Usual Adult Dose for Seizures

ORAL ADMINISTRATION: Extended-Release Capsules:

• Initial dose (phenytoin-naive): 100 mg orally 3 times a day
• Adjust dose as needed
• Maintenance dose: 100 mg orally 3 or 4 times a day; increases to 600 mg 3 times a day may be needed for some patients
• For patients with established seizure control at 100 mg orally 3 times a day, may consider 300 mg orally once a day

NOTE: Only extended-release capsules are recommended for once daily dosing; inherent differences in dissolution characteristics and resultant absorption rates due to manufacturing procedures and/or dosage forms preclude this recommendation for other phenytoin products; when a change in dose form or brand is prescribed, careful monitoring of phenytoin serum levels is advised.

ORAL LOADING DOSE (For Situations Requiring Rapid Steady-State Serum Levels) 1 g divided into 3 doses (400 mg, 300 mg, 300 mg) administered at 2-hour intervals

• Maintenance dose should be started 24 hours after the loading dose with frequent serum level determinations

NOTE: Use of an oral loading dose should be reserved for patients in a clinic or hospital setting where phenytoin serum levels can be closely monitored; patients with a history of renal or liver disease should not receive the oral loading regimen

ORAL ADMINISTRATION: Chewable Tablets:

• Initial dose (phenytoin-naive): 100 mg orally 3 times a day; tablets can be chewed thoroughly before swallowing or swallowed whole
• Adjust dose as needed; most adults can be maintained on 300 to 400 mg/day in divided doses
• Maximum dose: 600 mg/day

ORAL ADMINISTRATION: Oral Suspension:

• Initial dose (phenytoin-naive): 125 mg orally 3 times a day; adjust dose as needed
• Maximum dose: 625 mg/day

PARENTERAL USE: When oral administration is not possible
IV LOADING DOSE: 10 to 15 mg/kg IV at a rate not to exceed 50 mg per minutes; slower administration rates are recommended to minimize the cardiovascular adverse reactions; monitor closely during and after dosing

• Maintenance Dose: 100 mg IV every 6 to 8 hours

Parenteral Substitution for Oral Phenytoin Therapy: When substituting oral phenytoin with IV use, may substitute at the same total daily dose; oral capsules are approximately 90% bioavailable; IV is 100% bioavailable, therefore, serum phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy

IM ADMINISTRATION:

• Ordinarily not given IM because of the risk of necrosis, abscess formation, and erratic absorption; if IM administration is required, dosage adjustments are necessary to maintain therapeutic plasma levels.
• IM dose is generally 50% greater than the oral dose; with return to oral administration, the dose should be reduced by 50% of the original oral dose for 1 week to prevent excessive plasma levels due to sustained release from IM tissue sites.

Comments:

• When switching between phenytoin formulations, it is important to understand that the free acid form of phenytoin is used in the oral suspension and chewable tablets, while the extended-release capsules and parenteral formulations contain the sodium salt; there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt and dose adjustments and serum level monitoring may be necessary when switching products.
• For IV administration, consult Administration Advice for important guidance.

Uses: For the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

Usual Adult Dose for Status Epilepticus

LOADING DOSE: 10 to 15 mg/kg by slow IV infusion, not to exceed 50 mg/min
MAINTENANCE DOSE: 100 mg orally or IV every 6 to 8 hours

Comments:

• Electrocardiogram and blood pressure should be monitored continuously during and after therapy; observe for signs of respiratory depression.
• Monitor phenytoin plasma levels.
• Other measures, including concomitant administration of an IV benzodiazepine such as diazepam, or an IV short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of phenytoin.
• If IV administration does not terminate seizures, the use of other anticonvulsants, IV barbiturates, general anesthesia and other appropriate measures should be considered.
• For IV administration, consult Administration Advice for important guidance.
• IM administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours.

Use: For the control of generalized tonic-clonic status epilepticus.

Usual Adult Dose for Seizure Prophylaxis During or Following Neurosurgery

IV Use should be reserved for use when ORAL Administration is not possible

ORAL ADMINISTRATION: Extended-Release Capsules:

• Initial dose (phenytoin-naive): 100 mg orally 3 times a day
• Adjust dose as needed
• Maintenance dose: 100 mg orally 3 or 4 times a day; increases to 600 mg 3 times a day may be needed for some patients

ORAL LOADING DOSE (For Situations Requiring Rapid Steady-State Serum Levels) 1 g divided into 3 doses (400 mg, 300 mg, 300 mg) administered at 2-hour intervals

• Maintenance dose should be started 24 hours after the loading dose with frequent serum level determinations

ORAL ADMINISTRATION: Chewable Tablets:

• Initial dose (phenytoin-naive): 100 mg orally 3 times a day; tablets can be chewed thoroughly before swallowing or swallowed whole
• Adjust dose as needed; most adults can be maintained on 300 to 400 mg/day in divided doses
• Maximum dose: 600 mg/day

IV ADMINISTRATION:
LOADING DOSE: 10 to 15 mg/kg by slow IV infusion, not to exceed 50 mg/min
MAINTENANCE DOSE: 100 mg orally or IV every 6 to 8 hours

Comments:

• Electrocardiogram and blood pressure should be monitored continuously during and after therapy; observe for signs of respiratory depression.
• Monitor phenytoin plasma levels.
• For IV administration, consult Administration Advice for important guidance.

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

Usual Pediatric Dose for Seizures

IV Use should be reserved for use when ORAL Administration is not possible

ORAL ADMINISTRATION: Extended-Release Capsules; Chewable Tablets; Oral Suspension:

• Initial dose (phenytoin-naive): 5 mg/kg/day orally in equally divided doses 2 to 3 times a day; adjust dose as needed
• Maintenance dose: 4 to 8 mg/kg/day in equally divided doses; those over 6 years old may require up to 300 mg per day

NOTE: If the daily dosage cannot be divided equally, the larger dose should be given before retiring

IV ADMINISTRATION:
LOADING DOSE: 15 to 20 mg/kg IV at a rate not to exceed 1 to 3 mg/kg/min or 50 mg/minute, whichever is slower

• Monitor closely during and after dosing
• Maintenance Dose: Follow with maintenance doses orally or IV every 6 to 8 hours

Parenteral Substitution for Oral Phenytoin Therapy: When substituting oral phenytoin with IV use, may substitute at the same total daily dose; oral capsules are approximately 90% bioavailable; IV is 100% bioavailable, therefore, serum phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy

IM ADMINISTRATION:

• Ordinarily not given IM because of the risk of necrosis, abscess formation, and erratic absorption; if IM administration is required, dosage adjustments are necessary to maintain therapeutic plasma levels.
• IM dose is generally 50% greater than the oral dose; with return to oral administration, the dose should be reduced by 50% of the original oral dose for 1 week to prevent excessive plasma levels due to sustained release from IM tissue sites.

Comments:

• When switching between phenytoin formulations, it is important to understand that the free acid form of phenytoin is used in the oral suspension and chewable tablets, while the extended-release capsules and parenteral formulations contain the sodium salt; there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt and dose adjustments and serum level monitoring may be necessary when switching products.
• For IV administration, consult Administration Advice for important guidance.

Uses: For the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

Usual Pediatric Dose for Status Epilepticus

LOADING DOSE: 15 to 20 mg/kg IV at a rate not to exceed 1 to 3 mg/kg/min or 50 mg/min, whichever is slower
MAINTENANCE DOSE: The loading dose should be followed by maintenance doses by oral or IV administration every 6 to 8 hours
NOTE: In pediatric patients, a loading dose of 15 to 20 mg/kg IV will usually produce serum concentrations of phenytoin between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL)

Comments:

• Electrocardiogram and blood pressure should be monitored continuously during and after therapy; observe for signs of respiratory depression.
• Monitor phenytoin plasma levels.
• Other measures, including concomitant administration of an IV benzodiazepine such as diazepam, or an IV short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of phenytoin.
• If IV administration does not terminate seizures, the use of other anticonvulsants, IV barbiturates, general anesthesia and other appropriate measures should be considered.
• For IV administration, consult Administration Advice for important guidance.
• IM administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours.

Use: For the control of generalized tonic-clonic status epilepticus

Usual Pediatric Dose for Seizure Prophylaxis During or Following Neurosurgery

IV Use should be reserved for use when ORAL Administration is not possible

Oral Administration:
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 ADMINISTRATION:
LOADING DOSE: 15 to 20 mg/kg IV at a rate not to exceed 1 to 3 mg/kg/min or 50 mg/min, whichever is slower
MAINTENANCE DOSE: The loading dose should be followed by maintenance doses by oral or IV administration every 6 to 8 hours
NOTE: In pediatric patients, a loading dose of 15 to 20 mg/kg IV will usually produce serum concentrations of phenytoin between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL)

Comments:

• Electrocardiogram and blood pressure should be monitored continuously during and after therapy; observe for signs of respiratory depression.
• Monitor phenytoin plasma levels.
• For IV administration, consult Administration Advice for important guidance.

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

Renal Dose Adjustments

Renal disease: Monitoring of serum levels should be based on unbound fraction

Liver Dose Adjustments

Impaired liver function: Use caution monitoring for toxicity; monitoring of serum levels should be based on unbound fraction

Dose Adjustments

Elderly patients: A lower loading dose and/or infusion rate, and lower or less frequent maintenance dosing may be required. Phenytoin metabolism is slightly decreased in elderly patients.

Therapeutic Drug Monitoring:

• Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL); in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant
• Serum blood level determinations are recommended for optimal dosage adjustments; serum concentrations should be monitored when changing formulations, especially when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.
• With dose changes, a period of 7 to 10 days may be required to achieve steady-state blood levels

Precautions

US BOXED WARNINGS: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION:

• The rate of IV administration should not exceed 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg/min, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias.
• Careful cardiac monitoring is needed during and after IV administration of this drug.
• Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate.
• Reduction in rate of administration or discontinuation of dosing may be needed.

CONTRAINDICATIONS:

• Hypersensitivity to the active substance, other hydantoins, or any product ingredients; reactions have included angioedema
• Prior acute hepatotoxicity attributable to phenytoin
• Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors
• Parenteral Use: Sinus bradycardia, sinoatrial block, second- and third-degree atrioventricular block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity

NARROW THERAPEUTIC INDEX:

• This drug should be considered a narrow therapeutic index (NTI) drug as small differences in dose or blood concentrations may lead to serious therapeutic failures or adverse drug reactions.

Recommendations:

• Generic substitution should be done cautiously, if at all, as current bioequivalence standards are generally insufficient for NTI drugs.
• Additional and/or more frequent monitoring should be done to ensure receipt of an effective dose while avoiding unnecessary toxicities.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:
Oral Administration:

• Oral Suspension: A calibrated measuring device should be used to accurately measure dose
• Chewable Oral Tablets: Chew thoroughly before swallowing or swallow tablets whole

Parenteral Administration:

• IV administration should not exceed 50 mg/min in adults or 1 to 3 mg/kg/min or 50 mg/min (whichever is slower) as there is a risk of adverse cardiovascular reactions with rapid IV administration
• For non-emergency therapy, consider slower IV administration or intermittent infusion
• Because of the risk of local toxicity, IV drug should be administered directly into a large peripheral or central vein through a large-gauge catheter; prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline; each IV dose should be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution
• Careful cardiac monitoring is needed during and after IV administration; monitor for respiratory depression

IM Administration:

• Generally, this drug should not be given IM because of the risk of necrosis, abscess formation, and erratic absorption; if IM administration is required, dosage adjustments are necessary to maintain therapeutic serum levels (see dosing)
• IM administration should not be used in the treatment of status epilepticus because the attainment of peak serum levels may require up to 24 hours.

Storage requirements:

• Oral Suspension: Protect from light; do no freeze
• Oral Capsules: Protect from light; protect from moisture
• Chewable Oral Tablets: Protect from moisture

Reconstitution/preparation techniques:

• The manufacturer product information should be consulted.
• Intermittent infusion: Dilute this drug in normal saline to a final concentration of no less than 5 mg/mL; complete infusion within 1 to 4 hours using an in-line filter (0.22 to 0.55 microns)
• Do not refrigerate the diluted phenytoin mixture
• If undiluted drug is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature; the product is still suitable for use (a faint yellow coloration may develop, however this has no effect on the potency of the solution)

General:

• When a change in the dosage form or brand is prescribed, careful monitoring of phenytoin serum levels should be carried out.
• Literature reports have shown that concurrent administration of enteral feeding preparations and/or related nutritional supplements can reduce the oral absorption leading to lower phenytoin serum levels; it is suggested that phenytoin not be administered concomitantly with enteral feeding preparations.

Monitoring:

• Therapeutic drug monitoring is necessary for optimal dosing
• During IV therapy, continuous monitoring of the electrocardiogram and blood pressure; observe for signs of respiratory depression
• Monitor for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood and behavior
• Patients on chronic therapy should undergo routine laboratory testing including hematologic monitoring and monitoring bone health.

Patient advice:

• Patients should be instructed to read the US FDA-approved patient labeling (Medication Guide).
• Patients taking this drug should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug as prescribed (e.g., surgery, etc.).
• Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, cardiac, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, they should report any occurrence immediately to a physician even if mild or when occurring after extended use.
• Patients should be cautioned about the use of other drugs or alcoholic beverages without first seeking physician advice.
• Patients should discontinue this drug and seek immediate medical care if they develop signs or symptoms of angioedema.
• The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.
• Patients, their caregivers, and families should be counseled that antiepileptic drugs (AEDs) may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior.
• Women of childbearing potential should understand that use of this drug during pregnancy may cause fetal harm; women should be counseled about alternative therapeutic options if they wish to become pregnant and contraceptive measures if they are not planning a pregnancy.