010; 8:254-67. [PubMed 21358975]
266. Yager N, Wang K, Keshwani N et al. Phenytoin as an effective treatment for polymorphic ventricular tachycardia due to QT prolongation in a patient with multiple drug intolerances. BMJ Case Rep . 2015; 2015 [PubMed 26071440]
267. Engorrn B, and Flerlage J, eds. The Harriet Lane handbook: a manual for pediatric house officers. 20th ed. Philadelphia, PA: Elsevier: 2015:903-4.
268. von Winckelmann SL, Spriet I, Willems L. Therapeutic drug monitoring of phenytoin in critically ill patients. Pharmacotherapy . 2008; 28:1391-400. [PubMed 18956999]
269. Suzuki Y, Mimaki T, Cox S et al. Phenytoin age-dose-concentration relationship in children. Ther Drug Monit . 1994; 16:145-50. [PubMed 8009561]
270. Pfizer. Cerebyx® (fosphenytoin sodium) injection prescribing information. New York, NY; 2018 Jan.
271. Riviello JJ, Roe EJ, Sapin JI et al. Timing of maintenance phenytoin therapy after intravenous loading dose. Pediatr Neurol . 1991 Jul-Aug; 7:262-5. [PubMed 1930417]