Brand names: Dilantin, Dilantin Infatabs, Phenytek
Drug class: Hydantoins
VA class: CN400
CAS number: 57-41-0

Medically reviewed by Drugs.com on Oct 18, 2023. Written by ASHP.

Introduction

Hydantoin-derivative anticonvulsant.^b

Uses for Phenytoin

Seizure Disorders

Management of generalized tonic-clonic (grand mal) seizures.^{195 196 197 240}

Management of partial seizures with complex symptomatology (psychomotor and temporal lobe seizures).^{195 196 197 240 258}

Not recommended for treatment of pure absence (petit mal) seizures since the drug may increase frequency of these seizures, but may be used in conjunction with other anticonvulsants when mixed seizure types are present.^b

Seizures Associated with Neurosurgery

Prevention and treatment of seizures occurring during and following neurosurgery.^{194 195}

Status Epilepticus

Used IV for treatment of status epilepticus; however, use may be limited by its slow onset of action and need for slow administration.^{184 186 194 233}

Benzodiazepines (e.g., diazepam, lorazepam, midazolam) are considered drugs of choice for initial treatment of status epilepticus; IV phenytoin (or fosphenytoin) may be used as a second-line agent if seizures continue.^{186 187 188 189 191 192 233 235 236 262}

Concurrent administration with an IV benzodiazepine or short-acting barbiturate will usually be necessary for rapid control of seizures.¹⁹⁴

Fosphenytoin appears to be better tolerated than phenytoin, and some experts state that fosphenytoin is preferred when both drugs are available.²³³

Cardiac Arrhythmias

Has been used IV for treatment of cardiac arrhythmias^{† [off-label]}, particularly ventricular arrhythmias^{† [off-label]}, in patients who do not respond to conventional antiarrhythmic agents or cardioversion.^b However, current use as an antiarrhythmic agent is limited by the drug's narrow therapeutic window, multiple drug interactions, and adverse effect profile.²⁶⁶

Cardiac Glycoside Intoxication

Has been used IV for treatment of arrhythmias caused by cardiac glycoside intoxication^{† [off-label]}, especially in the presence of AV block, because the drug improves conduction through the AV node.^{b d}

Related/similar drugs

gabapentin, clonazepam, lamotrigine, lorazepam, pregabalin, topiramate, diazepam

Phenytoin Dosage and Administration

General

Seizure Disorders

• Carefully and slowly adjust dosage according to individual requirements and response.^b Generally initiate with a low dosage and gradually titrate over several weeks.²⁵⁸

• 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

• Withdraw phenytoin therapy slowly to avoid precipitating seizures or status epilepticus.¹⁹⁵ (See Discontinuance of Therapy under Cautions.)

• Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{100 102 195} (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 Some clinicians have recommended use of oral loading doses to achieve rapid steady-state concentrations when IV administration is not desirable.¹⁹⁵

• 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.^{195 b}

• Patients with a history of renal or liver disease should not receive an oral loading-dose regimen.^{195 b}

Therapeutic Drug Monitoring

• Therapeutic drug monitoring of serum phenytoin concentrations usually recommended to guide dosing.^{194 195 258 268}

• Trough concentrations (obtained just prior to 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

• Usual therapeutic range 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}

• Obtain serum concentrations 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 levels may be achieved.^b

• Patients with renal or hepatic impairment and those with hypoalbuminemia have an increased fraction of unbound (free) phenytoin; monitor free phenytoin concentrations rather than total serum concentrations in these patients.^{195 268}

Administration

Usually administered orally for management of seizure disorders;^{195 196 197 198} may be administered parenterally if oral administration temporarily not possible.¹⁹⁴

Administer by slow IV injection or IV infusion for treatment of status epilepticus.¹⁹⁴

IM administration generally not recommended because of risk of necrosis, abscess formation, and erratic absorption.^{184 194} (See IM Administration under Dosage and Administration.)

Because parenteral administration of phenytoin is associated with more frequent and severe complications, oral route generally preferred for maintaining therapeutic concentrations of the drug during nonemergency situations; routinely assess feasibility of oral therapy in patients receiving the drug parenterally.^{184 194}

Oral Administration

Administer orally as chewable tablets, oral suspension, or extended-release capsules.^{195 196 197 198}

Only extended-release phenytoin sodium capsules should be used for once-daily dosing regimens.^{195 198} 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} Carefully monitor serum phenytoin concentrations whenever there is a change in dosage form or preparation.^{195 198}

Suspension

Administer using a calibrated measuring device; a household teaspoon or tablespoon is not adequate.¹⁹⁷

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

Administer by slow IV injection or IV infusion.¹⁹⁴

To prevent local tissue irritation, administer directly into a large peripheral or central vein through a large-gauge IV catheter.¹⁹⁴ (See Local Toxicity under Cautions.) Use a 0.22–0.55-µm inline filter during infusion.¹⁹⁴ Must administer slowly to minimize cardiac toxicity.¹⁹⁴ (See Rate of Administration.)

Prior to administration, flush IV catheter with sterile saline to check patency.¹⁹⁴ Following administration, flush IV catheter again with saline to reduce local venous irritation from the alkaline solution.¹⁹⁴

Monitor ECG, BP, and respiratory status during IV administration.¹⁹⁴

Dilution

To prepare solution for IV infusion, dilute commercially available phenytoin sodium injection with 0.9% sodium chloride injection to a final concentration of no less than 5 mg/mL.¹⁹⁴ Start infusion immediately after preparation of the solution and complete administration within 1–4 hours.¹⁹⁴ (See Storage under Stability.)

Crystallization generally occurs in more acidic solutions (e.g., dilutions in 5% dextrose), which should not be used.^{194 HID} (See Solution Compatibility under Stability.)

Rate of Administration

Manufacturer states that 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.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 generally not recommended because of unreliable absorption and local adverse effects (e.g., pain, necrosis, abscess formation).^{184 195} Some experts state that phenytoin should not be administered IM under any circumstance; if IM administration is needed (e.g., when IV access not possible), IM fosphenytoin is preferred.^{184 270}

Do not administer IM for treatment of status epilepticus because of delay in reaching therapeutic drug concentrations.¹⁹⁴

Patients transitioning from oral to an equal dosage of IM phenytoin may experience a 50–60% decrease in peak plasma phenytoin concentrations as a result of slower IM absorption.¹⁹⁴ If IM administration is necessary, must increase dosage by 50% over previously established oral dosage to maintain therapeutic serum phenytoin concentrations; reduce dosage once oral therapy is resumed.¹⁹⁴ (See Dosage under Dosage and Administration.)

Experience with IM administration for >1 week is lacking; monitor serum phenytoin concentrations.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); consider the difference when switching from the free acid to sodium salt form or vice versa.^{194 195 196 197 198}

Pediatric Patients

Seizure Disorders

Oral

Recommended initial dosage is 5 mg/kg daily in 2 or 3 equally divided doses (as chewable tablets, extended-release capsules, or oral suspension).^{195 196 197 198 267} Adjust dosage based on individual requirements up to a maximum of 300 mg daily in divided doses.^{195 196 197 198 258}

A period of 7–10 days may be required to achieve steady-state concentrations; any change in dosage should not be made sooner than this interval.¹⁹⁵

Usual maintenance dosage in pediatric patients is 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 >6 years of age and adolescents may require minimum adult dosage of 300 mg daily.^{195 196 197 198}

Some clinicians state that usual daily maintenance dosage (administered in 2 or 3 divided doses) 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 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).^b

IV

When oral therapy is not feasible, may temporarily administer IV at the same total daily dosage.¹⁹⁴

Serum phenytoin concentrations may increase slightly when IV phenytoin is substituted for extended-release capsules since bioavailability of the capsules is about 90%.¹⁹⁴

If IV phenytoin is used in a nonemergent situation (e.g., prevention of seizures during neurosurgery), manufacturer states IV loading dose of 15–20 mg/kg will usually produce serum concentrations within generally accepted therapeutic range of 10–20 mcg/mL.¹⁹⁴ The rate of IV administration should not exceed 1–3 mg/kg per minute (or 50 mg/minute, whichever is slower); however, slower rates recommended to minimize risk of cardiovascular toxicity.¹⁹⁴ Following loading dose, administer maintenance IV or oral doses every 6–8 hours.¹⁹⁴

IM

Generally should not be administered IM; if IM administration required, dosage adjustment is necessary to maintain therapeutic serum concentrations.¹⁹⁴

Increase IM dosage by 50% over previously established oral dosage.¹⁹⁴ To avoid drug accumulation from eventual absorption from IM sites, reduce dosage to one-half the original oral dosage (one-third of the IM dosage) for the first week back on oral therapy.¹⁹⁴

Monitoring of serum concentrations is recommended.¹⁹⁴ Experience with IM therapy for periods >1 week is lacking.¹⁹⁴

Status Epilepticus

IV followed by IV/Oral

Manufacturer states IV 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; administer slowly at a rate not exceeding 1–3 mg/kg per minute (or 50 mg/minute, whichever is slower).¹⁹⁴

Some clinicians recommend initial IV dose of 20 mg/kg (administered at a rate not exceeding 1 mg/kg per minute); an additional dose of 5–10 mg/kg may be given after 10 minutes if seizures continue.^{236 262} However, individual requirements may vary, and as much as 30 mg/kg may be required in some patients for adequate seizure control.^{233 262 271}

Some clinicians recommend maximum total dose of 1.5 g in 24 hours for the loading dose.²⁶⁷

Following loading dose, administer IV or oral maintenance doses every 6–8 hours.¹⁹⁴

Because of required slow rate of IV phenytoin administration, concurrent use of an IV benzodiazepine usually is necessary for rapid control of seizures.¹⁹⁴

Monitor serum concentrations when IV phenytoin is used for status epilepticus; however, do not delay treatment to measure serum concentrations.^{194 262}

Cardiac Glycoside Intoxication

IV followed by IV/Oral

For arrhythmias secondary to cardiac glycoside intoxication, some clinicians recommend IV loading doses of 1.25 mg/kg every 5 minutes up to a total of 15 mg/kg, and IV or oral maintenance doses of 5–10 mg/kg daily in divided doses every 8–12 hours.²⁶⁷

Adults

Seizure Disorders

Oral

Recommended initial dosage in patients who have not previously received the drug is 100 mg 3 times daily (as chewable tablets or extended-release capsules) or 125 mg (5 mL) 3 times daily (as the oral suspension).^{195 196 197 198} Adjust dosage based on individual requirements up to a maximum of 200 mg 3 times daily (for chewable tablets or extended-release capsules) or 625 mg (25 mL) daily (for oral suspension).^{195 196 197 198}

May gradually increase daily dosage in increments of 100 mg every 2–4 weeks until desired response is obtained.^b Some experts recommend that dosage adjustments above 300 mg daily be made in 25- or 30-mg increments.²⁵⁸

A period of 7–10 days may be required to achieve steady-state concentrations; any change in dosage should not be made sooner than this interval.¹⁹⁵

For patients receiving extended-release phenytoin sodium capsules who are stabilized on a dosage of 100 mg 3 times daily, may consider once-daily dosing with 300 mg as extended-release phenytoin sodium capsules.^{195 198} Do not use oral suspension or chewable tablets for once-daily dosing.^{195 196 198}

Optimum daily dosage varies considerably, but usually in the range of 300–400 mg daily for most adults.^{195 196 198 200 258}

Therapeutic serum concentrations may be 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.^{195 196 198} Reserve oral loading-dose regimens for patients in a clinic or hospital setting where serum phenytoin concentrations can be closely monitored.^{195 196 198}

IV

When oral therapy is not feasible, may temporarily administer IV at same total daily dosage.¹⁹⁴

Serum phenytoin concentrations may increase slightly when IV phenytoin is substituted for extended-release capsules since bioavailability of the capsules is about 90%.¹⁹⁴

If IV phenytoin is used in a nonemergent situation (e.g., prevention of seizures during neurosurgery), manufacturer states that a loading dose of 10–15 mg/kg should be administered slowly.¹⁹⁴ The rate of IV administration should not exceed 50 mg/minute; however, slower rates recommended to minimize risk of cardiovascular toxicity.¹⁹⁴ Following loading dose, administer IV or oral maintenance doses every 6–8 hours.¹⁹⁴

IM

Generally should not be administered IM; if IM administration required, dosage adjustment is necessary to maintain therapeutic serum concentrations.¹⁹⁴

Increase IM dosage by 50% over previously established oral dosage.¹⁹⁴ To avoid drug accumulation from eventual absorption from IM sites, reduce dosage to one-half the original oral dosage (one-third of the IM dosage) for the first week back on oral therapy.¹⁹⁴

Monitoring of serum concentrations is recommended.¹⁹⁴ Experience with IM therapy for periods >1 week is lacking.¹⁹⁴

Status Epilepticus

IV followed by IV/Oral

Manufacturer recommends IV loading dose of 10–15 mg/kg, administered slowly at a rate not exceeding 50 mg/minute.¹⁹⁴

Some clinicians recommend initial IV dose of 20 mg/kg (administered at a rate not exceeding 50 mg/minute); an additional dose of 5–10 mg/kg may be given after 10 minutes if seizures continue.^{236 262} However, individual requirements may vary, and as much as 30 mg/kg may be required in some patients for adequate seizure control.^{233 262 271}

Some clinicians recommend maximum total dose of 1.5 g in 24 hours for the loading dose.²⁶⁷

Following loading dose, administer IV or oral maintenance doses every 6–8 hours.¹⁹⁴

Because of required slow rate of IV phenytoin administration, concurrent use of an IV benzodiazepine usually is necessary for rapid control of seizures.¹⁹⁴

Monitor serum concentrations when IV phenytoin is used for status epilepticus; however, do not delay treatment to measure serum concentrations.^{194 262}

Cardiac Arrhythmias

Ventricular Tachycardia† [off-label]

Oral

100 mg 2–4 times daily has been given.^b

IV

100 mg 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.^b

Cardiac Glycoside Intoxication† [off-label]

IV followed by PO

For arrhythmias secondary to cardiac glycoside intoxication, some clinicians recommend IV loading doses of 1.25 mg/kg every 5 minutes up to a total of 15 mg/kg, and an oral maintenance regimen consisting of 250 mg 4 times daily for 1 day, then 250 mg every 12 hours for 2 days, then 300–400 mg daily (in divided or once-daily doses).²⁶⁷

Prescribing Limits

Pediatric Patients

Seizure Disorders

Oral

Maximum 300 mg daily.^{195 196 197 198 258}

Adults

Seizure Disorders

Oral

Chewable tablets and extended-release capsules: Manufacturers state maximum of 200 mg 3 times daily.^{195 196 198}

Oral suspension: Manufacturers state maximum of 625 mg (25 mL) daily.¹⁹⁷

Special Populations

Hepatic Impairment

Consider reduced maintenance dosage in patients with hepatic cirrhosis.²⁰⁰

Do not use oral loading-dose regimens.¹⁹⁵

Renal Impairment

Do not use oral loading-dose regimens.¹⁹⁵

End-stage renal impairment: Generally can receive usual loading and maintenance dosages initially, adjusting as necessary.²⁰⁰

Geriatric Patients

Lower doses or less frequent dosing may be required in geriatric patients.¹⁹⁵

Obese Patients

Ideal or nonobese weight probably correlates best with maintenance dosages.²⁰⁰ Loading doses may require adjustment for increased volume of distribution.²⁰⁰

Pregnancy

Monitor serum phenytoin concentrations closely (concentrations may decline and protein binding may change) and adjust dosage as necessary.^{195 200 201} (See Pregnancy under Cautions.) Restoration of original dosage will probably be necessary postpartum.^{195 201}

Cautions for Phenytoin

Contraindications

• IV use contraindicated in patients with sinus bradycardia, SA block, second- or third-degree AV block, or Adams-Stokes syndrome.¹⁹⁴

• Concomitant use with delavirdine.^{194 195}

• History of prior acute hepatotoxicity with phenytoin.¹⁹⁵

• Known hypersensitivity to phenytoin, any ingredient in the formulation, or other hydantoins.^{194 195}

Warnings/Precautions

Warnings

Cardiovascular Toxicity

Rapid IV administration has caused severe hypotension and cardiac arrhythmias, including bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation; sometimes resulted in asystole, cardiac arrest, and death.¹⁹⁴

Severe complications reported more commonly in critically ill patients, elderly patients, and those with hypotension and severe myocardial insufficiency.¹⁹⁴

Administer IV with extreme caution in patients with respiratory depression, MI, frank or impending CHF, or otherwise damaged myocardium, and in patients in whom a sudden change in BP may lead to serious complications.^b

Do not exceed recommended rates of administration.¹⁹⁴ (See Boxed Warning.) Risk of toxicity increases with infusion rates above recommended rates; however, cardiac events also can occur at or below these rates.¹⁹⁴

Carefully monitor cardiac and respiratory function during and after IV administration; reduce rate of administration or discontinue drug if necessary.¹⁹⁴

IV use contraindicated in patients with cardiac conduction disorders because of the drug's effect on ventricular automaticity.¹⁹⁴ (See Contraindications under Cautions.)

Sensitivity Reactions

Serious Dermatologic Reactions

Serious dermatologic reactions, including acute generalized exanthematous pustulosis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), reported.^{195 196 197}

Discontinue phenytoin at the first sign of a rash unless it is clearly not drug related; do not resume if SJS/TEN is suspected.^{195 196 197}

Pharmacogenomic Considerations in the Development of Cutaneous Reactions

Limited data suggest an increased risk of SJS/TEN 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 presence of HLA-B*1502 and risk of SJS/TEN in patients with Chinese ancestry receiving carbamazepine; although evidence more limited, HLA-B*1502 also associated with SJS/TEN in such patients receiving structurally similar anticonvulsants such as phenytoin.^{195 196 197 231 232}

Phenytoin generally should not be used as an alternative to carbamazepine in HLA-B*1502-positive patients.^{195 196 197 231}

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) reported; can be fatal or life-threatening.^{195 196 197} Clinical presentation is variable but typically includes fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement (e.g., eosinophilia, hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).^{195 196 197}

If manifestations of DRESS occur, evaluate patient immediately.^{195 196 197} If an alternative etiology cannot be identified, discontinue phenytoin.^{195 196 197}

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and angioedema, reported.^{195 196 197} If manifestations (e.g., facial, perioral, or upper airway swelling) occur, discontinue drug immediately.^{195 196 197} (See Contraindications under Cautions.)

Consider alternatives to structurally similar compounds such as carboxamides, barbiturates, succinimides, and oxazolidinediones in patients who have experienced phenytoin hypersensitivity.^{195 196 197} Also consider alternatives to phenytoin if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family member.^{195 196 197}

General Precautions

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%).^{100 102 195 196} Increased suicidality risk was observed as early as 1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{100 102} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{100 102 195}

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.^{100 102 195}

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.)

Discontinuance of Therapy

Abrupt withdrawal can increase seizure frequency, including status epilepticus; reduce dosage, discontinue therapy, or substitute with another anticonvulsant gradually.¹⁹⁵ In the event of an allergic or hypersensitivity reaction, may consider more rapid substitution with an alternative non-hydantoin anticonvulsant.¹⁹⁵

Hepatotoxicity

Acute hepatotoxicity, including infrequent cases of acute hepatic failure, reported.¹⁹⁵ May or may not occur in association with DRESS.¹⁹⁵ (See Multi-organ Hypersensitivity under Cautions.)

If acute hepatotoxicity occurs, discontinue phenytoin immediately and do not resume.¹⁹⁵

Hematologic Effects

Adverse hematologic effects (e.g., thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression), sometimes fatal, reported.^{195 b}

Local or generalized lymphadenopathy (e.g., benign lymph node hyperplasia, pseudolymphoma, lymphoma, Hodgkin's disease) also reported, although a causal relationship not established.¹⁹⁵ Lymph node involvement may or may not occur in association with DRESS.¹⁹⁵ (See Multi-organ Hypersensitivity under Cautions.) If lymphadenopathy develops, further evaluate to establish a differential diagnosis; switch to an alternative anticonvulsant if possible.¹⁹⁵

May exacerbate porphyria; use with caution in patients with this condition.¹⁹⁵

Local Toxicity

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} May occur in presence or absence of extravasation.^{172 176}

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.^{173 174 175 176 177 178 179 180 181 182 184 194} 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.^{172 175 194} (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}

Effect on Vitamin D and Bone Metabolism

Long-term use in patients with epilepsy associated with decreased bone mineral density (BMD) and related bone effects (e.g., osteopenia, osteoporosis, osteomalacia, fractures).^{195 259} Thought to be caused by phenytoin’s interference with vitamin D metabolism.^{195 259}

Consider monitoring vitamin D concentrations and other measures of bone health in patients receiving long-term therapy with the drug.^{195 259}

Hyperglycemia

In large doses, may increase blood glucose concentrations resulting in hyperglycemia and glycosuria.^{195 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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.^{195 201}

Evidence of substantial risk of congenital malformations, fetal hydantoin syndrome (e.g., craniofacial abnormalities, nail and digital hypoplasia, prenatal growth deficiency, microcephaly, cognitive deficiency), and other developmental toxicity.^{195 201}

Life-threatening bleeding disorders secondary to decreased concentrations of vitamin K-dependent clotting factors may occur in neonates exposed to phenytoin in utero; administration of vitamin K to the mother prior to delivery and to the neonate after birth may prevent these complications.¹⁹⁵

Slow Metabolizers

A small percentage of individuals have been shown to metabolize phenytoin slowly; this appears to be genetically determined and may be due to limited enzyme availability and lack of induction.¹⁹⁵

CNS Toxicity

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 b}

Check serum phenytoin concentrations immediately at the first sign of toxicity.¹⁹⁵ Reduce dosage if serum concentrations are excessive; if symptoms persist, discontinue therapy.¹⁹⁵

Specific Populations

Pregnancy

May cause fetal harm if used during pregnancy.^{195 201} (See Fetal/Neonatal Morbidity and Mortality under Cautions.) However, risk-to-benefit ratio generally favors continued use during pregnancy in women whose seizure control depends on the drug.^{201 258}

Malignancies, including neuroblastoma, reported rarely in children whose mothers received phenytoin during pregnancy.¹⁹⁵

Because of altered pharmacokinetics of phenytoin during pregnancy, increased frequency of seizures may occur.¹⁹⁵ Monitor serum phenytoin concentrations and adjust dosage accordingly; restoration of the patient’s usual dosage will probably be necessary postpartum.^{195 201} Because of altered protein binding, monitor free phenytoin fraction in pregnant women.¹⁹⁵

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

Lactation

Distributed into milk.^{195 201} However, use generally considered compatible with breast-feeding.²⁰¹ Consider known benefits of breast-feeding 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

Geriatric Use

Clearance may be reduced in geriatric patients.¹⁹⁵

Geriatric patients may show early signs of toxicity.¹⁹⁵ Some adverse CNS effects (e.g., drowsiness, ataxia, diplopia) are more likely to occur at lower serum phenytoin concentrations in geriatric patients than in other patients.²⁵⁸ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Principally metabolized by the liver; patients with impaired liver function may show early signs of toxicity.¹⁹⁵

Since fraction of free phenytoin may be increased in patients with hepatic impairment, monitor free phenytoin concentration rather than total serum concentration in such patients.^{195 268}

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.^b

Since fraction of free phenytoin may be increased in patients with renal impairment, monitor free phenytoin concentration rather than total serum concentration in such patients.^{195 268}

Patients with Hypoalbuminemia

Since fraction of free phenytoin may be increased in patients with hypoalbuminemia, monitor free phenytoin concentration rather than total serum concentration in such patients.^{195 268}

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

Drug Interactions

Involved in multiple drug interactions because of extensive plasma protein binding, saturable metabolism, and potent hepatic enzyme-inducing properties.¹⁹⁵

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolized by CYP2C9 and CYP2C19.¹⁹⁵ Potent inducer of CYP isoenzymes.¹⁹⁵

Concomitant use with drugs that inhibit or induce CYP2C9 and CYP2C19 can alter serum phenytoin concentrations.^{195 258} Particularly susceptible to inhibitory interactions because of saturable metabolism.¹⁹⁵ If a drug interaction is suspected, monitor serum phenytoin concentrations and adjust dosage of phenytoin as necessary.¹⁹⁵

Because of its potent CYP-inducing properties, phenytoin can decrease plasma concentrations and possibly reduce efficacy of many drugs.^{195 241 258} Dosage adjustment of the concomitant drug may be necessary when phenytoin is added to or withdrawn from concomitant therapy.¹⁹⁵

Protein-bound Drugs

Phenytoin is extensively bound to plasma proteins.¹⁹⁵ Potential for phenytoin to displace or to be displaced by other protein-bound drugs.¹⁹⁵

Specific Drugs or Laboratory Tests

Phenytoin Pharmacokinetics

Absorption

Bioavailability

Studies using Dilantin have shown that phenytoin and its sodium salt are usually completely absorbed from the GI tract.^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 that 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.^{200 b}

Plasma Concentrations

Anticonvulsant effect: 10–20 mcg/mL.²⁰⁰

Antiarrhythmic effect: 10–20 mcg/mL.²⁰⁰

Extended-release phenytoin sodium, peak: 4–12 hours.^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.²⁰¹

Distributed into milk.^{201 b}

Elimination

Plasma Protein Binding

Approximately 95%.^b

Metabolism

Metabolized by hepatic CYP enzymes.¹⁹⁵ Metabolized 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

A small percentage of individuals metabolize phenytoin slowly.¹⁹⁵ (See Slow Metabolizers under Cautions.)

Elimination Route

Capacity-limited elimination, decreasing with increasing concentration.²⁰⁰

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

20–25°C; protect from moisture.¹⁹⁶

Suspension

20–25°C; protect from light and avoid freezing.¹⁹⁷

Extended-release Capsules

Tight, light- and moisture-resistant containers at 20–25°C.^{195 198}

Parenteral

Injection

20–25°C (may be exposed to 15–30°C).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.^b

Compatibility

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 CompatibilityHID

Drug Compatibility

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

• Importance of advising patients to read the patient information (medication guide).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 immediately reporting early manifestations of hematologic, dermatologic, hypersensitivity, or hepatic reactions such as fever, sore throat, infection, rash, mouth ulcers, easy bruising, lymphadenopathy, facial swelling, petechial or purpuric hemorrhage, anorexia, nausea/vomiting, or jaundice.¹⁹⁵ Advise patients to report these manifestations even if they are mild in severity or occur after extended use.¹⁹⁵

• Importance of seeking immediate medical care if signs or symptoms of angioedema (e.g., facial, perioral, or upper airway swelling) occur.¹⁹⁵

• Risk of severe hypotension and cardiac arrhythmias with rapid IV administration; advise patients to report any possible manifestations to their clinician.¹⁹⁵

• Risk of dizziness, gait disturbance, decreased coordination, and somnolence; advise patients to avoid driving, operating machinery, or performing hazardous tasks until such effects on the individual are known.¹⁹⁵

• Importance of not abruptly discontinuing therapy.¹⁹⁵

• Importance of cautioning patients not to use other drugs or alcoholic beverages without first seeking the clinician’s advice.¹⁹⁵

• Importance of stressing good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.¹⁹⁵

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

• Warn women of childbearing potential that phenytoin can cause teratogenic effects and neonatal clotting disorders.^{194 195} Advise women of childbearing potential to use effective contraceptive methods during phenytoin therapy.¹⁹⁵ Importance of women 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.^{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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

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

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