Class: Hydantoins
VA Class: CN400
CAS Number: 57-41-0
Brands: Dilantin, Dilantin Infatabs, Phenytek

Introduction

Phenytoin is a hydantoin-derivative anticonvulsant.^b

Uses for Phenytoin

Tonic-Clonic Seizures

Mainly in the prophylactic management of tonic-clonic (grand mal) seizures with complex symptomatology (psychomotor seizures).^{a b c d}

Partial Seizures

Mainly in the prophylactic management of partial seizures with complex symptomatology (psychomotor and temporal lobe seizures).^{a b c d}

Effective in controlling partial seizures with autonomic symptoms†.^b

Absence (Petit Mal) Seizures

Not recommended for the treatment of pure absence (petit mal) seizures† since the drug may increase the frequency of these seizures; however, may be useful in conjunction with succinimide or oxazolidinedione anticonvulsants in the management of combined absence and tonic-clonic seizures.^b

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Seizures Associated with Neurosurgery

Prevention and treatment of seizures occurring during and following neurosurgery.^{a b}

Status Epilepticus

May be used IV for treatment of status epilepticus; however, use may be limited by its slow onset of action and need for slow administration.^{184 185 186 b c}

Benzodiazepines (e.g., diazepam, lorazepam) generally considered drugs of choice for initial management of status epilepticus; IV phenytoin (or fosphenytoin) usually indicated if seizures continue or recur.^{186 187 188 189 191 192 b}

Concurrent administration with an IV benzodiazepine or short-acting barbiturate may be necessary for rapid control of seizures.¹⁸⁵

Cardiac Arrhythmias

Useful IV in the treatment of ventricular tachycardia† and paroxysmal atrial tachycardia†, particularly when conventional antiarrhythmic agents or cardioversion is ineffective.^b

Useful orally for maintenance therapy in the management of cardiac arrhythmias†.^b

Cardiac Glycoside Intoxication

Drug of choice IV for the treatment of arrhythmias caused by cardiac glycoside intoxication†.^b

Neuropathic Pain

May have beneficial effects in the symptomatic treatment of chronic pain arising from peripheral neuropathic syndromes† (e.g., trigeminal neuralgia†).^b

Phenytoin Dosage and Administration

General

Seizure Disorders

• Carefully and slowly adjust dosage according to individual requirements and response.^b

  Monitor serum phenytoin concentrations if necessary for optimal dosage adjustments.^{185 195}

• When a patient is transferred from phenytoin to another anticonvulsant, gradually reduce the phenytoin dosage over a period of about 1 week while at the same time therapy is instituted with a low dosage of the replacement drug.^b

• When phenytoin replaces phenobarbital or any other barbiturate anticonvulsant, reduce the dosage of the barbiturate gradually over a period of 1 week to prevent withdrawal symptoms.^b

• Withdraw phenytoin slowly to avoid precipitating seizures or status epilepticus.^b

• Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{100 101 102 195} (See Suicidality Risk under Cautions.)

Oral Loading-Dose Regimens

• Therapeutic serum phenytoin concentrations can be achieved more rapidly (in 2–24 hours) by the use of an oral loading-dose regimen.^b

• Various regimens have been suggested, and clinicians should consult published protocols for information on specific regimens.^b (See Pediatric Patients and also Adults under Dosage for suggested regimen.)

• Reserve oral loading-dose regimens for patients in a clinic or hospital setting where serum phenytoin concentrations can be closely monitored.^b

• Patients with a history of renal or liver disease should not receive an oral loading-dose regimen.^b

Administration

Phenytoin and its sodium salt are administered orally.^b

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.^{194 b} Oral route generally preferred for nonemergency use; routinely assess feasibility of oral therapy in patients receiving the drug parenterally.¹⁸⁴

Phenytoin sodium also has been infused IV† cautiously.^{b d HID} (See Dilution under IV Administration.)

Avoid sub-Q or perivascular injection because of risk of soft tissue irritation and inflammation.¹⁸⁵ Administer IM only as a last resort (e.g., during neurosurgery); do not administer IM for treatment of status epilepticus.^{184 b} (See IM Administration.)

Oral Administration

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.^b

Monitor serum phenytoin concentrations as necessary when a patient is switched from extended phenytoin sodium capsules to prompt phenytoin sodium capsules or from a phenytoin sodium to a phenytoin formulation and vice versa.^{195 b}

Do not use oral formulations containing phenytoin as the base (e.g., suspensions, chewable tablets) for once-daily dosing regimens.^b

Minimize loss of phenytoin oral suspension during oral administration via a nasogastric tube (secondary to adherence to PVC tubing) by diluting (e.g., threefold) the suspension 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.^b

IV Administration

Inject IV preferably directly into a large vein through a large-gauge needle or IV catheter.¹⁸⁵ Must administer slowly to minimize cardiac toxicity.¹⁸⁵ (See Rate of Administration.)

Following IV injection, inject 0.9% sodium chloride injection through the same needle or catheter to reduce local venous irritation from alkaline solution.^{b HID}

Monitor ECG, BP, and respiratory status during IV administration.¹⁸⁵

Generally not recommended for use in IV infusions† because of the possibility that precipitation may occur; however, can be infused IV safely provided adequate precautions are taken.^b (See Dilution.)

Dilution

IV infusion† is feasible provided appropriate precautions are taken, such as maintaining an optimal pH (e.g., ≥10 for 1 mg/mL dilutions), using a suitable infusion fluid (i.e., 0.9% sodium chloride injection or lactated Ringer’s), using a sufficiently diluted solution (e.g., <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.^{b d HID}

One suggested technique: Add 1 g to 1 L 0.9% sodium chloride or lactated Ringer’s to provide a concentration of 1 mg/mL; these solutions generally have a pH ≥10 but final pH is not predictable.^{d HID} Infuse IV† with caution; start the infusion immediately after preparation, complete within a relatively short period, and watch closely for possible crystallization.^HID Use a 0.22-mcm inline filter during infusion.^{d HID}

Crystallization generally occurs in more acidic solutions (e.g., dilutions in 5% dextrose), which should not be used.^{e HID} (See Solution Compatibility under Stability.)

Alternatively, fosphenytoin sodium, a prodrug of phenytoin, can be used for IV infusion.^c

Rate of Administration

Adults: ≤50 mg/minute; preferably ≤25–50 mg/minute.^{b g}

Pediatric patients: ≤1–3 mg/kg per minute; preferably, 0.5–1.5 mg/kg per minute.^{b f g}

Neonates: ≤1–3 mg/kg per minute;^HID preferably ≤0.5 mg/kg per minute.^f

IM Administration

Administer IM only as a last resort (e.g., during neurosurgery) because of slow and erratic absorption from IM injection sites and risk of local adverse effects (e.g., pain, necrosis, abscess formation).^{184 194 b} However, do not administer IM for treatment of status epilepticus because of delay in reaching therapeutic drug concentrations.^{185 194} Some experts state that phenytoin should not be administered IM under any circumstance.¹⁸⁴

May be of some value for sustaining established therapeutic plasma concentrations when oral administration is not feasible.^b

Information regarding IM administration for >1 week is lacking; consider alternate routes for administering phenytoin (e.g., gastric intubation) when oral administration is not feasible for >1 week.^b

Fosphenytoin sodium can be administered IM for short-term replacement of oral phenytoin.^b

Dosage

Each 100 mg of phenytoin sodium contains approximately 92 mg of phenytoin; consider the difference when switching from the base to its sodium salt or vice versa.^b

Pediatric Patients

Seizure Disorders

Oral

Usual dosage: Initially, 5 mg/kg or 250 mg/m² daily in 2 or 3 equally divided doses; total dosage ≤300 mg daily.^b

Therapeutic serum concentrations may be achieved more rapidly with an oral loading dose (e.g., 500- to 600-mg oral loading dose, in divided doses, followed by usual maintenance dosage 24 hours after initiating loading dose).^c

Adjust subsequent dosage carefully and slowly according to the patient’s requirements.^b

Neonates, maintenance dosage: Usually, 3–5 mg/kg daily.^g

Infants 1–12 months of age, maintenance dosage: Usually, 4–8 mg/kg daily.^b

Children 1–11 years of age, maintenance dosage: 4–10 mg/kg daily.^g

Adolescents, 12–17 years of age, maintenance dosage: 4–8 mg/kg daily.^g

Status Epilepticus

IV

15–20 mg/kg, at a rate ≤1–3 mg/kg per minute.^b

Preferably, 10–15 mg/kg, at a usual rate of 0.5–1.5 mg/kg per minute (maximum total dose of 20 mg/kg in 24 hours).^b

Replace parenteral administration with oral therapy as soon as possible.^b

Adults

Seizure Disorders

Prompt- and Extended-Release Preparations

Oral

Usual dosage: Initially, 100 mg 3 times daily.^b

A period of 5–10 days may be required to achieve anticonvulsant effects.^b

Increases to >300 mg daily may lead to markedly increased serum phenytoin concentrations; therefore, adjust dosage above this level carefully and slowly.^b

Therapeutic serum concentrations achieved more rapidly with a 1-g oral loading dose given as 400, 300, and 300 mg at 2-hour intervals, followed by usual maintenance dosage 24 hours after initiating loading dose.^b

Increase daily dosage gradually, if necessary, in increments of 100 mg every 2–4 weeks until desired response is achieved.^b

Dosing at 100 mg 4 times daily may benefit some patients, and others may require dosages up to 200 mg 3 times daily.^b

Optimum daily dose: Varies considerably but usually in the range of 4–7 mg/kg (300–600 mg daily for most adults).^{b g}

For patients stabilized on a dosage of 100 mg 3 times daily, once-daily dosing with 300 mg as extended phenytoin sodium capsules may be considered.^b

Do not use prompt phenytoin sodium capsules nor oral phenytoin base suspensions or chewable tablets for once-daily dosing.^b

Status Epilepticus

IV

Initially, manufacturers recommend 10–15 mg/kg, by direct IV administration at a rate ≤50 mg/minute; the initial dose should be followed by IV or oral maintenance doses of 100 mg every 6–8 hours.^b

Preferably, most clinicians recommend 15–18 mg/kg, at a rate ≤25–50 mg/minute (maximum total dose of 1.5 g in 24 hours).^{b g}

Oral therapy should replace parenteral administration as soon as possible.^b

Neurosurgery

IV or IM

100–200 mg at approximately 4-hour intervals during surgery and the immediate postoperative period.^{185 b}

In neurosurgical patients previously stabilized on oral phenytoin therapy, increase the IM dosage by 50% over the previously established oral dosage.^b

First week back on oral therapy, reduce oral dosage to one-half the original oral dosage to avoid drug accumulation resulting from eventual absorption from the IM injection site; monitoring of serum concentrations recommended.^b

Limit IM therapy to 1 week. (See IM Administration under Dosage and Administration.)

Cardiac Arrhythmias

Ventricular Tachycardia

Oral

100 mg 2–4 times daily.^b

IV

100 mg by direct IV injection at 5-minute intervals until the arrhythmia is abolished or undesirable effects appear or until a total of 1 g is given.^b

Paroxysmal Atrial Tachycardia

Oral

100 mg 2–4 times daily.^b

IV

100 mg by direct IV injection at 5-minute intervals until the arrhythmia is abolished or undesirable effects appear or until a total of 1 g is given.^b

Cardiac Glycoside Intoxication

Oral

100 mg 2–4 times daily.^b

IV

100 mg by direct IV injection at 5-minute intervals until the arrhythmia is abolished or undesirable effects appear or until a total of 1 g is given.^b

Prescribing Limits

Pediatric Patients

Seizure Disorders

Oral

Maximum 300 mg daily.^b

Status Epilepticus

IV

Maximum total dose of 20 mg/kg in 24 hours recommended by most clinicians.^b

Adults

Seizure Disorders

Prompt-Release Preparations

Oral

Increases in dosage to >300 mg daily may lead to markedly increased serum phenytoin concentrations; therefore, adjust dosage above this level carefully and slowly.^b

Status Epilepticus

IV

Maximum 1.5 g in 24 hours.^b

Cardiac Arrhythmias

Ventricular Tachycardia

IV

Maximum total IV dose of 1 g.^b

Paroxysmal Atrial Tachycardia

IV

Maximum total IV dose of 1 g.^b

Cardiac Glycoside Intoxication

IV

Maximum IV dose of 1 g.^b Do not use oral loading-dose regimens.^b

Special Populations

Hepatic Impairment

Consider reduced maintenance dosage in hepatic cirrhosis.^g Do not use oral loading-dose regimens.^b

Renal Impairment

Do not use oral loading-dose regimens.^b

End-stage renal impairment: Generally can receive usual loading and maintenance dosages initially, adjusting as necessary.^g

Geriatric Patients

May show early signs of toxicity.^a

Geriatric patients with heart disease: It has been recommended that the drug be given at a rate of 50 mg over 2–3 minutes.^b

Obese Patients

Ideal or nonobese weight probably correlates best with maintenance dosages.^g Loading doses may require adjustment for increased volume of distribution.^g

Pregnancy

Monitor phenytoin therapy closely (phenytoin concentrations may decline) to ensure optimum seizure control.^{g h}

Cautions for Phenytoin

Contraindications

• IV use contraindicated in patients with sinus bradycardia, SA block, second- or third-degree AV block, or Adams-Stokes syndrome.^b

• Known hypersensitivity to phenytoin or any ingredient in the respective formulation or to other hydantoins.^b

Warnings/Precautions

Warnings

Shares the toxic potentials of the hydantoin-derivative anticonvulsants, and the usual precautions of anticonvulsant therapy should be observed.^{b c}

Withdrawal

Abrupt withdrawal can precipitate status epilepticus.^a Reduce dosage, discontinue drug, and/or substitute other anticonvulsants cautiously and slowly.^{195 a b} If allergic or hypersensitivity reaction occurs, may be necessary to more rapidly substitute other anticonvulsants that do not belong to the hydantoin class.¹⁹⁵

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various oral anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).^{100 101 102 195 196} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{100 101 102} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{100 101 102 195}

Closely monitor all patients currently receiving or beginning oral anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behaviors or depression.^{100 101 102 195} Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.¹⁰⁰

Balance risk of suicidality with the risk of untreated illness.^{100 195} Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.^{195 196} If suicidal thoughts or behaviors emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.^{195 196} (See Advice to Patients.)

Porphyria

May exacerbate porphyria; use with caution.^b

Lymphadenopathy

Possible local or generalized lymphadenopathy (e.g., benign lymph node hyperplasia, pseudolymphoma, lymphoma, Hodgkin’s disease).^{185 194 195} May occur with or without manifestations resembling serum sickness (e.g., fever, rash, liver involvement).^{185 194 195}

If lymphadenopathy occurs, differentiate the condition from other types of lymph node pathology and observe patient for an extended period; use alternative anticonvulsants, if possible, for seizure control.^{185 194 195}

IM Injection

Not recommended IM for status epilepticus because of delayed and unpredictable blood concentrations.^b

Cardiovascular Effects

Hypotension if administered too rapidly IV.^b

May cause severe, potentially life-threatening cardiotoxic reactions (e.g., decreased cardiac output, atrial or ventricular conduction depression, ventricular depression).^b May be due in part to propylene glycol (cardiac depressant) in parenteral formulation.^g

Administer IV only with extreme caution to patients with MI, frank or impending CHF, or otherwise damaged myocardium, and in patients in whom a sudden change in BP may lead to serious complications (e.g., those with hypotension or severe myocardial insufficiency).^b Contraindicated in patients with some cardiac conduction disorders.^{185 b} (See Contraindications under Cautions.)

Respiratory Disorders

Administer IV only with extreme caution to patients with respiratory depression.^b

Hepatic Effects

Toxic hepatitis and liver damage (sometimes fatal) have occurred.^{185 b}

Hematologic Effects

Adverse hematologic effects (e.g., thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression), sometimes fatal, reported.^{185 b} (See Lymphadenopathy under Cautions.)

Local Effects

Local soft-tissue reactions (e.g., irritation, inflammation, pain, necrosis, sloughing) reported at site of injection following IV administration; amputation required rarely.^{172 173 174 175 176 177 178 179 180 181 182 184 185} May occur in presence or absence of extravasation.^{172 176 185}

Purple glove syndrome (PGS), characterized by progressive pain, discoloration, and edema of the distal limb, reported in patients receiving peripheral IV injections of phenytoin; may occur with or without extravasation.^{173 174 175 176 177 178 179 180 181 182 184 185 194} Generally mild and self-limiting; however, tissue necrosis and limb ischemia requiring surgical intervention (e.g., fasciotomies, skin grafting, amputation) have occurred.^{173 174 175 176 177 178 179 180 181 182} Possible risk factors include young or advanced age, female gender, use of small-bore IV catheters, preexisting cardiovascular disease, multiple or large doses, and rapid rates of IV infusion.^{172 173 174 175 177 178 179 180 181 182 184}

To minimize risk of PGS or other types of soft-tissue injury, follow appropriate IV administration procedures and precautions.^{172 175 185 194} (See Administration under Dosage and Administration.)Monitor injection sites frequently during and for 72 hours following administration.^{177 182 184} If PGS occurs, discontinue drug immediately, remove IV catheter, and institute appropriate supportive measures (e.g., elevate affected extremity, apply dry heat).^{175 176 177 178 180 184}

Alcohol

Acute alcohol intake may increase serum phenytoin concentrations and chronic alcohol use may decrease serum concentrations.^a

Sensitivity Reactions

Rash

If a rash develops, discontinue phenytoin; do not resume if the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected.^b

Possible increased risk of developing toxic epidermal necrolysis or Stevens-Johnson syndrome in individuals of Asian ancestry who carry the human leukocyte antigen (HLA)-B*1502 allele.^{103 104 105} FDA is evaluating the relationship between use of phenytoin and serious dermatologic reactions in individuals with this allele.¹⁰³ Screening for presence of HLA-B*1502 allele before initiating phenytoin therapy not recommended at this time.¹⁰³ Phenytoin should not be used as an alternative to carbamazepine in HLA-B*1502-positive patients.¹⁰³

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.^b

Structurally Similar Compounds

Caution if using structurally similar compounds (e.g., barbiturates, succinimides, oxazolidinediones) in patients who have experienced phenytoin hypersensitivity.^b

Major Toxicities

Blood Concentrations

Concentrations <25 mcg/mL: Most patients tolerate.^b

Concentrations of 25 mcg/mL: In some patients, are associated with nystagmus, ataxia, and diplopia.^b

Concentrations >30 mcg/mL: Drowsiness and lethargy, and rarely asterixis, may result.^b

Concentrations >50 mcg/mL: Extreme lethargy and, occasionally, comatose states occur.^b

Some patients metabolize phenytoin slowly and thus exhibit signs of toxicity even with low to moderate dosage.^b

IV Phenytoin Toxicity

Most important signs of toxicity associated with the IV use of phenytoin sodium are cardiovascular collapse and/or CNS depression.^b

Hypotension occurs if the drug is administered too rapidly by the IV route.^b

Administer the drug slowly at a rate not exceeding 50 mg/minute to minimize these effects.^b

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 since severe complications are most common in geriatric or debilitated patients.^b

General Precautions

Osteomalacia

Has been associated with phenytoin therapy and is thought to be caused by phenytoin’s interference with vitamin D metabolism.

Hyperglycemia

In large doses, may increase blood glucose concentrations resulting in hyperglycemia and glycosuria.^{a b}

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.^b

Hypertrichosis

Usually confined to extremities but can affect trunk and face and may be irreversible.^b

Slow Metabolizers

A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly; this appears to be genetically determined and may be due to limited enzyme availability and lack of induction.^a

Seizures Due to Hypoglycemia or Other Metabolic Causes

Not indicated for seizures due to hypoglycemia or other metabolic causes; appropriate diagnostic procedures should be performed as indicated.^b

Specific Populations

Pregnancy

Category D.^h

North American Antiepileptic Drug (NAAED) pregnancy registry (for patients) at 888-233-2334 or .^{193 195}

Evidence of significant risk of fetal congenital abnormalities, fetal hydantoin syndrome (consisting of prenatal growth deficiency, microcephaly, and mental deficiency), and hemorrhage at birth.^h

Use during pregnancy only when clearly needed;^b risk-to-benefit ratio generally favors continued use during pregnancy in women whose seizure control depends on the drug.^h

Malignancies, including neuroblastoma, reported rarely in children whose mothers received phenytoin during pregnancy.^b

Coagulation defects reported within 24 hours of birth in neonates born to epileptic women receiving phenobarbital and/or phenytoin; manufacturers recommend administration of vitamin K to the mother prior to delivery and to the neonate after birth to prevent or correct these defects.^{185 194}

Because of altered absorption or metabolism of phenytoin during pregnancy, an increased frequency of seizures may occur in pregnant women receiving the drug.^b

If administered during pregnancy, serum phenytoin concentrations should be monitored and dosage adjusted accordingly to the lowest possible level required to control seizures; however, restoration of the patient’s usual dosage will probably be necessary postpartum.^{b h}

Consider monitoring maternal folate concentration and administering supplemental folic acid early in pregnancy or before conception as indicated.^h

Lactation

Distributed into breast milk.^{b h} However, use generally is considered compatible with breast-feeding.^h

Geriatric Use

Liver is the chief site for biotransformation; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.^a

Hepatic Impairment

Liver is the chief site for biotransformation; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.^a

Renal Impairment

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.^{a b}

Common Adverse Effects

Adverse GI effects include nausea and vomiting, constipation, epigastric pain, dysphagia, loss of taste, anorexia, and weight loss.^b Adverse CNS effects include mental confusion, nystagmus, ataxia, blurred vision, diplopia, toxic amblyopia, dizziness, insomnia, transient nervousness, motor twitching, and headache.^b

Phenytoin frequently produces gingival hyperplasia, especially in children, which occasionally is so severe that it may require surgical removal.^b

Interactions for Phenytoin

Specific Drugs or Laboratory Tests

Drug or Test	Interaction	Comments
Alcohol intake, acute	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Alcohol intake, chronic	May decrease serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Amiodarone	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Antacids, calcium-containing	Calcium ions interfere with GI absorption of phenytoinb	Ingestion times of phenytoin and antacid preparations containing calcium should be staggered in patients with low serum phenytoin concentrations to prevent absorption problemsb
Anticoagulants, coumarin	Efficacy is impaired by phenytoina
Antidepressants, tricyclic	Antidepressant may precipitate seizures in susceptible patientsa	Phenytoin dosage may need adjustmentb
Carbamazepine	May decrease serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Chloramphenicol	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Chlordiazepoxide	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Corticosteroids	Efficacy is impaired by phenytoina
Diazepam	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Dicumarol	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Disulfiram	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Doxycycline	Efficacy impaired by phenytoina
Estrogens	May increase serum phenytoin concentrationsa Efficacy impaired by phenytoina	Monitor and adjust dosage accordingly Observe for possible decreased estrogen efficacy
Furosemide	Efficacy impaired by phenytoina
H2-Antagonists	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Halothane	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Isoniazid	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Methylphenidate	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Oral contraceptives	Efficacy impaired by phenytoina
Phenobarbital	May increase or decrease serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Phenothiazines	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Quinidine	Efficacy impaired by phenytoina	Monitor and adjust dosage accordingly
Reserpine	May decrease serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Rifampin	Efficacy impaired by phenytoina
Salicylates	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Succinimides	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Sucralfate	May decrease serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Sulfonamides	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Test, alkaline phosphatase, serum	May increase serum alkaline phosphatase concentrations
Test, dexamethasone	Phenytoin may cause slight decreases in urinary 17-hydroxycorticosteroids and 17-ketosteroids while urinary 6-β-hydroxycortisol excretion is increasedb Phenytoin may produce lower than normal values for the dexamethasone test
Test, γ-glutamyl transferase (γ-glutamyltranspeptidase, GGT, GGTP)	Phenytoin may produce increased serum γ-glutamyl transferase concentrations
Test, metyrapone	Phenytoin may cause slight decreases in urinary 17-hydroxycorticosteroids and 17-ketosteroids while urinary 6-β-hydroxycortisol excretion is increasedb Phenytoin may produce lower than normal values for the metyrapone testsb
Test, protein-bound iodine (PBI)	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 decreasedb	The 24-hour I 131 thyroidal uptake is apparently not affected Phenytoin may produce increased resin or red cell T3 uptake valuesb 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 discontinuedb
Theophylline	Efficacy impaired by phenytoina	Monitor and adjust dosage accordingly
Tolbutamide	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Trazodone	May increase serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Valproic acid	May increase or decrease serum phenytoin concentrationsa	Monitor and adjust dosage accordingly
Vitamin D	Efficacy impaired by phenytoina

Phenytoin Pharmacokinetics

Absorption

Bioavailability

Studies using Dilantin have shown that phenytoin and its sodium salt are usually completely absorbed from the GI tract.^b

Extended phenytoin sodium capsules, peak: 4–12 hours.^b

Extended phenytoin sodium capsules are formulated so that they undergo slower dissolution with more prolonged absorption than prompt phenytoin sodium capsules.^b

Bioavailability may vary enough among oral phenytoin sodium preparations of different manufacturers to result in toxic serum concentrations or a loss of seizure control; this should be considered before dispensing a brand or dosage form, which differs from that currently taken by a patient.^b Consult FDA’s Approved Drug Products and Therapeutic Equivalence Evaluations (Orange Book).

IM: Absorption may be erratic due to precipitation at injection site.^{b g}

Plasma Concentrations

Anticonvulsant effect: 10–20 mcg/mL.^g

Antiarrhythmic effect: 10–20 mcg/mL.^g (See Blood Concentrations under Major Toxicities for other concentrations.)

Prompt phenytoin capsules, peak: 1.5–3 hours.^b

Extended phenytoin sodium, peak: 4–12 hours.^b

Serum concentration determinations: Obtain 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.^b

Therapeutic plasma concentrations, oral: Achieved after about 1 week of therapy.^b

Following oral administration, therapeutic plasma concentrations can be obtained more rapidly and maintained by administering an initial oral loading dose.^b

Therapeutic plasma concentrations, IV: Within 1–2 hours.^b

Distribution

Extent

Crosses the placenta.^h

Distributed into breast milk.^{b h}

Plasma Protein Binding

Approximately 95%.^b

Elimination

Metabolism

Oxidation by the liver to an inactive metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH).^b

This metabolism is a saturable process; therefore, small increases in dosage may produce substantial increases in plasma phenytoin concentrations.^b

Elimination Route

Capacity-limited elimination, decreasing with increasing concentration.^g

Inactive metabolite (HPPH) is excreted in urine, mainly as the glucuronide;^b approximately 60–75% of the daily dose is excreted in this form.^b

Half-life

Oral: About 22 hours.^b

IV: Ranges from 10–15 hours.^b

Special Populations

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.^b

Stability

Storage

Oral

Tablets

Tight, light- and moisture-resistant containers at room temperature <30°C.^{a b}

Suspension

Tight, light-resistant containers at 20–25°C; avoid freezing.^{b d}

Extended and Prompt Capsules

Tight, light- and moisture-resistant containers at room temperature <30°C, although one manufacturer recommends storage of their extended phenytoin sodium capsules (Phenytek) at 15–30°C.^b

Parenteral

Injection

20–25°C (may be exposed to 15–30°C).^{185 194}

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.^{185 194}

Slight yellowish discoloration of the injection will not affect potency or efficacy, but the injection should not be used if the solution is not clear or if a precipitate is present.^{185 194}

Precipitation of free phenytoin will occur at a pH of ≤11.5.^b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

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).^b

Solution Compatibility^HID

Incompatible
Dextrose 5% in sodium chloride 0.9%
Dextrose 5% in water
Fat emulsion 10%, IV
Ringer’s injection, lactated
Sodium chloride 0.45%e HID
Variable
Sodium chloride 0.9%e HID

Drug Compatibility

Admixture CompatibilityHID

Compatible
Verapamil HCl
Incompatible
Amikacin sulfate
Bretylium tosylate
Dobutamine HCl
Lidocaine HCl
Lincomycin HCl
Meperidine HCl
Metaraminol bitartrate
Morphine sulfate
Nitroglycerin
Norepinephrine bitartrate
Pentobarbital sodium
Procaine HCl
Streptomycin sulfate

Y-site CompatibilityHID

Compatible
Esmolol HCl
Famotidine
Fluconazole
Foscarnet sodium
Tacrolimus
Incompatible
Amphotericin B cholesteryl sulfate complex
Cefepime HCI
Ceftazidime
Ciprofloxacin
Clarithromycin
Diltiazem HCl
Enalaprilat
Fenoldopam mesylate
Fentanyl citrate
Heparin sodium
Heparin sodium with hydrocortisone sodium succinate
Hydromorphone HCl
Lansoprazole
Linezolid
Methadone HCl
Morphine sulfate
Potassium chloride
Propofol
Sufentanil citrate
Theophylline
Vitamin B complex with C

Actions

• Limitation of seizure propagation by reduction of post-tetanic potentiation (PTP), possibly by reducing the passive influx of sodium ions or by increasing the efficiency of the sodium pump so that excess accumulation of intracellular sodium does not occur during tetanic stimulation.^c

• Loss of PTP also prevents cortical seizure foci from detonating adjacent cortical areas.^c

• Exhibits antiarrhythmic properties similar to those of quinidine or procainamide.^b

• Although little effect on the electrical excitability of cardiac muscle, it decreases the force of contraction, depresses pacemaker action, and improves AV conduction, particularly when it has been depressed by digitalis glycosides.^b

• Prolongs the effective refractory period relative to the action potential duration.^b

• May produce hypotension following IV administration.^b

• Little hypnotic activity.^b

Advice to Patients

• A medication guide should be dispensed with every prescription for oral phenytoin formulations; importance of patient reading this information prior to taking the drug.¹⁹⁵

• Risk of suicidality (oral anticonvulsants, including phenytoin, may increase risk of suicidal thoughts or actions in about 1 in 500 people).^{100 195 196} Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).^{100 195}

• Importance of cautioning patients not to use other drugs or alcoholic beverages without first seeking the clinician’s advice.^a

• Importance of instructing patients to contact a clinician if skin rash develops.^a

• Importance of stressing good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.^a

• Advise patient of possible development of hypertrichosis and lymphadenopathy.^{a b}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Warn women of childbearing potential that phenytoin can cause teratogenic effects and neonatal clotting disorders.^{185 194 195} Advise women of childbearing potential to use effective contraceptive methods during phenytoin therapy.¹⁹⁵ Importance of women immediately informing clinicians if they are or plan to become pregnant or plan to breast-feed; discuss therapeutic options with their clinician if pregnancy is planned.¹⁹⁵ Importance of clinicians informing women about the existence of and encouraging enrollment in the NAAED pregnancy registry (see Pregnancy under Cautions).^{193 195}

• Importance of informing patients of other important precautionary information.^{185 194 195} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Phenytoin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Suspension	125 mg/5 mL*	Dilantin-125	Pfizer
			Phenytoin Oral Suspension
	Tablets, chewable	50 mg	Dilantin Infatabs	Pfizer

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Phenytoin Sodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	50 mg/mL*	Phenytoin Sodium Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Phenytoin Sodium, Extended

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	30 mg	Dilantin Kapseals	Pfizer
		100 mg*	Dilantin	Pfizer
			Phenytoin Sodium Extended Capsules
		200 mg*	Phenytek	Mylan
		300 mg*	Phenytek	Mylan

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Phenytoin Sodium, Prompt

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	100 mg*	Phenytoin Sodium Prompt Capsules

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Dilantin 100MG Capsules (PFIZER U.S.): 90/$58.99 or 270/$150.97

Dilantin 125MG/5ML Suspension (PFIZER U.S.): 237/$82.99 or 711/$220.97

Dilantin 30MG Capsules (PFIZER U.S.): 90/$54.99 or 270/$164.96

Dilantin Infatabs 50MG Chewable Tablets (PFIZER U.S.): 90/$53.99 or 270/$142.97

Phenytek 200MG Capsules (MYLAN): 30/$42.89 or 90/$92.36

Phenytek 300MG Capsules (MYLAN): 100/$175.00 or 300/$474.98

Phenytoin 125MG/5ML Suspension (MORTON GROVE PHARMACEUTICALS): 237/$28.98 or 711/$80.96

Phenytoin Sodium Extended 100MG Capsules (SUN PHARMACEUTICAL): 90/$31.99 or 270/$75.98