Phenytoin

Mechanism Of Action

Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonicclonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures.

Pharmacokinetics And Drug Metabolism

The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL.

Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19.

A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels.

When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms.

Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5- phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (onethird of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended.

Special Populations

Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations.

Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION).

Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics.

Pediatrics: A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1- 3 mg/kg/min or 50 mg per minute, whichever is slower.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

See "Drug Precautions".

Phenytoin may cause other serious side effects including:

• Softening of your bones (osteomalacia). This can cause broken bones.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The most common side effects of phenytoin include:

• problems with walking and coordination
• slurred speech
• confusion
• dizziness
• trouble sleeping
• nervousness
• tremor
• headache
• nausea
• vomiting
• constipation
• rash

These are not all the possible side effects of phenytoin. For more information, ask your healthcare provider or pharmacist.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Do not stop taking phenytoin without first talking to your healthcare provider.

Stopping phenytoin suddenly can cause serious problems.

Phenytoin can cause serious side effects including:

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase activity and talking (mania)
• other unusual changes in behavior or mood

Watch for early symptoms of suicidal thoughts and actions:

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop taking phenytoin without first talking to a healthcare provider.

• Stopping phenytoin suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

• If you take phenytoin during pregnancy, your baby is at risk for serious birth defects.
• Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
• If you take phenytoin during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.
• All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin. If the decision is made to use phenytoin, you should use effective birth control (contraception) unless you are planning to become pregnant.
• Tell your healthcare provider right away if you become pregnant while taking phenytoin. You and your healthcare provider should decide if you will take phenytoin while you are pregnant.
• Pregnancy Registry: If you become pregnant while taking phenytoin, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

• swelling of your face, eyes, lips, or tongue
• trouble swallowing or breathing
• a skin rash
• hives
• fever, swollen glands, or sore throat that do not go away or come and go
• painful sores in the mouth or around your eyes
• yellowing of your skin or eyes
• unusual bruising or bleeding
• severe fatigue or weakness
• severe muscle pain
• frequent infections or an infection that does not go away

Call your healthcare provider right away if you have any of the symptoms listed above.

Do not take phenytoin if you:

• are allergic to phenytoin or any of the ingredients in phenytoin.
• have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).

Do not drink alcohol while you take phenytoin without first talking to your healthcare provider. Drinking alcohol while taking phenytoin may change your blood levels of phenytoin which can cause serious problems.

Do not drive, operate heavy machinery, or do other dangerous activities until you know how phenytoin affects you. Phenytoin can slow your thinking and motor skills.

Tell your doctor if you are breastfeeding. Phenytoin is excreted in human breast milk. 

If you take too much phenytoin, call your healthcare provider or local Poison Control Center right away.

You should not use this medicine if you are allergic to phenytoin or similar medicines such as ethotoin, fosphenytoin, or mephenytoin, or if you have:

• a history of liver problems caused by phenytoin;

• a heart condition called 2nd or 3rd degree "AV block";

• a history of slow heartbeats that have caused you to faint; or

• a condition for which you also take delavirdine (Rescriptor).

To make sure phenytoin is safe for you, tell your doctor if you have:

• liver disease;

• a history of abnormal heart rhythm found on an EKG (electrocardiograph);

• diabetes;

• a history of depression;

• a history of suicidal thoughts or actions;

• a vitamin D deficiency or any other condition that causes thinning of the bones;

• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system); or

• if you drink large amounts of alcohol.

You may have thoughts about suicide while taking this medicine. Your doctor will need to check your progress at regular visits while you are using phenytoin. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Patients of Asian ancestry may have a higher risk of developing a rare but serious skin reaction to phenytoin. Your doctor may recommend a blood test before you start the medication to determine your risk of this skin reaction.

Seizure control is very important during pregnancy. Do not start or stop taking this medicine without your doctor's advice if you are pregnant. Phenytoin may cause harm to an unborn baby, but having a seizure during pregnancy could harm both mother and baby. Tell your doctor right away if you become pregnant while taking this medicine.

If you become pregnant while taking phenytoin, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of phenytoin on the baby.

Phenytoin can make birth control pills less effective. Ask your doctor about using non hormonal birth control (condom, diaphragm with spermicide) to prevent pregnancy while taking phenytoin.

Phenytoin can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using phenytoin.

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.)

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

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

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

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

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

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

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.)

100 mg 2–4 times daily.b

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

100 mg 2–4 times daily.b

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

100 mg 2–4 times daily.b

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

Maximum 300 mg daily.b

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

Adults

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

Maximum 1.5 g in 24 hours.b

Maximum total IV dose of 1 g.b

Maximum total IV dose of 1 g.b

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

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

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

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.)

May exacerbate porphyria; use with caution.b

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

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

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.)

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

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

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 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

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

Sensitivity Reactions

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

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

Major Toxicities

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

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

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

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

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

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

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

Specific Populations

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

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

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

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

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

Specific Drugs or Laboratory Tests

Take phenytoin only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

phenytoin should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

phenytoin may be used with other seizure medicines. Keep using all of your seizure medicines unless your doctor tells you to stop.

Do not change brands or dosage forms of phenytoin without first checking with your doctor. Different products may not work the same way. If you refill your medicine and it looks different, check with your pharmacist.

Swallow the tablet whole or chew it thoroughly before being swallowed together with a glass of water.

Measure the oral suspension with a marked measuring spoon, oral syringe, or medicine cup. Rinse the dosing spoon or cup with water after each use.

If you are receiving tube feeding preparations, it is best to take phenytoin before or after a feeding.

Dosing

The dose of phenytoin will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of phenytoin. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For seizures:
  • For oral dosage form (extended-release capsules):
    • Adults—At first, 100 milligrams (mg) three times a day or 300 mg once a day. Your doctor may increase your dose as needed. For patients in the clinic or hospital (except with a history of liver or kidney disease), a loading dose of 1000 mg is divided into three doses (400 mg, 300 mg, 300 mg) and given every 2 hours. Then, normal maintenance dose may be started 24 hours after the loading dose.
    • Teenagers and children older than 6 years of age—300 mg per day. Your doctor may adjust your dose as needed.
    • Children 6 years of age and below—Dose is based on body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in two or three divided doses per day. The doctor may adjust the dose as needed.
  • For oral dosage form (suspension):
    • Adults—At first, 5 milliliters (mL) or one teaspoonful three times a day. Your doctor may adjust your dose as needed.
    • Teenagers and children older than 6 years of age—300 mg per day. Your doctor may adjust your dose as needed.
    • Children 6 years of age and below—Dose is based on age and body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in two or three divided doses per day. Your doctor may adjust your dose as needed.
  • For oral dosage form (tablets):
    • Adults—At first, 100 milligrams (mg) three times a day. Your doctor may adjust your dose as needed.
    • Teenagers and children older than 6 years of age—300 mg per day, given in two or three divided doses per day. Your doctor may adjust your dose as needed.
    • Children 6 years of age and below—Dose is based on age and body weight and must be determined by your doctor. At first, 5 milligrams (mg) per kilogram (kg) of body weight given in two or three divided doses per day. The doctor may adjust the dose as needed.

Missed Dose

If you miss a dose of phenytoin, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Increased fraction of unbound phenytoin may occur.

Prevention of early (within 1 week) post-traumatic seizures following traumatic brain injury

Data from a randomized, double-blind, placebo-controlled trial in patients with serious head trauma supports the use of phenytoin to prevent post-traumatic seizures (PTS) in patients who recently (within 1 week) experienced a traumatic brain injury. Phenytoin did not reduce the incidence of late (≥day 8) PTS [Temkin 1990].

Based on the Brain Trauma Foundation's Guidelines for the Management of Severe Traumatic Brain Injury and the American Association of Neurology (AAN) Practice Parameter for Antiepileptic Drug Prophylaxis in Severe Traumatic Brain Injury, phenytoin is effective and recommended to decrease the risk of PTS occurring within the first 7 days of traumatic brain injury.

IV: May be further diluted in NS to a final concentration ≥5 mg/mL; infusion must be completed within 4 hours after preparation. Do not refrigerate.

Concerns related to adverse effects:

• Blood dyscrasias: A spectrum of hematologic effects have been reported (eg, agranulocytosis, leukopenia, granulocytopenia, thrombocytopenia, and pancytopenia with or without bone marrow suppression) and may be fatal; patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage.

• Bone effects: Chronic use of phenytoin has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Chronic use may result in decreased vitamin D concentrations due to hepatic enzyme induction and may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia; monitor as appropriate and consider implementing vitamin D and calcium supplementation.

• Cardiovascular events: [US Boxed Warning]: Phenytoin must be administered slowly. Intravenous administration should not exceed 50 mg/minute in adult patients. In pediatric patients, intravenous administration rate should not exceed 1-3 mg/kg/minute or 50 mg/minute whichever is slower. Hypotension and severe cardiac arrhythmias (eg, heart block, ventricular tachycardia, ventricular fibrillation) may occur with rapid administration; adverse cardiac events have been reported at or below the recommended infusion rate. Cardiac monitoring is necessary during and after administration of intravenous phenytoin; reduction in rate of administration or discontinuation of infusion may be necessary. For nonemergency use, intravenous phenytoin should be administered more slowly; the use of oral phenytoin should be used whenever possible.

• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (some fatal) have been reported; the onset of symptoms is usually within 28 days of treatment, but can occur later. Discontinue phenytoin if there are any signs of rash and evaluate for signs and symptoms of drug reaction with eosinophilia and systemic symptoms (DRESS). Data suggests a genetic susceptibility for serious skin reactions in patients of Asian descent (see "Special populations" below).

• Extravasation: Vesicant (intravenous administration); ensure proper catheter or needle position prior to and during infusion. Avoid extravasation. IV formulation may cause soft tissue irritation and inflammation, and skin necrosis at IV site; avoid IV administration in small veins. The "purple glove syndrome" (ie, discoloration with edema and pain of distal limb) may occur following peripheral IV administration of phenytoin. This syndrome may or may not be associated with drug extravasation. Symptoms may resolve spontaneously; however, skin necrosis and limb ischemia may occur; interventions such as fasciotomies, skin grafts, and amputation (rare) may be required. To decrease the risk of this syndrome, inject phenytoin slowly and directly into a large vein through a large gauge needle or IV catheter; follow with NS flushes through the same needle or IV catheter.

• Hepatotoxicity: Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported. Other manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. Immediately discontinue phenytoin in patients who develop acute hepatotoxicity and do not readminister.

• Hypersensitivity: Consider alternative therapy in patients who have experienced hypersensitivity to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione).

• Lymphadenopathy: May occur (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin disease; cause and effect relationship has not been established.

• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported with some antiepileptic drugs; including phenytoin; monitor for signs and symptoms of possible manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; gradual discontinuation and conversion to alternate therapy may be required.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with underlying cardiac disease; IV use is contraindicated in patients with sinus bradycardia, sinoatrial block, or second and third degree heart block.

• Diabetes: Use with caution in patients with diabetes mellitus; phenytoin may inhibit insulin release and increase serum glucose in patients with diabetes.

• Hepatic impairment: Use with caution in patients with hepatic impairment; use free (unbound) serum concentrations to monitor.

• Hypoalbuminemia: Use with caution in patients with any condition associated with low serum albumin levels, which will increase the free fraction of phenytoin in the serum and, therefore, the pharmacologic response. Use free (unbound) serum concentrations to monitor.

• Hypothyroidism: Use with caution in patients with hypothyroidism; phenytoin may alter thyroid hormone serum concentrations (with chronic administration).

• Porphyria: May cause exacerbation of porphyria; use with caution in patients with porphyria.

• Renal impairment: Use with caution in patients with renal impairment; use free (unbound) serum concentrations to monitor.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Asian ancestry: Asian patients with the variant HLA-B*1502 may be at an increased risk of developing Stevens-Johnson syndrome and/or TEN. Note: Carbamazepine, another antiepileptic with a chemical structure similar to phenytoin, includes in the manufacturer labeling a recommendation to screen patients of Asian descent for the HLA-B*1502 allele prior to initiating therapy; this is not a current recommendation in the phenytoin manufacturer labeling. Patients with a positive result should avoid phenytoin.

• Critically-ill patients: Use with caution in critically ill patients.

• Debilitated patients: Use with caution in patients who are debilitated.

• Elderly: Use with caution in the elderly.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Other warnings/precautions:

• Appropriate use: Not indicated for the treatment of absence seizures or seizures due to hypoglycemia or other metabolic causes.

• Sustained serum concentrations: Plasma concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as delirium, psychosis, or encephalopathy, or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy. Measure plasma phenytoin concentrations at the first sign of acute toxicity; dosage reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, discontinue administration.

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

CBC, liver function; vitamin D status (chronic use); suicidality (eg, suicidal thoughts, depression, behavioral changes); plasma phenytoin concentrations (if available, free phenytoin concentrations should be obtained in patients with renal impairment and/or hypoalbuminemia; if free phenytoin concentrations are unavailable, the adjusted total concentration may be determined based upon equations in adult patients). Trough concentrations are generally recommended for routine monitoring.

Additional monitoring with IV use: Continuous cardiac monitoring (rate, rhythm, blood pressure) and observation during administration recommended; blood pressure and pulse should be monitored every 15 minutes for 1 hour after administration (Meek, 1999); infusion site reactions

Consult individual institutional policies and procedures.

Phenytoin crosses the placenta (Harden and Pennell 2009). An increased risk of congenital malformations and adverse outcomes may occur following in utero phenytoin exposure. Reported malformations include orofacial clefts, cardiac defects, dysmorphic facial features, nail/digit hypoplasia, growth abnormalities including microcephaly, and mental deficiency. Isolated cases of malignancies (including neuroblastoma) and coagulation defects in the neonate (may be life threatening) following delivery have also been reported. Maternal use of phenytoin should be avoided when possible to decrease the risk of cleft palate and poor cognitive outcomes. Polytherapy may also increase the risk of congenital malformations; monotherapy is recommended (Harden and Meader 2009). The maternal use of folic acid throughout pregnancy is recommended to reduce the risk of major congenital malformations (Harden and Pennell 2009). Potentially life-threatening bleeding disorders in the newborn may also occur due to decreased concentrations of vitamin K-dependent clotting factors following phenytoin exposure in utero; vitamin K administration to the mother prior to delivery and the newborn after birth is recommended.

Total plasma concentrations of phenytoin are decreased in the mother during pregnancy; unbound plasma (free) concentrations are also decreased and plasma clearance is increased. Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of phenytoin in order to maintain clinical response; monitoring during pregnancy should be considered (Harden and Pennell 2009). For women with epilepsy who are planning a pregnancy in advance, baseline serum concentrations should be measured once or twice prior to pregnancy during a period when seizure control is optimal. Monitoring can then be continued once each trimester during pregnancy and postpartum; more frequent monitoring may be needed in some patients. Monitoring of unbound plasma concentrations is recommended (Patsalos 2008). In women taking phenytoin who are trying to avoid pregnancy, potentially significant interactions may exist with hormone-containing contraceptives; consult drug interactions database for more detailed information.

Patients exposed to phenytoin during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at https:\\aedpregnancyregistry.org.

Usual Adult Dose for Seizures:

Oral (except suspension) Loading dose: Only when indicated for inpatients.
1 g orally divided in 3 doses (400 mg, 300 mg, 300 mg) given at 2 hour intervals. Then normal maintenance dosage started 24 hours after loading dose.
Initial dose: 100 mg extended release orally 3 times a day.
Maintenance dose: 100 mg orally 3 to 4 times a day. If seizure control is established with divided doses of three 100 mg capsules daily, once-a-day dosage with 300 mg of extended release phenytoin sodium may be considered. Alternatively, the dosage may need to be increased up to 200 mg orally 3 times a day, if necessary.

Suspension: Patients who have received no previous treatment may be started on 125 mg (one teaspoonful) of the suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily may be made, if necessary.

IV: Do not exceed the infusion rate of 50 mg/min.
Loading dose: 10 to 15 mg/kg IV slowly.
Maintenance dose: 100 mg IV every 6 to 8 hours.

IM: Avoid the IM route due to erratic absorption.

Usual Adult Dose for Arrhythmias:

Loading Dose:
1.25 mg/kg IV every 5 minutes. May repeat up to a loading dose of 15 mg/kg, or
250 mg orally 4 times a day for 1 day, then 250 mg twice daily for 2 days

Maintenance Dose:
300 to 400 mg/day orally in divided doses 1 to 4 times a day

Usual Adult Dose for Status Epilepticus:

IV:
Loading dose: Manufacturer recommends 10 to 15 mg/kg by slow IV administration (at a rate not exceeding 50 mg/minute). Alternatively, generally accepted guidelines suggest 15 to 20 mg/kg by slow IV administration (at a rate not exceeding 50 mg/minute).
Maintenance rate: 100 mg orally or IV every 6 to 8 hours
Maximum rate: 50 mg/minute

Maintenance dose: IV or Oral: 100 mg every 6 to 8 hours

Usual Adult Dose for Neurosurgery:

Neurosurgery (prophylactic): 100 to 200 mg IM at about 4 hour intervals during surgery and the immediate postoperative period. (Note: While the manufacturer recommends IM administration, this route may cause severe local tissue destruction and necrosis. Some clinicians recommend the use of fosphenytoin if IM administration is necessary.) If IM administration is not necessary, accepted protocol has been 100 to 200 mg IV at about 4 hour intervals during surgery and the immediate postoperative period.

Usual Pediatric Dose for Seizures:

Status Epilepticus: Loading Dose:
Infants, Children: 15 to 20 mg/kg IV in a single or divided doses

Anticonvulsant: Loading Dose:
All ages: 15 to 20 mg/kg orally (based on phenytoin serum concentrations and recent dosing history). The oral loading dose should be given in 3 divided doses administered every 2 to 4 hours.

Anticonvulsant: Maintenance Dose:
(IV or oral) (Note: May initially divided daily dose into 3 doses/day, then adjust to suit individual requirements.)
Less than or equal to 4 weeks: Initial: 5 mg/kg/day in 2 divided doses
Usual: 5 to 8 mg/kg/day IV in 2 divided doses (may require dosing every 8 hours).
Greater than or equal to 4 weeks: Initial: 5 mg/kg/day in 2 to 3 divided doses
Usual: (may require up to every 8 hour dosing)
6 months to 3 years: 8 to 10 mg/kg/day
4 to 6 years: 7.5 to 9 mg/kg/day
7 to 9 years: 7 to 8 mg/kg/day
10 to 16 years: 6 to 7 mg/kg/day

Usual Pediatric Dose for Arrhythmias:

Greater than 1 year:
Loading Dose: 1.25 mg/kg IV every 5 minutes. May repeat up to a loading dose of 15 mg/kg.
Maintenance Dose: 5 to 10 mg/kg/day orally or IV in 2 to 3 divided doses

Commonly reported side effects of phenytoin include: congenital anomalies. Other side effects include: hepatic necrosis, ataxia, confusion, constipation, depression, dizziness, drowsiness, fatigue, hypertrichosis, mental status changes, myasthenia, nervousness, numbness, tremor, tremor of hands, vertigo, excitement, irritability, mood changes, and restlessness. See below for a comprehensive list of adverse effects.

-ORAL:
Initial dose: 5 mg/kg/day orally in 2 or 3 equally divided doses, with subsequent dosage individualized to a maximum of 300 mg orally daily
-Maintenance dose: 4 to 8 mg/kg. Children over 6 years old and adolescents may require the minimum adult dose (300 mg/day)

-IV:
Loading dose: Do not exceed an infusion rate of 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients

Comments:
-Because of the increased risk of adverse cardiovascular reactions associated with rapid IV administration, the rate should not exceed 1 to 3 mg/kg/min or 50 mg per minute in children, whichever is slower.

Use: For the prevention and treatment of seizures occurring during or following neurosurgery

Data not available