Parenteral Phenytoin Sodium Injection is indicated for the treatment of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Intravenous phenytoin can also be substituted, as short-term use, for oral phenytoin. Parenteral phenytoin should be used only when oral phenytoin administration is not possible [see Dosage and Administration (2.1, 2.3) and Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Parenteral Phenytoin Sodium Injection is indicated for the treatment of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Intravenous phenytoin can also be substituted, as short-term use, for oral phenytoin. Parenteral phenytoin should be used only when oral phenytoin administration is not possible [see Dosage and Administration (2.1, 2.3) and Warnings and Precautions (5.1)]." }

2.1 General Dosing Information

{ "type": "p", "children": [], "text": "\n2.1 General Dosing Information\n" }

Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower.

{ "type": "p", "children": [], "text": "Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower." }

As non-emergency therapy, Phenytoin Sodium Injection should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous phenytoin, oral phenytoin should be used whenever possible.

{ "type": "p", "children": [], "text": "As non-emergency therapy, Phenytoin Sodium Injection should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous phenytoin, oral phenytoin should be used whenever possible." }

Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Phenytoin Sodium Injection. Reduction in rate of administration or discontinuation of dosing may be needed.

{ "type": "p", "children": [], "text": "Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Phenytoin Sodium Injection. Reduction in rate of administration or discontinuation of dosing may be needed." }

Because of the risk of local toxicity, intravenous Phenytoin Sodium Injection should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the intravenous (IV) catheter should be tested with a flush of sterile saline. Each injection of parenteral Phenytoin Sodium Injection should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution.

{ "type": "p", "children": [], "text": "Because of the risk of local toxicity, intravenous Phenytoin Sodium Injection should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the intravenous (IV) catheter should be tested with a flush of sterile saline. Each injection of parenteral Phenytoin Sodium Injection should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution." }

Phenytoin Sodium Injection can be given diluted with normal saline. The additional of parenteral Phenytoin Sodium Injection to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation.

{ "type": "p", "children": [], "text": "Phenytoin Sodium Injection can be given diluted with normal saline. The additional of parenteral Phenytoin Sodium Injection to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation." }

Treatment with Phenytoin Sodium Injection can be initiated either with a loading dose or an infusion:

{ "type": "p", "children": [], "text": "Treatment with Phenytoin Sodium Injection can be initiated either with a loading dose or an infusion:" }

Loading Dose: A loading dose of parenteral Phenytoin Sodium Injection should be injected slowly, not exceeding 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients.

{ "type": "p", "children": [], "text": "\nLoading Dose: A loading dose of parenteral Phenytoin Sodium Injection should be injected slowly, not exceeding 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients." }

Infusion: For infusion administration, parenteral Phenytoin Sodium Injection should be diluted in normal saline with the final concentration of phenytoin sodium in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22 to 0.55 microns) should be used.

{ "type": "p", "children": [], "text": "\nInfusion: For infusion administration, parenteral Phenytoin Sodium Injection should be diluted in normal saline with the final concentration of phenytoin sodium in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22 to 0.55 microns) should be used." }

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit.

{ "type": "p", "children": [], "text": "Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit." }

The diluted infusion mixture (Phenytoin Sodium Injection plus normal saline) should not be refrigerated. If the undiluted parenteral Phenytoin Sodium Injection 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.

{ "type": "p", "children": [], "text": "The diluted infusion mixture (Phenytoin Sodium Injection plus normal saline) should not be refrigerated. If the undiluted parenteral Phenytoin Sodium Injection 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." }

For single-dose only. After opening, any unused product should be discarded.

{ "type": "p", "children": [], "text": "For single-dose only. After opening, any unused product should be discarded." }

Monitoring Levels: Trough levels provide information about clinically effective serum level range and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.3)].

{ "type": "p", "children": [], "text": "\nMonitoring Levels: Trough levels provide information about clinically effective serum level range and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.3)]." }

2.2 Status Epilepticus

{ "type": "p", "children": [], "text": "\n2.2 Status Epilepticus\n" }

In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6 to 8 hours.

{ "type": "p", "children": [], "text": "In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6 to 8 hours." }

In the pediatric population, a loading dose of 15 to 20 mg/kg of phenytoin sodium intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower.

{ "type": "p", "children": [], "text": "In the pediatric population, a loading dose of 15 to 20 mg/kg of phenytoin sodium intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower." }

Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression.

{ "type": "p", "children": [], "text": "Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression." }

Determination of phenytoin serum levels is advised when using phenytoin in the management of status epileptics and in the subsequent establishment of maintenance dosage.

{ "type": "p", "children": [], "text": "Determination of phenytoin serum levels is advised when using phenytoin in the management of status epileptics and in the subsequent establishment of maintenance dosage." }

Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of phenytoin.

{ "type": "p", "children": [], "text": "Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of phenytoin." }

If administration of parenteral Phenytoin Sodium Injection does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered.

{ "type": "p", "children": [], "text": "If administration of parenteral Phenytoin Sodium Injection does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered." }

Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak serum levels may require up to 24 hours.

{ "type": "p", "children": [], "text": "Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak serum levels may require up to 24 hours." }

2.3 Non-emergent Loading and Maintenance Dosing

{ "type": "p", "children": [], "text": "\n2.3 Non-emergent Loading and Maintenance Dosing\n" }

Because of the risks of cardiac and local toxicity associated with intravenous phenytoin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients.

{ "type": "p", "children": [], "text": "Because of the risks of cardiac and local toxicity associated with intravenous phenytoin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients." }

Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential.

{ "type": "p", "children": [], "text": "Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential." }

The loading dose should be followed by maintenance doses of oral or intravenous phenytoin every 6 to 8 hours. Ordinarily, Phenytoin Sodium Injection should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic serum levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive serum levels due to sustained release from intramuscular tissue sites.

{ "type": "p", "children": [], "text": "The loading dose should be followed by maintenance doses of oral or intravenous phenytoin every 6 to 8 hours. Ordinarily, Phenytoin Sodium Injection should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic serum levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive serum levels due to sustained release from intramuscular tissue sites." }

Monitoring serum levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected.

{ "type": "p", "children": [], "text": "Monitoring serum levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected." }

2.4 Parenteral Substitution for Oral Phenytoin Therapy

{ "type": "p", "children": [], "text": "\n2.4 Parenteral Substitution for Oral Phenytoin Therapy\n" }

When treatment with oral phenytoin is not possible, IV phenytoin can be substituted for oral phenytoin at the same total daily dose. Phenytoin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, serum phenytoin concentrations may crease modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV phenytoin should be no greater than 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients.

{ "type": "p", "children": [], "text": "When treatment with oral phenytoin is not possible, IV phenytoin can be substituted for oral phenytoin at the same total daily dose. Phenytoin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, serum phenytoin concentrations may crease modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV phenytoin should be no greater than 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients." }

When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the serum level within the therapeutic range. Where oral dose is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to minimize toxic symptoms [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the serum level within the therapeutic range. Where oral dose is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to minimize toxic symptoms [see Clinical Pharmacology (12.3)]." }

Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Phenytoin Sodium Injection is formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

{ "type": "p", "children": [], "text": "Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Phenytoin Sodium Injection is formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa." }

2.5 Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia

{ "type": "p", "children": [], "text": "\n2.5 Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia\n" }

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

{ "type": "p", "children": [], "text": "Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients." }

2.6 Dosing in Geriatrics

{ "type": "p", "children": [], "text": "\n2.6 Dosing in Geriatrics\n" }

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)]." }

2.7 Dosing During Pregnancy

{ "type": "p", "children": [], "text": "\n2.7 Dosing During Pregnancy\n" }

Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the Phenytoin Sodium Injection dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)]. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

{ "type": "p", "children": [], "text": "Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the Phenytoin Sodium Injection dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)]. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction." }

2.8 Dosing in Pediatrics

{ "type": "p", "children": [], "text": "\n2.8 Dosing in Pediatrics\n" }

A loading dose of 15 to 20 mg/kg of Phenytoin Sodium injection intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower.

{ "type": "p", "children": [], "text": "A loading dose of 15 to 20 mg/kg of Phenytoin Sodium injection intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower." }

Phenytoin Sodium Injection, USP: 50 mg phenytoin sodium per milliliter is available as:

{ "type": "p", "children": [], "text": "Phenytoin Sodium Injection, USP: 50 mg phenytoin sodium per milliliter is available as:" }

• 2 mL (100 mg) Single Dose vials

{ "type": "p", "children": [], "text": "• 2 mL (100 mg) Single Dose vials" }

• 5 mL (250 mg) Single Dose vials

{ "type": "p", "children": [], "text": "• 5 mL (250 mg) Single Dose vials" }

Phenytoin Sodium Injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Phenytoin Sodium Injection is contraindicated in patients with:" }

• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": " • A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins [see Warnings and Precautions (5.5)]." }

• Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity.

{ "type": "p", "children": [], "text": " • Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity." }

• A history of prior acute hepatotoxicity attributable to phenytoin [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": " • A history of prior acute hepatotoxicity attributable to phenytoin [see Warnings and Precautions (5.6)]." }

• 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.

{ "type": "p", "children": [], "text": " • 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." }

5.1 Cardiovascular Risk Associated with Rapid Infusion Rapid intravenous administration of Phenytoin Sodium Injection increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.

{ "type": "p", "children": [], "text": "\n5.1 Cardiovascular Risk Associated with Rapid Infusion\nRapid intravenous administration of Phenytoin Sodium Injection increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates." }

Intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, administer the drug at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower.

{ "type": "p", "children": [], "text": "Intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, administer the drug at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower." }

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.

{ "type": "p", "children": [], "text": "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." }

As non-emergency therapy, Phenytoin Sodium Injection should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous phenytoin, oral phenytoin should be used whenever possible.

{ "type": "p", "children": [], "text": "As non-emergency therapy, Phenytoin Sodium Injection should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous phenytoin, oral phenytoin should be used whenever possible." }

Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac and respiratory monitoring is needed during and after the administration of intravenous Phenytoin Sodium Injection. Reduction in rate of administration or discontinuation of dosing may be needed.

{ "type": "p", "children": [], "text": "Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac and respiratory monitoring is needed during and after the administration of intravenous Phenytoin Sodium Injection. Reduction in rate of administration or discontinuation of dosing may be needed." }

5.2 Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

{ "type": "p", "children": [], "text": "\n5.2 Withdrawal Precipitated Seizure, Status Epilepticus\nAntiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class." }

5.3 Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Phenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "\n5.3 Serious Dermatologic Reactions\nSerious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Phenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)]." }

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding Phenytoin Sodium Injection as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.5)].

{ "type": "p", "children": [], "text": "Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding Phenytoin Sodium Injection as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.5)]." }

The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

{ "type": "p", "children": [], "text": "The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied." }

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Phenytoin Sodium Injection should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

{ "type": "p", "children": [], "text": "\n5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity\nDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Phenytoin Sodium Injection should be discontinued if an alternative etiology for the signs or symptoms cannot be established." }

5.5 Hypersensitivity Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4)]. Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to phenytoin.

{ "type": "p", "children": [], "text": "\n5.5 Hypersensitivity\nPhenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4)]. Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to phenytoin." }

5.6 Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4)]. Other common 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. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered.

{ "type": "p", "children": [], "text": "\n5.6 Hepatic Injury\nCases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4)]. Other common 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. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered." }

5.7 Hematopoietic Complications Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

{ "type": "p", "children": [], "text": "\n5.7 Hematopoietic Complications\nHematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression." }

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS [see Warnings and Precautions (5.4)]." }

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

{ "type": "p", "children": [], "text": "In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs." }

5.8 Local Toxicity (Including Purple Glove Syndrome) Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin.

{ "type": "p", "children": [], "text": "\n5.8 Local Toxicity (Including Purple Glove Syndrome)\nSoft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin." }

Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation.

{ "type": "p", "children": [], "text": "Edema, discoloration and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation." }

Because of the risk of local toxicity, intravenous Phenytoin Sodium Injection 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 injection of parenteral Phenytoin Sodium Injection should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation caused by the alkalinity of the solution.

{ "type": "p", "children": [], "text": "Because of the risk of local toxicity, intravenous Phenytoin Sodium Injection 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 injection of parenteral Phenytoin Sodium Injection should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation caused by the alkalinity of the solution." }

Intramuscular Phenytoin Sodium Injection administration may cause pain, necrosis, and abscess formation at the injection site [see Dosage and Administration (2.3)].

{ "type": "p", "children": [], "text": "Intramuscular Phenytoin Sodium Injection administration may cause pain, necrosis, and abscess formation at the injection site [see Dosage and Administration (2.3)]." }

5.9 Renal or Hepatic Impairment or Hypoalbuminemia Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

{ "type": "p", "children": [], "text": "\n5.9 Renal or Hepatic Impairment or Hypoalbuminemia\nBecause the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients." }

5.10 Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

{ "type": "p", "children": [], "text": "\n5.10 Exacerbation of Porphyria\nIn view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease." }

5.11 Teratogenicity and Other Harm to the Newborn Phenytoin Sodium Injection may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\n5.11 Teratogenicity and Other Harm to the Newborn\nPhenytoin Sodium Injection may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes [see Use in Specific Populations (8.1)]." }

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma.

{ "type": "p", "children": [], "text": "Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma." }

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

{ "type": "p", "children": [], "text": "A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth." }

5.12 Hyperglycemia Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.

{ "type": "p", "children": [], "text": "\n5.12 Hyperglycemia\nHyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients." }

5.13 Serum Phenytoin Levels Above Therapeutic Range Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.

{ "type": "p", "children": [], "text": "\n5.13 Serum Phenytoin Levels Above Therapeutic Range\nSerum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as \"delirium\", \"psychosis\", or \"encephalopathy\", or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended." }

The following serious adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are described elsewhere in the labeling:" }

• Cardiovascular Risk Associated with Rapid Infusion [see Warnings and Precautions (5.1)]

{ "type": "p", "children": [], "text": "• Cardiovascular Risk Associated with Rapid Infusion [see Warnings and Precautions (5.1)]" }

• Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.2)]

{ "type": "p", "children": [], "text": "• Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.2)]" }

• Serious Dermatologic Reactions [see Warnings and Precautions (5.3)]

{ "type": "p", "children": [], "text": "• Serious Dermatologic Reactions [see Warnings and Precautions (5.3)]" }

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.4)]

{ "type": "p", "children": [], "text": "• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.4)]" }

• Hypersensitivity [see Warnings and Precautions (5.5)]

{ "type": "p", "children": [], "text": "• Hypersensitivity [see Warnings and Precautions (5.5)]" }

• Hepatic Injury [see Warnings and Precautions (5.6)]

{ "type": "p", "children": [], "text": "• Hepatic Injury [see Warnings and Precautions (5.6)]" }

• Hematopoietic Complications [see Warnings and Precautions (5.7)]

{ "type": "p", "children": [], "text": "• Hematopoietic Complications [see Warnings and Precautions (5.7)]" }

• Local toxicity (Including Purple Glove Syndrome) [see Warnings and Precautions (5.8)]

{ "type": "p", "children": [], "text": "• Local toxicity (Including Purple Glove Syndrome) [see Warnings and Precautions (5.8)]" }

• Exacerbation of Porphyria [see Warnings and Precautions (5.10)]

{ "type": "p", "children": [], "text": "• Exacerbation of Porphyria [see Warnings and Precautions (5.10)]" }

• Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.11)]

{ "type": "p", "children": [], "text": "• Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.11)]" }

• Hyperglycemia [see Warnings and Precautions (5.13)]

{ "type": "p", "children": [], "text": "• Hyperglycemia [see Warnings and Precautions (5.13)]" }

The following adverse reactions associated with the use of Phenytoin Sodium Injection were identified in clinical studies or postmarking reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "The following adverse reactions associated with the use of Phenytoin Sodium Injection were identified in clinical studies or postmarking reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure." }

The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or CNS depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or CNS depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.1)]." }

Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS [see Warnings and Precautions (5.4)] have been observed. Anaphylaxis has also been reported.

{ "type": "p", "children": [], "text": "\nBody as a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS [see Warnings and Precautions (5.4)] have been observed. Anaphylaxis has also been reported." }

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.

{ "type": "p", "children": [], "text": "There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities." }

Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients [see Boxed Warning and Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "\nCardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients [see Boxed Warning and Warnings and Precautions (5.1)]." }

Digestive System: Acute hepatic failure [see Warnings and Precautions (5.6)], toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.

{ "type": "p", "children": [], "text": "\nDigestive System: Acute hepatic failure [see Warnings and Precautions (5.6)], toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia." }

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin [see Warnings and Precautions (5.7)]. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s Disease have been reported [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "\nHematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin [see Warnings and Precautions (5.7)]. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s Disease have been reported [see Warnings and Precautions (5.7)]." }

Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

{ "type": "p", "children": [], "text": "\nLaboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT)." }

Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.14)].

{ "type": "p", "children": [], "text": "\nNervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesia, and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.14)]." }

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

{ "type": "p", "children": [], "text": "A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy." }

Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)]. There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "\nSkin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)]. There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin [see Warnings and Precautions (5.8)]." }

Special Senses: Altered taste sensation including metallic taste.

{ "type": "p", "children": [], "text": "\nSpecial Senses: Altered taste sensation including metallic taste." }

Urogenital: Peyronie’s disease

{ "type": "p", "children": [], "text": "\nUrogenital: Peyronie’s disease" }

Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.

{ "type": "p", "children": [], "text": "Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected." }

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.

{ "type": "p", "children": [], "text": "Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes." }

7.1 Drugs That Affect Phenytoin Concentrations

{ "type": "p", "children": [], "text": "\n7.1 Drugs That Affect Phenytoin Concentrations\n" }

Table 1 includes commonly occurring drug interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.

{ "type": "p", "children": [], "text": "Table 1 includes commonly occurring drug interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted." }

The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

{ "type": "p", "children": [], "text": "The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome." }

7.2 Drugs Affected by Phenytoin

{ "type": "p", "children": [], "text": "\n7.2 Drugs Affected by Phenytoin\n" }

Table 2 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment to the dose of these agents to achieve optimal clinical outcome.

{ "type": "p", "children": [], "text": "Table 2 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment to the dose of these agents to achieve optimal clinical outcome." }

7.3 Drug/Laboratory Test Interactions

{ "type": "p", "children": [], "text": "\n7.3 Drug/Laboratory Test Interactions\n" }

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations following fosphenytoin administration.

{ "type": "p", "children": [], "text": "Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations following fosphenytoin administration." }

8.1 Pregnancy

{ "type": "p", "children": [], "text": "\n8.1 Pregnancy\n" }

Pregnancy Exposure Registry

{ "type": "p", "children": [], "text": "\nPregnancy Exposure Registry\n" }

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as Phenytoin Sodium Injection, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

{ "type": "p", "children": [], "text": "There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as Phenytoin Sodium Injection, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/." }

Risk Summary

{ "type": "p", "children": [], "text": "\nRisk Summary\n" }

In humans, prenatal exposure to phenytoin may increase the risk for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations (including orofacial clefts and cardiac defects). In addition, the fetal hydantoin syndrome a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data]. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

{ "type": "p", "children": [], "text": "In humans, prenatal exposure to phenytoin may increase the risk for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations (including orofacial clefts and cardiac defects). In addition, the fetal hydantoin syndrome a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data]. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy." }

Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavior abnormalities) in multiple species at clinically relevant doses [see Data].

{ "type": "p", "children": [], "text": "Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavior abnormalities) in multiple species at clinically relevant doses [see Data]." }

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

{ "type": "p", "children": [], "text": "In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown." }

Clinical Considerations

{ "type": "p", "children": [], "text": "\nClinical Considerations\n" }

Disease-associated maternal risk

{ "type": "p", "children": [], "text": "\nDisease-associated maternal risk\n" }

An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.1, 2.7)]. However, postpartum restoration of the original dosage will probably be indicated.

{ "type": "p", "children": [], "text": "An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.1, 2.7)]. However, postpartum restoration of the original dosage will probably be indicated." }

Fetal/Neonatal adverse reactions

{ "type": "p", "children": [], "text": "Fetal/Neonatal adverse reactions" }

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

{ "type": "p", "children": [], "text": "A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth." }

Data

{ "type": "p", "children": [], "text": "\nData\n" }

Human Data

{ "type": "p", "children": [], "text": "\nHuman Data\n" }

Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantion syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digit hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.

{ "type": "p", "children": [], "text": "Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantion syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digit hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies." }

Animal Data

{ "type": "p", "children": [], "text": "\nAnimal Data\n" }

Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth retardation. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively.

{ "type": "p", "children": [], "text": "Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth retardation. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively." }

8.2 Lactation

{ "type": "p", "children": [], "text": "\n8.2 Lactation\n" }

Risk Summary

{ "type": "p", "children": [], "text": "\nRisk Summary\n" }

Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Phenytoin Sodium Injection and any potential adverse effects on the breastfed infant from Phenytoin Sodium Injection or from the underlying maternal condition.

{ "type": "p", "children": [], "text": "Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Phenytoin Sodium Injection and any potential adverse effects on the breastfed infant from Phenytoin Sodium Injection or from the underlying maternal condition." }

8.4 Pediatric Use

{ "type": "p", "children": [], "text": "\n8.4 Pediatric Use\n" }

A loading dose of 15 to 20 mg/kg of Phenytoin Sodium Injection intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Phenytoin Sodium Injection should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower [see Dosage and Administration (2.8) and Warnings and Precautions(5.1)].

{ "type": "p", "children": [], "text": "A loading dose of 15 to 20 mg/kg of Phenytoin Sodium Injection intravenously will usually produce serum concentrations of phenytoin within the generally accepted serum total concentrations between 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Phenytoin Sodium Injection should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower [see Dosage and Administration (2.8) and Warnings and Precautions(5.1)]." }

8.5 Geriatric Use

{ "type": "p", "children": [], "text": "\n8.5 Geriatric Use\n" }

Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3)]. Lower or less frequent dosing may be required [see Dosage and Administration (2.6)].

{ "type": "p", "children": [], "text": "Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3)]. Lower or less frequent dosing may be required [see Dosage and Administration (2.6)]." }

8.6 Renal and/or Hepatic Impairment or Hypoalbuminemia

{ "type": "p", "children": [], "text": "\n8.6 Renal and/or Hepatic Impairment or Hypoalbuminemia\n" }

The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity.

{ "type": "p", "children": [], "text": "The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity." }

Because of the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

{ "type": "p", "children": [], "text": "Because of the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients." }

8.7 Use in Patients with Decreased CYP2C9 Function Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g.,*1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1 ). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)].

{ "type": "p", "children": [], "text": "\n8.7 Use in Patients with Decreased CYP2C9 Function\nPatients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g.,*1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1 ). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)]." }

The lethal dose in pediatric patients is not known. The lethal dose in adult is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is caused by respiratory and circulatory depression.

{ "type": "p", "children": [], "text": "The lethal dose in pediatric patients is not known. The lethal dose in adult is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is caused by respiratory and circulatory depression." }

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

{ "type": "p", "children": [], "text": "There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported." }

Treatment: Treatment is nonspecific since there is no known antidote.

{ "type": "p", "children": [], "text": "\nTreatment: Treatment is nonspecific since there is no known antidote." }

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

{ "type": "p", "children": [], "text": "The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients." }

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

{ "type": "p", "children": [], "text": "In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind." }

Phenytoin Sodium Injection, USP is a sterile solution containing in each mL phenytoin sodium 50 mg, propylene glycol 0.4 mL and alcohol 0.1 mL in Water for Injection. pH 10.0-12.3; sodium hydroxide added, if needed, for pH adjustment.

{ "type": "p", "children": [], "text": "Phenytoin Sodium Injection, USP is a sterile solution containing in each mL phenytoin sodium 50 mg, propylene glycol 0.4 mL and alcohol 0.1 mL in Water for Injection. pH 10.0-12.3; sodium hydroxide added, if needed, for pH adjustment." }

Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2,4-imidazolidinedione represented by the following structural formula:

{ "type": "p", "children": [], "text": "Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2,4-imidazolidinedione represented by the following structural formula:" }

12.1 Mechanism of Action

{ "type": "p", "children": [], "text": "\n12.1 Mechanism of Action\n" }

The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

{ "type": "p", "children": [], "text": "The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges." }

12.3 Pharmacokinetics

{ "type": "p", "children": [], "text": "\n12.3 Pharmacokinetics\n" }

Absorption

{ "type": "p", "children": [], "text": "\nAbsorption\n" }

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

{ "type": "p", "children": [], "text": "A fall in serum levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, because of the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels." }

Patients stabilized on a daily oral regimen of phenytoin experience a drop in peak blood levels to 50 to 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.

{ "type": "p", "children": [], "text": "Patients stabilized on a daily oral regimen of phenytoin experience a drop in peak blood levels to 50 to 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 cross over to the intramuscular route if the phenytoin IMG dose is increased by 50 percent over the previously established oral dose. To avoid drug accumulation caused by absorption from the muscle depots, it is recommended that for the first week back on oral phenytoin, the dose be reduced to half of the original oral dose (one-third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended.

{ "type": "p", "children": [], "text": "A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when cross over to the intramuscular route if the phenytoin IMG dose is increased by 50 percent over the previously established oral dose. To avoid drug accumulation caused by absorption from the muscle depots, it is recommended that for the first week back on oral phenytoin, the dose be reduced to half of the original oral dose (one-third of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended." }

Therapeutic effect without clinical signs of toxicity occurs most often with serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).

{ "type": "p", "children": [], "text": "Therapeutic effect without clinical signs of toxicity occurs most often with serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL)." }

Distribution

{ "type": "p", "children": [], "text": "\nDistribution\n" }

Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement.

{ "type": "p", "children": [], "text": "Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement." }

Elimination

{ "type": "p", "children": [], "text": "\nElimination\n" }

The serum half-life in man after intravenous administration ranges from 10 to 15 hours.

{ "type": "p", "children": [], "text": "The serum half-life in man after intravenous administration ranges from 10 to 15 hours." }

Metabolism

{ "type": "p", "children": [], "text": "\nMetabolism\n" }

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

{ "type": "p", "children": [], "text": "Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19." }

Excretion

{ "type": "p", "children": [], "text": "\nExcretion\n" }

Most of the drug is excreted in the bile as inactive metabolites. Urinary excretion of phenytoin and its metabolites occurs partly by glomerular filtration but, more importantly, by tubular secretion.

{ "type": "p", "children": [], "text": "Most of the drug is excreted in the bile as inactive metabolites. Urinary excretion of phenytoin and its metabolites occurs partly by glomerular filtration but, more importantly, by tubular secretion." }

Specific Populations

{ "type": "p", "children": [], "text": "\nSpecific Populations\n" }

Age: Geriatric Population:

{ "type": "p", "children": [], "text": "\nAge: Geriatric Population:\n" }

Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration, (2.6)].

{ "type": "p", "children": [], "text": "Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration, (2.6)]." }

Sex/Race:

{ "type": "p", "children": [], "text": "\nSex/Race:\n" }

Gender and race have no significant impact on phenytoin pharmacokinetics.

{ "type": "p", "children": [], "text": "Gender and race have no significant impact on phenytoin pharmacokinetics." }

Renal and Hepatic Impairment:

{ "type": "p", "children": [], "text": "\nRenal and Hepatic Impairment:\n" }

Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported.

{ "type": "p", "children": [], "text": "Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported." }

Pregnancy:

{ "type": "p", "children": [], "text": "\nPregnancy:\n" }

It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery.

{ "type": "p", "children": [], "text": "It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery." }

Drug Interaction Studies

{ "type": "p", "children": [], "text": "\nDrug Interaction Studies\n" }

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

{ "type": "p", "children": [], "text": "Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19." }

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)].

{ "type": "p", "children": [], "text": "Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)]." }

12.5 Pharmacogenomics CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11 ).

{ "type": "p", "children": [], "text": "\n12.5 Pharmacogenomics\nCYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11 )." }

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2-3% in the White population, 0.5-4% in the Asian population, and <1 % in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15-36% in the Asian population [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

{ "type": "p", "children": [], "text": "The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2-3% in the White population, 0.5-4% in the Asian population, and <1 % in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15-36% in the Asian population [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)]." }

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

{ "type": "p", "children": [], "text": "\n13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility\n" }

Carcinogenesis [see Warnings and Precautions (5.7)]

{ "type": "p", "children": [], "text": "\nCarcinogenesis [see Warnings and Precautions (5.7)]" }

In carcinogenicity studies, phenytoin was administrated in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepat0cellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations.

{ "type": "p", "children": [], "text": "In carcinogenicity studies, phenytoin was administrated in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepat0cellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations." }

In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats.

{ "type": "p", "children": [], "text": "In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats." }

Mutagenesis

{ "type": "p", "children": [], "text": "\nMutagenesis\n" }

Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells.

{ "type": "p", "children": [], "text": "Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells." }

In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells.

{ "type": "p", "children": [], "text": "In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells." }

Fertility

{ "type": "p", "children": [], "text": "\nFertility\n" }

Phenytoin has not been adequately assessed for effects on male or female fertility.

{ "type": "p", "children": [], "text": "Phenytoin has not been adequately assessed for effects on male or female fertility." }

16.1 How Supplied

{ "type": "p", "children": [], "text": "\n16.1 How Supplied\n" }

Phenytoin Sodium Injection, USP 50 mg/mL

{ "type": "p", "children": [], "text": "Phenytoin Sodium Injection, USP 50 mg/mL" }

2 mL (100 mg) Single Dose vials packaged in 25s (NDC 0641-0493-25)

{ "type": "p", "children": [], "text": "2 mL (100 mg) Single Dose vials packaged in 25s (NDC 0641-0493-25)" }

5 mL (250 mg) Single Dose vials packaged in 25s (NDC 0641-2555-45)

{ "type": "p", "children": [], "text": "5 mL (250 mg) Single Dose vials packaged in 25s (NDC 0641-2555-45)" }

<div class="scrollingtable"><table width="100%"> <caption> <span>Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 </span> </caption> <tbody class="Headless"> <tr class="First"> <td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit </td> </tr> <tr> <td>NDC 0641-0493-25<br/>Single Dose vials packaged in 25s</td><td>NDC 0404-9932-02<br/>1 2mL Single Dose Vial in a bag<br/>(Vial bears NDC 0641-0493-21)</td><td>50 mg/mL<br/>2 ml (100 mg)</td> </tr> <tr> <td>NDC 0641-2555-45<br/>Single Dose vials packaged in 25s</td><td>NDC 0404-9933-05<br/>1 5 mL Single Dose Vial in a bag<br/>(Vial bears NDC 0641-2555-41)</td><td>50 mg/mL<br/>5 mL (250 mg)</td> </tr> <tr class="Last"> <td>NDC 0641-2555-10<br/>Single Dose vials packaged in 10s</td><td>NDC 0404-9808-05<br/>1 5 mL Single Dose Vial in a bag<br/>(Vial bears NDC 0641-2555-41)</td><td>50 mg/mL<br/>5 mL (250 mg)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 </span>\n</caption>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit </td>\n</tr>\n<tr>\n<td>NDC 0641-0493-25<br/>Single Dose vials packaged in 25s</td><td>NDC 0404-9932-02<br/>1 2mL Single Dose Vial in a bag<br/>(Vial bears NDC 0641-0493-21)</td><td>50 mg/mL<br/>2 ml (100 mg)</td>\n</tr>\n<tr>\n<td>NDC 0641-2555-45<br/>Single Dose vials packaged in 25s</td><td>NDC 0404-9933-05<br/>1 5 mL Single Dose Vial in a bag<br/>(Vial bears NDC 0641-2555-41)</td><td>50 mg/mL<br/>5 mL (250 mg)</td>\n</tr>\n<tr class=\"Last\">\n<td>NDC 0641-2555-10<br/>Single Dose vials packaged in 10s</td><td>NDC 0404-9808-05<br/>1 5 mL Single Dose Vial in a bag<br/>(Vial bears NDC 0641-2555-41)</td><td>50 mg/mL<br/>5 mL (250 mg)</td>\n</tr>\n</tbody>\n</table></div>" }

16.2 Storage and Handling

{ "type": "p", "children": [], "text": "\n16.2 Storage and Handling\n" }

For single-dose only. After opening, any unused product should be discarded.

{ "type": "p", "children": [], "text": "For single-dose only. After opening, any unused product should be discarded." }

Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].\n" }

Withdrawal of Antiepileptic Drugs

{ "type": "p", "children": [], "text": "\nWithdrawal of Antiepileptic Drugs\n" }

Advise patients not to discontinue use of phenytoin without consulting with their healthcare provider. Phenytoin should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Advise patients not to discontinue use of phenytoin without consulting with their healthcare provider. Phenytoin should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.2)]." }

Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions

{ "type": "p", "children": [], "text": "\nPotential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions\n" }

Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7)].

{ "type": "p", "children": [], "text": "Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7)]." }

Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions

{ "type": "p", "children": [], "text": "\nEffects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions\n" }

Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [see Warnings and Precautions (5.9) and Drug Interactions (7.1, 7.2)].

{ "type": "p", "children": [], "text": "Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [see Warnings and Precautions (5.9) and Drug Interactions (7.1, 7.2)]." }

Inform patients that certain over-the-counter medications (e.g., cimetidine and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels.

{ "type": "p", "children": [], "text": "Inform patients that certain over-the-counter medications (e.g., cimetidine and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels." }

Hyperglycemia

{ "type": "p", "children": [], "text": "\nHyperglycemia\n" }

Advise patients that phenytoin may cause an increase in blood glucose levels [see Warnings and Precautions (5.13)].

{ "type": "p", "children": [], "text": "Advise patients that phenytoin may cause an increase in blood glucose levels [see Warnings and Precautions (5.13)]." }

Gingival Hyperplasia

{ "type": "p", "children": [], "text": "\nGingival Hyperplasia\n" }

Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.

{ "type": "p", "children": [], "text": "Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications." }

Neurologic Effects

{ "type": "p", "children": [], "text": "\nNeurologic Effects\n" }

Counsel patients that phenytoin may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin.

{ "type": "p", "children": [], "text": "Counsel patients that phenytoin may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin." }

Use in Pregnancy

{ "type": "p", "children": [], "text": "\nUse in Pregnancy\n" }

Inform pregnant women and women of childbearing potential that use of phenytoin during pregnancy can cause fetal harm, including an increased risk of cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using phenytoin, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)].

{ "type": "p", "children": [], "text": "Inform pregnant women and women of childbearing potential that use of phenytoin during pregnancy can cause fetal harm, including an increased risk of cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using phenytoin, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)]." }

Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2)].

{ "type": "p", "children": [], "text": "Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2)]." }

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)]." }

Manufactured by:

{ "type": "p", "children": [], "text": "\nManufactured by:\n" }

Hikma Pharmaceuticals USA Inc.Berkeley Heights, NJ 07922

{ "type": "p", "children": [], "text": "Hikma Pharmaceuticals USA Inc.Berkeley Heights, NJ 07922" }

Revised December 2022

{ "type": "p", "children": [], "text": "Revised December 2022" }

462-348-13

{ "type": "p", "children": [], "text": "462-348-13" }

Phenytoin oral suspension is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

{ "type": "p", "children": [], "text": "Phenytoin oral suspension is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures." }

FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE

A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.

The recommended starting dosage for adult patients who have received no previous treatment is 5 mL (125 mg/5 mL), or one teaspoonful, by mouth three times daily. Adjust the dosage to suit individual requirements, up to a maximum of 25 mL daily [see Dosage and Administration (2.4)].

The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses. A recommended daily maintenance dosage is usually 4 mg/kg/day to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).

Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments. Trough levels provide information about clinically effective serum level range and confirm patient compliance, and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 mcg/mL and 20 mcg/mL (unbound phenytoin concentrations of 1 mcg/mL to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.6)].

With recommended dosages, a period of seven to ten days may be required to achieve phenytoin steady-state blood levels, and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

The free acid form of phenytoin is used in phenytoin oral suspension and phenytoin chewable tablets. Phenytoin extended capsules and parenteral phenytoin are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.11)and Use in Specific Populations (8.6)].

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)] .

Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the phenytoin dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)]. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

Phenytoin oral suspension is available as a 125 mg phenytoin/5 mL oral suspension of orange color with an orange-vanilla flavor.

{ "type": "p", "children": [], "text": "Phenytoin oral suspension is available as a 125 mg phenytoin/5 mL oral suspension of orange color with an orange-vanilla flavor." }

Phenytoin oral suspension is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Phenytoin oral suspension is contraindicated in patients with:" }

{ "type": "ul", "children": [ "A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins\n \n [see\n \n Warnings and Precautions (5.5)].\n \n Reactions have included angioedema.\n \n ", "A history of prior acute hepatotoxicity attributable to phenytoin\n \n [see\n \n Warnings and Precautions (5.8)].\n \n \n", "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." ], "text": "" }

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class.

Antiepileptic drugs (AEDs), including phenytoin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1 Risk by indication for antiepileptic drugs in the pooled analysis</span> </caption> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Indication</th><th align="left" class="Rrule">Placebo Patients with Events Per 1000 Patients</th><th align="left" class="Rrule">Drug Patients with Events Per 1000 Patients</th><th align="left" class="Rrule">Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients</th><th align="left" class="Rrule">Risk Difference: Additional Drug Patients with Events Per 1000 Patients</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Epilepsy</td><td align="left" class="Rrule">1.0</td><td align="left" class="Rrule">3.4</td><td align="left" class="Rrule">3.5</td><td align="left" class="Rrule">2.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric</td><td align="left" class="Rrule">5.7</td><td align="left" class="Rrule">8.5</td><td align="left" class="Rrule">1.5</td><td align="left" class="Rrule">2.9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="left" class="Rrule">1.0</td><td align="left" class="Rrule">1.8</td><td align="left" class="Rrule">1.9</td><td align="left" class="Rrule">0.9</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Total</td><td align="left" class="Rrule">2.4</td><td align="left" class="Rrule">4.3</td><td align="left" class="Rrule">1.8</td><td align="left" class="Rrule">1.9</td> </tr> </tbody> </table></div>

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing phenytoin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Phenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)]. The onset of symptoms is usually within 28 days, but can occur later. Phenytoin oral suspension should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a severe cutaneous adverse reaction, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of SCARs.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding phenytoin oral suspension as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.5)].

The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4)and Warnings and Precautions (5.7)] . Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to phenytoin.

Cases of bradycardia and cardiac arrest have been reported in phenytoin-treated patients, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity [see Overdosage (10)] . Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.

Angioedema has been reported in patients treated with phenytoin in the postmarketing setting. Phenytoin oral suspension should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Phenytoin oral suspension should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4)]. Other common 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. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not readministered.

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS [see Warnings and Precautions (5.4)].

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Phenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes [see Use in Specific Populations (8.1)] .

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma.

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.

Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.

The following serious adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are described elsewhere in the labeling:" }

{ "type": "ul", "children": [ "Withdrawal Precipitated Seizure, Status Epilepticus\n \n [see\n \n Warnings and Precautions (5.1)]\n \n \n", "Suicidal Behavior and Ideation\n \n [see\n \n Warnings and Precautions (5.2)]\n \n \n", "Serious Dermatologic Reactions\n \n [see\n \n Warnings and Precautions (5.3)]\n \n \n", "Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity\n \n [see\n \n Warnings and Precautions (5.4)]\n \n \n", "Hypersensitivity\n \n [see\n \n Warnings and Precautions (5.5)]\n \n \n", "Cardiac Effects\n \n [see\n \n Warnings and Precautions (5.6)]\n \n \n", "Angioedema\n \n [see\n \n Warnings and Precautions (5.7)]\n \n \n", "Hepatic Injury\n \n [see\n \n Warnings and Precautions (5.8)]\n \n \n", "Hematopoietic Complications\n \n [see\n \n Warnings and Precautions (5.9)]\n \n \n", "Effects on Vitamin D and Bone\n \n [see\n \n Warnings and Precautions (5.10)]\n \n \n", "Exacerbation of Porphyria\n \n [see\n \n Warnings and Precautions (5.12)]\n \n \n", "Teratogenicity and Other Harm to the Newborn\n \n [see\n \n Warnings and Precautions (5.13)]\n \n \n", "Hyperglycemia\n \n [see\n \n Warnings and Precautions (5.14)]\n \n \n" ], "text": "" }

The following adverse reactions associated with the use of phenytoin were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "The following adverse reactions associated with the use of phenytoin were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure." }

Body as a Whole:Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema [see Warnings and Precautions (5.3, 5.4, 5.7)] . Anaphylaxis has also been reported.

{ "type": "p", "children": [], "text": "\nBody as a Whole:Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema\n \n [see\n \n Warnings and Precautions (5.3,\n \n 5.4,\n \n 5.7)]\n \n . Anaphylaxis has also been reported.\n\n " }

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.

{ "type": "p", "children": [], "text": "There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities." }

Digestive System:Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.

{ "type": "p", "children": [], "text": "\nDigestive System:Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.\n\n " }

Hematologic and Lymphatic System:Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "\nHematologic and Lymphatic System:Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported\n \n [see\n \n Warnings and Precautions (5.9)].\n \n \n" }

Laboratory Test Abnormality:Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose [see Warnings and Precautions (5.14)], alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

{ "type": "p", "children": [], "text": "\nLaboratory Test Abnormality:Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose\n \n [see\n \n Warnings and Precautions (5.14)],\n \n alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).\n\n " }

Nervous System:The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.15)].

{ "type": "p", "children": [], "text": "\nNervous System:The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use\n \n [see\n \n Warnings and Precautions (5.15)].\n \n \n" }

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

{ "type": "p", "children": [], "text": "A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy." }

Skin and Appendages:Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)] . There have also been reports of hypertrichosis and urticaria.

{ "type": "p", "children": [], "text": "\nSkin and Appendages:Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis\n \n [see\n \n Warnings and Precautions (5.3)]\n \n . There have also been reports of hypertrichosis and urticaria.\n\n " }

Special Senses:Altered taste sensation including metallic taste.

{ "type": "p", "children": [], "text": "\nSpecial Senses:Altered taste sensation including metallic taste.\n\n " }

Urogenital:Peyronie's disease

{ "type": "p", "children": [], "text": "\nUrogenital:Peyronie's disease\n\n " }

Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.

The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

<div class="scrollingtable"><table width="95%"> <caption> <span>Table 2: Drugs That Affect Phenytoin Concentrations</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="left" valign="middle" width="70%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Interacting Agent</th><th align="left" class="Rrule">Examples</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Antacids may affect absorption of phenytoin.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>The induction potency of St. John's wort may vary widely based on preparation.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs that may increase phenytoin serum levels</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antiepileptic drugs</td><td align="left" class="Rrule">Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Azoles</td><td align="left" class="Rrule">Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antineoplastic agents</td><td align="left" class="Rrule">Capecitabine, fluorouracil</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antidepressants</td><td align="left" class="Rrule">Fluoxetine, fluvoxamine, sertraline</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Gastric acid reducing agents</td><td align="left" class="Rrule">H <span class="Sub">2</span>antagonists (cimetidine), omeprazole </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Sulfonamides</td><td align="left" class="Rrule">Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="left" class="Rrule">Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs that may decrease phenytoin serum levels</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antacids <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="left" class="Rrule">Calcium carbonate, aluminum hydroxide, magnesium hydroxide <br/> <span class="Italics"><span class="Underline">Prevention or Management:</span></span>Phenytoin and antacids should not be taken at the same time of day </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antineoplastic agents <br/> (usually in combination) </td><td align="left" class="Rrule">Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antiviral agents</td><td align="left" class="Rrule">Fosamprenavir, nelfinavir, ritonavir</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antiepileptic drugs</td><td align="left" class="Rrule">Carbamazepine, vigabatrin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="left" class="Rrule">Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a>, sucralfate, theophylline </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs that may either increase or decrease phenytoin serum levels</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Antiepileptic drugs</td><td align="left" class="Rrule">Phenobarbital, valproate sodium, valproic acid</td> </tr> </tbody> </table></div>

Table 3 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.

<div class="scrollingtable"><table width="95%"> <caption> <span>Table 3: Drugs Affected by Phenytoin</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="left" valign="middle" width="70%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Interacting Agent</th><th align="left" class="Rrule">Examples</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs whose efficacy is impaired by phenytoin</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Azoles</td><td align="left" class="Rrule">Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antineoplastic agents</td><td align="left" class="Rrule">Irinotecan, paclitaxel, teniposide</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Delavirdine</td><td align="left" class="Rrule">Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance <span class="Italics">[see <a href="#S4">Contraindications (4)</a>]. </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Neuromuscular blocking agents</td><td align="left" class="Rrule">Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. <br/> <span class="Italics"><span class="Underline">Prevention or Management:</span></span>Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Warfarin</td><td align="left" class="Rrule">Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="left" class="Rrule">Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs whose level is decreased by phenytoin</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antiepileptic drugs <a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></td><td align="left" class="Rrule">Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antilipidemic agents</td><td align="left" class="Rrule">Atorvastatin, fluvastatin, simvastatin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Antiviral agents</td><td align="left" class="Rrule">Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Calcium channel blockers</td><td align="left" class="Rrule">Nifedipine, nimodipine, nisoldipine, verapamil</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Other</td><td align="left" class="Rrule">Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine</td> </tr> </tbody> </table></div>

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin serum levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients.

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as phenytoin, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the tollfree number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Risk Summary

In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data] . There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data].

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-associated maternal risk

An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.4, 2.8)] . However, postpartum restoration of the original dosage will probably be indicated [see Clinical Pharmacology (12.3)] .

Fetal/Neonatal Adverse Reactions

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Data

Human Data

Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.

Animal Data

Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100 mg/kg, 75 mg/kg, and 12.5 mg/kg, respectively.

Risk Summary

Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for phenytoin and any potential adverse effects on the breastfed infant from phenytoin or from the underlying maternal condition.

Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 mg/kg to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see Dosage and Administration (2.3)].

Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3)] . Lower or less frequent dosing may be required [see Dosage and Administration (2.7)] .

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

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)].

Treatment:Treatment is nonspecific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Phenytoin is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula:

{ "type": "p", "children": [], "text": "Phenytoin is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula:" }

Each 5 mL of the oral suspension contains 125 mg of phenytoin, USP; carboxymethylcellulose sodium, citric acid anhydrous, FD&C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial.

{ "type": "p", "children": [], "text": "Each 5 mL of the oral suspension contains 125 mg of phenytoin, USP; carboxymethylcellulose sodium, citric acid anhydrous, FD&C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial." }

The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

Absorption

For phenytoin oral suspension, peak levels occur 1½ to 3 hours after administration. Steady-state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5 to 7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved.

Distribution

Phenytoin is extensively bound to serum plasma proteins.

Elimination

The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours.

Metabolism

Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high serum levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin serum levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

Excretion

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion.

Specific Populations

Age: Geriatric Population:

Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration (2.7)] .

Sex/Race:

Gender and race have no significant impact on phenytoin pharmacokinetics.

Renal or Hepatic Impairment:

Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported.

Pregnancy:

It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery.

Drug Interaction Studies

Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)] .

CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11).

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in the White population, 0.5 to 4% in the Asian population, and <1% in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15 to 36% in the Asian population [see Warnings and Precautions (5.3)and Use in Specific Populations (8.7)].

Carcinogenesis[see Warnings and Precautions (5.9)]

In carcinogenicity studies, phenytoin was administered in the diet to mice (10 mg/kg/day, 25 mg/kg/day, or 45 mg/kg/day) and rats (25 mg/kg/day, 50 mg/kg/day, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations.

In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 160 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats.

Mutagenesis

Phenytoin was negative in the Ames test and in the in vitroclastogenicity assay in Chinese hamster ovary (CHO) cells.

In studies reported in the literature, phenytoin was negative in the in vitromouse lymphoma assay and the in vivomicronucleus assay in mouse. Phenytoin was clastogenic in the in vitrosister chromatid exchange assay in CHO cells.

Fertility

Phenytoin has not been adequately assessed for effects on male or female fertility.

Phenytoin Oral Suspension USP, 125 mg phenytoin/5 mL is supplied as follows:

<div class="scrollingtable"><table width="75%"> <col align="left" valign="top" width="34%"/> <col align="left" valign="top" width="33%"/> <col align="left" valign="top" width="33%"/> <thead> <tr class="First First Last Last"> <th align="left" class="Lrule Rrule">Package Configuration</th><th align="left" class="Rrule">Strength</th><th align="left" class="Rrule">NDC</th> </tr> </thead> <tbody> <tr class="First First Last Last"> <td align="left" class="Lrule Rrule">cup 72 ct UD </td><td align="left" class="Rrule">PHENYTOIN 100MG/4ML - 4 ML </td><td align="left" class="Rrule">NDC 17856-4070-01</td> </tr> </tbody> </table></div>

Store at 20° to 25°C (68° to 77°F)[see USP Controlled Room Temperature].

Protect from light. Do not freeze.

Administration Information

Advise patients taking phenytoin 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 orally as prescribed, e.g., surgery, etc.

Instruct patients to use an accurately calibrated measuring device when using this medication to ensure accurate dosing.

Withdrawal of Antiepileptic Drugs

Advise patients not to discontinue use of phenytoin without consulting with their healthcare provider. Phenytoin should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.1)] .

Suicidal Ideation and Behavior

Counsel patients, their caregivers, and families that AEDs, including phenytoin, may increase the risk of suicidal thoughts and behavior and advise them 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, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.2)] .

Serious Dermatologic Reactions

Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.3)] .

Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions

Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.8, 5.9)].

Cardiac Effects

Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity. Patients should report cardiac signs or symptoms to their healthcare provider [see Warnings and Precautions (5.6)and Overdosage (10)] .

Angioedema

Advise patients to discontinue phenytoin oral suspension and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling [see Warnings and Precautions (5.7)] .

Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions

Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician's advice [see Drug Interactions (7.1, 7.2)] .

Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John's wort) can alter their phenytoin levels.

Hyperglycemia

Advise patients that phenytoin may cause an increase in blood glucose levels [see Warnings and Precautions (5.14)] .

Gingival Hyperplasia

Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.

Neurologic Effects

Counsel patients that phenytoin may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin.

Use in Pregnancy

Inform pregnant women and women of childbearing potential that use of phenytoin during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using phenytoin, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)].

Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2)] .

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)] .

Mfd. by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel 2624761

{ "type": "p", "children": [], "text": "Mfd. by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel 2624761" }

DISTRIBUTED BY:

{ "type": "p", "children": [], "text": "\nDISTRIBUTED BY:\n" }

ATLANTIC BIOLOGICALS CORP.

{ "type": "p", "children": [], "text": "ATLANTIC BIOLOGICALS CORP." }

MIAMI, FL 33179

{ "type": "p", "children": [], "text": "MIAMI, FL 33179" }

Dispense with Medication Guide available at: https://www.taro.com/usa-medication-guides

{ "type": "p", "children": [], "text": "Dispense with Medication Guide available at: https://www.taro.com/usa-medication-guides" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="22%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="17%"/> <col align="left" valign="top" width="17%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="25%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="7">This Medication Guide has been approved by the U.S. Food and Drug Administration <br/> Revised: July 2021 </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="7"><span class="Italics">Dispense with Medication Guide available at: <span class="Underline">https://www.taro.com/usa-medication-guides</span></span> <br/> <span class="Bold">MEDICATION GUIDE <br/> Phenytoin (fen' i toin) Oral Suspension, USP </span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What is the most important information I should know about phenytoin oral suspension?</span> <ul> <li> <span class="Bold">Do not stop taking phenytoin oral suspension without first talking to your healthcare provider.</span> <ul class="Disc"> <li>Stopping phenytoin oral suspension suddenly can cause serious problems.</li> <li>Stopping a seizure medicine suddenly can cause you to have seizures more often or seizures that will not stop (status epilepticus).</li> </ul> </li> <li> <span class="Bold">Like other antiepileptic drugs, phenytoin oral suspension may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule" colspan="2"> <ul class="Disc"> <li>Thoughts about suicide or dying</li> <li>Attempts to commit suicide</li> <li>New or worse depression</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>New or worse anxiety</li> <li>Feeling agitated or restless</li> <li>Panic attacks</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>Trouble sleeping (insomnia)</li> <li>New or worse irritability</li> <li>Acting aggressive, being angry, or violent</li> </ul> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>Acting on dangerous impulses</li> <li>An extreme increase in activity and talking (mania)</li> <li>Other unusual changes in behavior or mood</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7">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. <br/> <span class="Bold">How can I watch for early symptoms of suicidal thoughts and actions?</span> <ul class="Disc"> <li>Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.</li> <li>Keep all follow-up visits with your healthcare provider as scheduled.</li> </ul>Call your healthcare provider between visits as needed, especially if you are worried about symptoms. <ul> <li> <span class="Bold">Phenytoin oral suspension can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>Fever</li> <li>Rash</li> <li>Swollen lymph glands</li> <li>Swelling of your face, eye, lips, or tongue</li> <li>Trouble swallowing or breathing</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>Sore throat</li> <li>Sores in your mouth</li> <li>Bruise easily</li> <li>Purple or red spots on your skin</li> <li>Increase infections</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>Not wanting to eat (anorexia)</li> <li>Nausea</li> <li>Vomiting</li> <li>Yellowing of the skin and the white part of your eyes (jaundice)</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7">Call your healthcare provider even if the symptoms are mild or if you have been taking phenytoin for an extended period of time. These symptoms can be a sign of a serious allergic reaction.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <ul> <li> <span class="Bold">Phenytoin oral suspension can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:</span> </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"></td><td align="left" colspan="3"> <ul class="Disc"> <li>dizziness</li> <li>feeling like your heart is beating slowly or skipping beats</li> </ul> </td><td align="left" class="Rrule" colspan="3"> <ul class="Disc"> <li>tiredness</li> <li>chest pain</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What is phenytoin oral suspension?</span> <br/> Phenytoin oral suspension is a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Do not take phenytoin oral suspension if you:</span> <ul class="Disc"> <li>Are allergic to phenytoin or any of the ingredients in phenytoin oral suspension. See the end of this leaflet for a complete list of ingredients in phenytoin oral suspension.</li> <li>Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).</li> <li>Have had liver problems from taking phenytoin.</li> <li>Take delavirdine.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Before taking phenytoin oral suspension, tell your healthcare provider about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>Have or have had depression, mood problems, or suicidal thoughts or behavior</li> <li>Have had an allergic reaction to a medicine similar to phenytoin called carboxamides, barbiturates, succinimides, and oxazolidinediones</li> <li>Have or had liver or kidney problems</li> <li>Have or had an enzyme problem called porphyria</li> <li>Have or had high blood sugar (hyperglycemia)</li> <li>Drink alcohol</li> <li>Are pregnant or plan to become pregnant. Phenytoin oral suspension may harm your unborn baby. <ul class="Circle"> <li>If you take phenytoin oral suspension during pregnancy, your baby is at risk for serious birth defects.</li> <li>If you become pregnant while taking phenytoin oral suspension, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of phenytoin oral suspension.</li> <li>If you take phenytoin oral suspension 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.</li> <li>All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin oral suspension.</li> <li>If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking phenytoin oral suspension.</li> <li> <span class="Bold">Pregnancy Registry:</span>If you become pregnant while taking phenytoin oral suspension, 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. </li> </ul> </li> <li>Are breastfeeding or plan to breastfeed. Phenytoin can pass into breast milk. You and your healthcare provider should decide if you will take phenytoin oral suspension while you are breastfeeding.</li> </ul>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of phenytoin in your blood. <br/> Taking phenytoin oral suspension with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. <br/> Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">How should I take phenytoin oral suspension?</span> <ul class="Disc"> <li>Take phenytoin oral suspension exactly as your healthcare provider tells you.</li> <li>Your healthcare provider will tell you how much phenytoin oral suspension to take and when to take it.</li> <li>Your healthcare provider may change your dose if needed. Do not change your dose of phenytoin oral suspension without talking to your healthcare provider.</li> <li>If your healthcare provider has prescribed phenytoin oral suspension, ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of phenytoin oral suspension. <span class="Bold">Do not</span>use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way. </li> <li>Do not stop taking phenytoin oral suspension without first talking to your healthcare provider. Stopping phenytoin suddenly can cause serious problems.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What should I avoid while taking phenytoin oral suspension?</span> <ul class="Disc"> <li>Do not drink alcohol while you take phenytoin oral suspension without first talking to your healthcare provider. Drinking alcohol while taking phenytoin oral suspension may change your blood levels of phenytoin which can cause serious problems.</li> <li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how phenytoin oral suspension affects you. Phenytoin can slow your thinking and motor skills.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What are the possible side effects of phenytoin oral suspension?</span> <br/> See <span class="Bold">" <a href="#Important">What is the most important information I should know about phenytoin oral suspension?</a>" <br/> Phenytoin oral suspension may cause other serious side effects including: </span> <ul class="Disc"> <li>Liver problems.</li> <li>Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue.</li> <li>Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures).</li> <li>High blood sugar (hyperglycemia).</li> <li>High levels of phenytoin in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy).</li> </ul>Call your healthcare provider right away, if you have any of the symptoms listed above. <br/> The most common side effects of phenytoin oral suspension include: </td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>Irregular movement of the eye (nystagmus)</li> <li>Problems with movement and balance (ataxia)</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>Slurred speech</li> <li>Decrease in coordination</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>Drowsiness (somnolence)</li> <li>Confusion</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7">Phenytoin can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking phenytoin oral suspension can help prevent this from happening. <br/> These are not all of the possible side effects of phenytoin oral suspension. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">How should I store phenytoin oral suspension?</span> <ul class="Disc"> <li>Store phenytoin oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Protect from light.</li> <li> <span class="Bold">Do not</span>freeze. </li> </ul> <span class="Bold">Keep phenytoin oral suspension and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">General information about the safe and effective use of phenytoin oral suspension.</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phenytoin oral suspension for a condition for which it was not prescribed. Do not give phenytoin oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about phenytoin oral suspension that is written for health professionals. </td> </tr> <tr> <td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What are the ingredients in phenytoin oral suspension? <br/> Active ingredient: </span>phenytoin, USP <br/> <span class="Bold">Inactive ingredients:</span>carboxymethylcellulose sodium, citric acid anhydrous, FD&amp;C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial. <br/> Trademarks are the property of their respective owners. <br/> Mfd. by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel 2624761 <br/> Dist. by: <span class="Bold">Taro Pharmaceuticals U.S.A., Inc.,</span>Hawthorne, NY 10532 <br/> For more information about phenytoin oral suspension, visit www.taro.com or call 1-866-923-4914. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"22%\"/>\n<col align=\"left\" valign=\"top\" width=\"8%\"/>\n<col align=\"left\" valign=\"top\" width=\"17%\"/>\n<col align=\"left\" valign=\"top\" width=\"17%\"/>\n<col align=\"left\" valign=\"top\" width=\"8%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"7\">This Medication Guide has been approved by the U.S. Food and Drug Administration \n <br/> Revised: July 2021\n </td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Italics\">Dispense with Medication Guide available at:\n \n <span class=\"Underline\">https://www.taro.com/usa-medication-guides</span></span>\n<br/>\n<span class=\"Bold\">MEDICATION GUIDE \n <br/> Phenytoin (fen' i toin) Oral Suspension, USP\n </span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What is the most important information I should know about phenytoin oral suspension?</span>\n<ul>\n<li>\n<span class=\"Bold\">Do not stop taking phenytoin oral suspension without first talking to your healthcare provider.</span>\n<ul class=\"Disc\">\n<li>Stopping phenytoin oral suspension suddenly can cause serious problems.</li>\n<li>Stopping a seizure medicine suddenly can cause you to have seizures more often or seizures that will not stop (status epilepticus).</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Like other antiepileptic drugs, phenytoin oral suspension may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Thoughts about suicide or dying</li>\n<li>Attempts to commit suicide</li>\n<li>New or worse depression</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>New or worse anxiety</li>\n<li>Feeling agitated or restless</li>\n<li>Panic attacks</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Trouble sleeping (insomnia)</li>\n<li>New or worse irritability</li>\n<li>Acting aggressive, being angry, or violent</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>Acting on dangerous impulses</li>\n<li>An extreme increase in activity and talking (mania)</li>\n<li>Other unusual changes in behavior or mood</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">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. \n <br/>\n<span class=\"Bold\">How can I watch for early symptoms of suicidal thoughts and actions?</span>\n<ul class=\"Disc\">\n<li>Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.</li>\n<li>Keep all follow-up visits with your healthcare provider as scheduled.</li>\n</ul>Call your healthcare provider between visits as needed, especially if you are worried about symptoms.\n \n <ul>\n<li>\n<span class=\"Bold\">Phenytoin oral suspension can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>Fever</li>\n<li>Rash</li>\n<li>Swollen lymph glands</li>\n<li>Swelling of your face, eye, lips, or tongue</li>\n<li>Trouble swallowing or breathing</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Sore throat</li>\n<li>Sores in your mouth</li>\n<li>Bruise easily</li>\n<li>Purple or red spots on your skin</li>\n<li>Increase infections</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Not wanting to eat (anorexia)</li>\n<li>Nausea</li>\n<li>Vomiting</li>\n<li>Yellowing of the skin and the white part of your eyes (jaundice)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">Call your healthcare provider even if the symptoms are mild or if you have been taking phenytoin for an extended period of time. These symptoms can be a sign of a serious allergic reaction.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<ul>\n<li>\n<span class=\"Bold\">Phenytoin oral suspension can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>dizziness</li>\n<li>feeling like your heart is beating slowly or skipping beats</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>tiredness</li>\n<li>chest pain</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What is phenytoin oral suspension?</span>\n<br/> Phenytoin oral suspension is a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Do not take phenytoin oral suspension if you:</span>\n<ul class=\"Disc\">\n<li>Are allergic to phenytoin or any of the ingredients in phenytoin oral suspension. See the end of this leaflet for a complete list of ingredients in phenytoin oral suspension.</li>\n<li>Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).</li>\n<li>Have had liver problems from taking phenytoin.</li>\n<li>Take delavirdine.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Before taking phenytoin oral suspension, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>Have or have had depression, mood problems, or suicidal thoughts or behavior</li>\n<li>Have had an allergic reaction to a medicine similar to phenytoin called carboxamides, barbiturates, succinimides, and oxazolidinediones</li>\n<li>Have or had liver or kidney problems</li>\n<li>Have or had an enzyme problem called porphyria</li>\n<li>Have or had high blood sugar (hyperglycemia)</li>\n<li>Drink alcohol</li>\n<li>Are pregnant or plan to become pregnant. Phenytoin oral suspension may harm your unborn baby.\n \n <ul class=\"Circle\">\n<li>If you take phenytoin oral suspension during pregnancy, your baby is at risk for serious birth defects.</li>\n<li>If you become pregnant while taking phenytoin oral suspension, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of phenytoin oral suspension.</li>\n<li>If you take phenytoin oral suspension 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.</li>\n<li>All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin oral suspension.</li>\n<li>If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking phenytoin oral suspension.</li>\n<li>\n<span class=\"Bold\">Pregnancy Registry:</span>If you become pregnant while taking phenytoin oral suspension, 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.\n \n </li>\n</ul>\n</li>\n<li>Are breastfeeding or plan to breastfeed. Phenytoin can pass into breast milk. You and your healthcare provider should decide if you will take phenytoin oral suspension while you are breastfeeding.</li>\n</ul>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of phenytoin in your blood. \n <br/> Taking phenytoin oral suspension with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. \n <br/> Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.\n \n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">How should I take phenytoin oral suspension?</span>\n<ul class=\"Disc\">\n<li>Take phenytoin oral suspension exactly as your healthcare provider tells you.</li>\n<li>Your healthcare provider will tell you how much phenytoin oral suspension to take and when to take it.</li>\n<li>Your healthcare provider may change your dose if needed. Do not change your dose of phenytoin oral suspension without talking to your healthcare provider.</li>\n<li>If your healthcare provider has prescribed phenytoin oral suspension, ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of phenytoin oral suspension.\n \n <span class=\"Bold\">Do not</span>use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way.\n \n </li>\n<li>Do not stop taking phenytoin oral suspension without first talking to your healthcare provider. Stopping phenytoin suddenly can cause serious problems.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What should I avoid while taking phenytoin oral suspension?</span>\n<ul class=\"Disc\">\n<li>Do not drink alcohol while you take phenytoin oral suspension without first talking to your healthcare provider. Drinking alcohol while taking phenytoin oral suspension may change your blood levels of phenytoin which can cause serious problems.</li>\n<li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how phenytoin oral suspension affects you. Phenytoin can slow your thinking and motor skills.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What are the possible side effects of phenytoin oral suspension?</span>\n<br/> See\n \n <span class=\"Bold\">\"\n \n <a href=\"#Important\">What is the most important information I should know about phenytoin oral suspension?</a>\" \n <br/> Phenytoin oral suspension may cause other serious side effects including:\n \n </span>\n<ul class=\"Disc\">\n<li>Liver problems.</li>\n<li>Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue.</li>\n<li>Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures).</li>\n<li>High blood sugar (hyperglycemia).</li>\n<li>High levels of phenytoin in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy).</li>\n</ul>Call your healthcare provider right away, if you have any of the symptoms listed above. \n <br/> The most common side effects of phenytoin oral suspension include:\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>Irregular movement of the eye (nystagmus)</li>\n<li>Problems with movement and balance (ataxia)</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Slurred speech</li>\n<li>Decrease in coordination</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Drowsiness (somnolence)</li>\n<li>Confusion</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">Phenytoin can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking phenytoin oral suspension can help prevent this from happening. \n <br/> These are not all of the possible side effects of phenytoin oral suspension. \n <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">How should I store phenytoin oral suspension?</span>\n<ul class=\"Disc\">\n<li>Store phenytoin oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Protect from light.</li>\n<li>\n<span class=\"Bold\">Do not</span>freeze.\n \n </li>\n</ul>\n<span class=\"Bold\">Keep phenytoin oral suspension and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">General information about the safe and effective use of phenytoin oral suspension.</span>\n<br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phenytoin oral suspension for a condition for which it was not prescribed. Do not give phenytoin oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about phenytoin oral suspension that is written for health professionals.\n \n </td>\n</tr>\n<tr>\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What are the ingredients in phenytoin oral suspension? \n <br/> Active ingredient:\n </span>phenytoin, USP \n <br/>\n<span class=\"Bold\">Inactive ingredients:</span>carboxymethylcellulose sodium, citric acid anhydrous, FD&amp;C yellow no. 6, magnesium aluminum silicate, orange flavor spray dry natural and artificial, polysorbate 60, purified water, sodium benzoate, sucrose and vanilla flavored powder artificial. \n <br/> Trademarks are the property of their respective owners. \n <br/> Mfd. by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel 2624761 \n <br/> Dist. by:\n \n <span class=\"Bold\">Taro Pharmaceuticals U.S.A., Inc.,</span>Hawthorne, NY 10532 \n <br/> For more information about phenytoin oral suspension, visit www.taro.com or call 1-866-923-4914.\n \n </td>\n</tr>\n</tbody>\n</table></div>" }

NDC 17856-4070-1

{ "type": "p", "children": [], "text": "\nNDC 17856-4070-1\n" }

Dispense the accompanying Medication Guide to each patient.

{ "type": "p", "children": [], "text": "Dispense the accompanying \n Medication Guide to each patient.\n " }

Phenytoin Oral Suspension USP, 120 mg/4 mL potency

{ "type": "p", "children": [], "text": "\nPhenytoin \n Oral Suspension \n USP, 120 mg/4 mL \n potency\n \n" }

IMPORTANT-SHAKE WELL BEFORE EACH USE

{ "type": "p", "children": [], "text": "\nIMPORTANT-SHAKE WELL BEFORE EACH USE\n" }

NOT FOR PARENTERAL USE Rx only

{ "type": "p", "children": [], "text": "\nNOT FOR PARENTERAL USE \n Rx only\n \n" }

Extended phenytoin sodium capsules are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

{ "type": "p", "children": [], "text": "Extended phenytoin sodium capsules are indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery." }

Divided daily dosage: The recommended starting dose for adult patients who have received no previous treatment is one 100 mg extended phenytoin sodium capsule by mouth three times daily. Adjust the dosage to suit individual requirements up to a maximum of two capsules three times a day. For most adults, the satisfactory maintenance dosage will be one capsule three to four times a day. Once-a-day dosage: In adults, if seizure control is established with divided doses of three 100 mg extended phenytoin sodium capsules daily, once-a-day dosage with 300 mg of extended phenytoin sodium capsules may be considered. Studies comparing divided doses of 300 mg with a single daily dose of this quantity indicated absorption, peak serum levels, biologic half-life, difference between peak and minimum values, and urinary recovery were equivalent. Once-a-day dosage offers a convenience to the individual patient or to nursing personnel for institutionalized patients and is intended to be used only for patients requiring this amount of drug daily. A major problem in motivating noncompliant patients may also be lessened when the patient can take this drug once a day. However, patients should be cautioned not to miss a dose, inadvertently. Only extended phenytoin sodium capsules are recommended for once-a-day dosing. Inherent differences in dissolution characteristics and resultant absorption rates of phenytoin due to different manufacturing procedures and/or dosage forms preclude such recommendation for other phenytoin products. When a change in the dosage form or brand is prescribed, careful monitoring of phenytoin serum levels should be carried out. Loading dose: Some authorities have advocated use of an oral loading dose of phenytoin in adults who require rapid steady-state serum levels and where intravenous administration is not desirable. This dosing regimen 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. Initially, one gram of extended phenytoin sodium capsules are divided into three doses (400 mg, 300 mg, 300 mg) and administered at two-hour intervals. Normal maintenance dosage is then instituted 24 hours after the loading dose, with frequent serum level determinations.

The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses. A recommended daily maintenance dosage is usually 4 to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).

Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments. Trough levels provide information about clinically effective serum level range and confirm patient compliance, and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations between 1 and 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.5)]. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

Extended phenytoin sodium capsules are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see  Warnings and Precautions (5.11)and Use in Specific Populations (8.6)] .

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)] .

Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the extended phenytoin sodium capsules dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)]. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

Extended Phenytoin Sodium Capsules USP, 100 mgare white/white, size ‘2’ hard gelatin capsule filled with white to off-white powder and imprinted with ‘X’ on white cap and ‘51’ on white body with black ink.

{ "type": "p", "children": [], "text": "\nExtended Phenytoin Sodium Capsules USP, 100 mgare white/white, size ‘2’ hard gelatin capsule filled with white to off-white powder and imprinted with ‘X’ on white cap and ‘51’ on white body with black ink.\n\n " }

Phenytoin sodium is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Phenytoin sodium is contraindicated in patients with:" }

{ "type": "ul", "children": [ "A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins\n \n [see\n \n Warnings and Precautions (5.5)]\n \n . Reactions have included angioedema.\n \n ", "A history of prior acute hepatotoxicity attributable to phenytoin\n \n [see\n \n Warnings and Precautions (5.8)].\n \n \n", "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." ], "text": "" }

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant drug not belonging to the hydantoin chemical class.

Antiepileptic drugs (AEDs), including phenytoin sodium, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 1 Risk by indication for antiepileptic drugs in the pooled analysis </span> </caption> <col width="12.76%"/> <col width="20.9%"/> <col width="20.2%"/> <col width="25%"/> <col width="21.16%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Indication</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Placebo Patients with Events Per 1000 Patients</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Drug Patients with Events Per 1000 Patients</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Relative Risk:</span> <br/> <span class="Bold">Incidence of Events in Drug Patients/Incidence in Placebo Patients</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Risk Difference:</span> <br/> <span class="Bold">Additional Drug</span> <br/> <span class="Bold">Patients with</span> <br/> <span class="Bold">Events Per 1000</span> <br/> <span class="Bold">Patients</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Epilepsy <br/> </td><td align="center" class="Rrule" valign="middle">1.0 <br/> </td><td align="center" class="Rrule" valign="middle">3.4 <br/> </td><td align="center" class="Rrule" valign="middle">3.5 <br/> </td><td align="center" class="Rrule" valign="middle">2.4 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Psychiatric <br/> </td><td align="center" class="Rrule" valign="middle">5.7 <br/> </td><td align="center" class="Rrule" valign="middle">8.5 <br/> </td><td align="center" class="Rrule" valign="middle">1.5 <br/> </td><td align="center" class="Rrule" valign="middle">2.9 <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Other <br/> </td><td align="center" class="Rrule" valign="middle">1.0 <br/> </td><td align="center" class="Rrule" valign="middle">1.8 <br/> </td><td align="center" class="Rrule" valign="middle">1.9 <br/> </td><td align="center" class="Rrule" valign="middle">0.9 <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Total <br/> </td><td align="center" class="Rrule" valign="middle">2.4 <br/> </td><td align="center" class="Rrule" valign="middle">4.3 <br/> </td><td align="center" class="Rrule" valign="middle">1.8 <br/> </td><td align="center" class="Rrule" valign="middle">1.9 <br/> </td> </tr> </tbody> </table></div>

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing phenytoin sodium or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Phenytoin sodium can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)]. The onset of symptoms is usually within 28 days, but can occur later. Phenytoin sodium should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a severe cutaneous adverse reaction, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of SCARs.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding phenytoin sodium as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers [see  Use in Specific Populations (8.7)and Clinical Pharmacology (12.5)].

The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin sodium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such  as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Phenytoin sodium should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Phenytoin sodium and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.7)] . Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to phenytoin sodium.

Cases of bradycardia and cardiac arrest have been reported in phenytoin sodium-treated patients, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity [see Overdosage (10)] . Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.

Angioedema has been reported in patients treated with phenytoin sodium in the postmarketing setting. Phenytoin sodium should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Phenytoin sodium should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin sodium. These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4)] . Other common 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. In these patients with acute hepatotoxicity, phenytoin sodium should be immediately discontinued and not readministered.

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin sodium. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS [see Warnings and Precautions (5.4)] . In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Phenytoin sodium may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes [see Use in Specific Populations (8.1)] . Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.

Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.

The following serious adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are described elsewhere in the labeling:" }

{ "type": "ul", "children": [ "Withdrawal Precipitated Seizure, Status Epilepticus\n \n [see\n \n Warnings and Precautions (5.1)]\n \n \n", "Suicidal Behavior and Ideation\n \n [see\n \n Warnings and Precautions (5.2)]\n \n \n", "Serious Dermatologic Reactions\n \n [see\n \n Warnings and Precautions (5.3)]\n \n \n", "Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity\n \n [see\n \n Warnings and Precautions (5.4)]\n \n \n", "Hypersensitivity\n \n [see\n \n Warnings and Precautions (5.5)]\n \n \n", "Cardiac Effects \n \n [see\n \n Warnings and Precautions (5.6)]\n \n \n", "Angioedema\n \n [see\n \n Warnings and Precautions (5.7)]\n \n \n", "Hepatic Injury\n \n [see\n \n Warnings and Precautions (5.8)]\n \n \n", "Hematopoietic Complications\n \n [see\n \n Warnings and Precautions (5.9)]\n \n \n", "Effects on Vitamin D and Bone\n \n [see\n \n Warnings and Precautions (5.10)]\n \n \n", "Exacerbation of Porphyria\n \n [see\n \n Warnings and Precautions (5.12)]\n \n \n", "Teratogenicity and Other Harm to the Newborn\n \n [see\n \n Warnings and Precautions (5.13)]\n \n \n", "Hyperglycemia\n \n [see\n \n Warnings and Precautions (5.14)]\n \n \n" ], "text": "" }

The following adverse reactions associated with the use of phenytoin sodium were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "The following adverse reactions associated with the use of phenytoin sodium were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure." }

Body as a Whole:Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema [see Warnings and Precautions (5.3, 5.4, 5.7)] . Anaphylaxis has also been reported.

{ "type": "p", "children": [], "text": "\nBody as a Whole:Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema\n \n [see\n \n Warnings and Precautions (5.3,\n \n 5.4,\n \n 5.7)]\n \n . Anaphylaxis has also been reported.\n\n " }

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.

{ "type": "p", "children": [], "text": "There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities." }

Digestive System:Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.

{ "type": "p", "children": [], "text": "\nDigestive System:Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.\n\n " }

Hematologic and Lymphatic System:Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported [see Warnings and Precautions (5.9)] . Pure red cell aplasia has also been reported.

{ "type": "p", "children": [], "text": "\nHematologic and Lymphatic System:Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported\n \n [see\n \n Warnings and Precautions (5.9)]\n \n . Pure red cell aplasia has also been reported.\n\n " }

Laboratory Test Abnormality:Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose [see Warnings and Precautions (5.14)] , alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

{ "type": "p", "children": [], "text": "\nLaboratory Test Abnormality:Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose\n \n [see\n \n Warnings and Precautions (5.14)]\n \n , alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).\n\n " }

Nervous System:The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.15)] . A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

{ "type": "p", "children": [], "text": "\nNervous System:The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use\n \n [see\n \n Warnings and Precautions (5.15)]\n \n . \n \n A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.\n\n " }

Skin and Appendages:Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)] . There have also been reports of hypertrichosis and urticaria. Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie's disease

{ "type": "p", "children": [], "text": "\nSkin and Appendages:Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis\n \n [see\n \n Warnings and Precautions (5.3)]\n \n . There have also been reports of hypertrichosis and urticaria. \n \n\n Special Senses:\n Altered taste sensation including metallic taste. \n \n\n Urogenital:\n Peyronie's disease\n\n " }

Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted. The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2: Drugs That Affect Phenytoin Concentrations </span> </caption> <col width="43.42%"/> <col width="56.58%"/> <tfoot> <tr class="First Last"> <td colspan="2"><span class="Sup">a</span> Antacids may affect absorption of phenytoin. <br/> <span class="Sup">b</span> The induction potency of St. John's wort may vary widely based on preparation. <br/> <span class="Sup">c</span>Valproate sodium and valproic acid are similar medications. The term valproate has been used to represent these medications.  </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Interacting Agent</span><span class="Bold"></span> <br/> </td><td class="Rrule" valign="middle"><span class="Bold">Examples</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Drugs that may increase phenytoin serum levels</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Antiepileptic drugs <br/> </td><td align="justify" class="Rrule" valign="top">Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Azoles <br/> </td><td align="justify" class="Rrule" valign="top">Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Antineoplastic agents <br/> </td><td align="justify" class="Rrule" valign="middle">Capecitabine, fluorouracil <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Antidepressants <br/> </td><td align="justify" class="Rrule" valign="middle">Fluoxetine, fluvoxamine, sertraline <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Gastric acid reducing agents <br/> </td><td align="justify" class="Rrule" valign="middle">H <span class="Sub">2</span>antagonists (cimetidine), omeprazole <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Sulfonamides <br/> </td><td align="justify" class="Rrule" valign="top">Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Other <br/> </td><td align="justify" class="Rrule" valign="top">Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Drugs that may decrease phenytoin serum levels</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Antacids <span class="Sup">a</span> <br/> </td><td align="justify" class="Rrule" valign="top">Calcium carbonate, aluminum hydroxide, magnesium hydroxide <br/> <span class="Italics">Prevention or Management:</span>Phenytoin and antacids should not be taken at the same time of day <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Antineoplastic agents usually in combination <br/> </td><td align="justify" class="Rrule" valign="middle">Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Antiviral agents <br/> </td><td align="justify" class="Rrule" valign="middle">Fosamprenavir, nelfinavir, ritonavir <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Antiepileptic drugs <br/> </td><td align="justify" class="Rrule" valign="middle">Carbamazepine, vigabatrin <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Other <br/> </td><td align="justify" class="Rrule" valign="top">Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort <span class="Sup">b</span>, sucralfate, theophylline <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Drugs that may either increase or decrease phenytoin serum levels</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Antiepileptic drugs <br/> </td><td align="justify" class="Rrule" valign="middle">Phenobarbital, valproate sodium <span class="Sup">c</span>, valproic acid <span class="Sup">c</span> <br/> </td> </tr> </tbody> </table></div>

Table 3 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome. Table 3: Drugs Affected by Phenytoin

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <col width="42.78%"/> <col width="57.22%"/> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Interacting Agent</span><span class="Bold"></span> <br/> </td><td class="Rrule" valign="middle"><span class="Bold">Examples</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Drugs whose efficacy is impaired by phenytoin</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Azoles <br/> </td><td align="justify" class="Rrule" valign="top">Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Antineoplastic agents <br/> </td><td align="justify" class="Rrule" valign="top">Irinotecan, paclitaxel, teniposide <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Delavirdine <br/> </td><td align="justify" class="Rrule" valign="top">Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance <span class="Italics">[see Contraindications (4)].</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Neuromuscular blocking agents <br/> </td><td align="justify" class="Rrule" valign="top">Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. <br/> <span class="Italics"><span class="Underline">Prevention or Management:</span></span><span class="Italics"></span>Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Warfarin <br/> </td><td align="justify" class="Rrule" valign="top">Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Other <br/> </td><td align="justify" class="Rrule" valign="top">Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Drugs whose level is decreased by phenytoin</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Anticoagulants <br/> </td><td align="justify" class="Rrule" valign="top">Apixaban, dabigatran, edoxaban, rivaroxaban <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Antiepileptic drugs <span class="Sup">a</span> <br/> </td><td align="justify" class="Rrule" valign="top">Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Antilipidemic agents <br/> </td><td align="justify" class="Rrule" valign="middle">Atorvastatin, fluvastatin, simvastatin <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Antiplatelets <br/> </td><td align="justify" class="Rrule" valign="middle">Ticagrelor <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">Antiviral agents <br/> </td><td align="justify" class="Rrule" valign="top">Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Calcium channel blockers <br/> </td><td align="justify" class="Rrule" valign="middle">Nifedipine, nimodipine, nisoldipine, verapamil <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">Other <br/> </td><td align="justify" class="Rrule" valign="top">Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine <br/> </td> </tr> </tbody> </table></div>

aThe effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable

Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia. Patients treated concomitantly with these two drugs should be monitored for signs and symptoms of hyperammonemia.

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin serum levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients.

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as phenytoin sodium, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin sodium enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/

Risk Summary In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data]. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated maternal risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of  serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.3, 2.7)] . However, postpartum restoration of the original dosage will probably be indicated [see Clinical Pharmacology (12.3)]. Fetal/Neonatal Adverse Reactions A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth. Data

Human Data

Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.

Animal Data Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively.

Risk Summary Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for phenytoin sodium and any potential adverse effects on the breastfed infant from phenytoin sodium or from the underlying maternal condition.

Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see Dosage and Administration (2.2)] .

Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3)] . Lower or less frequent dosing may be required [see Dosage and Administration (2.6)] .

The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)].

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Bradycardia and cardiac arrest have been reported [see Warnings and Precautions (5.6)]. Death is caused by respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

{ "type": "p", "children": [], "text": "The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Bradycardia and cardiac arrest have been reported\n \n [see\n \n Warnings and Precautions (5.6)].\n \n Death is caused by respiratory and circulatory depression. \n \n There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported. \n \n\n Treatment:\n Treatment is nonspecific since there is no known antidote. \n \n The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients. \n \n In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.\n\n " }

Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula:

{ "type": "p", "children": [], "text": "Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula:" }

Each 100 mg extended phenytoin sodium capsule USP contains 100 mg phenytoin sodium USP. Also contains confectioner’s sugar, hypromellose, magnesium oxide, magnesium stearate, microcrystalline cellulose, and talc. In addition, the empty hard gelatin capsule shells also contain gelatin, sodium lauryl sulphate, and titanium dioxide. The capsules are imprinted with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac. Product in vivoperformance is characterized by a slow and extended rate of absorption with peak blood concentrations expected in 4 to 12 hours as contrasted to Prompt Phenytoin Sodium Capsules, USP with a rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours. Meets USP Dissolution Test 2.

{ "type": "p", "children": [], "text": "Each 100 mg extended phenytoin sodium capsule USP contains 100 mg phenytoin sodium USP. Also contains confectioner’s sugar, hypromellose, magnesium oxide, magnesium stearate, microcrystalline cellulose, and talc. In addition, the empty hard gelatin capsule shells also contain gelatin, sodium lauryl sulphate, and titanium dioxide. The capsules are imprinted with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac. Product\n \n in vivoperformance is characterized by a slow and extended rate of absorption with peak blood concentrations expected in 4 to 12 hours as contrasted to\n \n Prompt Phenytoin Sodium Capsules, USP with a rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours. \n \n Meets USP Dissolution Test 2.\n\n " }

The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

Absorption For phenytoin sodium, peak serum levels occur 4 to 12 hours after administration. Steady-state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5 to 7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Distribution Phenytoin is extensively bound to serum plasma proteins. Elimination The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Metabolism Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high serum levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin serum levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Excretion Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Specific Populations Age: Geriatric Population: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration (2.6)]. Sex/Race: Gender and race have no significant impact on phenytoin pharmacokinetics. Renal or Hepatic Impairment : Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported. Pregnancy: It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery. Drug Interaction Studies Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)] .

CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11).

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in the White population, 0.5 to 4% in the Asian population, and <1% in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15 to 36% in the Asian population [see  Warnings and Precautions (5.3)and Use in Specific Populations (8.7)].

Carcinogenesis[see Warnings and Precautions (5.9)] In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations. In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 160 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Mutagenesis Phenytoin was negative in the Ames test and in the in vitroclastogenicity assay in Chinese hamster ovary (CHO) cells. In studies reported in the literature, phenytoin was negative in the in vitromouse lymphoma assay and the in vivomicronucleus assay in mouse. Phenytoin was clastogenic in the in vitrosister chromatid exchange assay in CHO cells. Fertility Phenytoin has not been adequately assessed for effects on male or female fertility.

16.1 How Supplied Extended Phenytoin Sodium Capsules USP, 100 mg are white/white, size ‘2’ hard gelatin capsule filled with white to off-white powder and imprinted with ‘X’ on white cap and ‘51’ on white body with black ink.

{ "type": "p", "children": [], "text": "16.1 How Supplied \n Extended Phenytoin Sodium Capsules USP, 100 mg are white/white, size ‘2’ hard gelatin capsule filled with white to off-white powder and imprinted with ‘X’ on white cap and ‘51’ on white body with black ink.\n " }

NDC: 72162-2514-00: 1000 Capsules in a BOTTLE

{ "type": "p", "children": [], "text": "NDC: 72162-2514-00: 1000 Capsules in a BOTTLE" }

NDC: 72162-2514-01: 100 Capsules in a BOTTLE

{ "type": "p", "children": [], "text": "NDC: 72162-2514-01: 100 Capsules in a BOTTLE" }

16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Preserve in tight, light-resistant containers. Protect from moisture.

{ "type": "p", "children": [], "text": "16.2 Storage and Handling \n Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Preserve in tight, light-resistant containers. Protect from moisture.\n " }

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

{ "type": "p", "children": [], "text": "Repackaged/Relabeled by: \n Bryant Ranch Prepack, Inc. \n Burbank, CA 91504\n " }

Advise patients to read the FDA-approved patient labeling ( Medication Guide). Administration Information Advise patients taking phenytoin 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 orally as prescribed, e.g., surgery, etc. Advise patients not to use capsules which are discolored. Withdrawal of Antiepileptic Drugs Advise patients not to discontinue use of phenytoin sodium without consulting with their healthcare provider. Phenytoin sodium should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.1)] . Suicidal Ideation and Behavior Counsel patients, their caregivers, and families that AEDs, including phenytoin sodium, may increase the risk of suicidal thoughts and behavior and advise them 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, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.2)] .

{ "type": "p", "children": [], "text": "Advise patients to read the FDA-approved patient labeling (\n \n Medication Guide). \n \n\n Administration Information \n \n\n Advise patients taking phenytoin 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 orally as prescribed, e.g., surgery, etc. \n \n\n Advise patients not to use capsules which are discolored. \n \n\n Withdrawal of Antiepileptic Drugs \n \n\n Advise patients not to discontinue use of phenytoin sodium without consulting with their healthcare provider. Phenytoin sodium should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus\n \n [see\n \n Warnings and Precautions (5.1)]\n \n . \n \n\n Suicidal Ideation and Behavior \n \n\n Counsel patients, their caregivers, and families that AEDs, including phenytoin sodium, may increase the risk of suicidal thoughts and behavior and advise them 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, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers\n \n [see\n \n Warnings and Precautions (5.2)]\n \n .\n\n " }

Serious Dermatologic Reactions

{ "type": "p", "children": [], "text": "\nSerious Dermatologic Reactions\n" }

Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "\n Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician\n \n [see\n \n Warnings and Precautions (5.3)].\n \n \n" }

Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.8, 5.9)] . Cardiac Effects Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at   recommended phenytoin doses and levels, and in association with phenytoin toxicity. Patients should report cardiac signs or symptoms to their healthcare provider [see  Warnings and Precautions (5.6)and Overdosage (10)].

{ "type": "p", "children": [], "text": "\n\n Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions \n \n\n Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use\n \n [see\n \n Warnings and Precautions (5.3,\n \n 5.4,\n \n 5.5,\n \n 5.8,\n \n 5.9)]\n \n . \n \n\n Cardiac Effects \n \n\n Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at   recommended phenytoin doses and levels, and in association with phenytoin toxicity. Patients should report cardiac signs or symptoms to their healthcare provider\n \n [see \n \n Warnings and Precautions (5.6)and\n \n Overdosage (10)].\n \n \n" }

Angioedema

{ "type": "p", "children": [], "text": "\nAngioedema\n" }

Advise patients to discontinue phenytoin sodium and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "\n Advise patients to discontinue phenytoin sodium and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling\n \n [see\n \n Warnings and Precautions (5.7)].\n \n \n" }

Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician's advice [ Drug Interactions (7.1, 7.2)] . Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John's wort) can alter their phenytoin levels. Hyperglycemia Advise patients that phenytoin sodium may cause an increase in blood glucose levels [see Warnings and Precautions (5.14)] . Gingival Hyperplasia Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications. Neurologic Effects Counsel patients that phenytoin sodium may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin sodium not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin sodium. Use in Pregnancy Inform pregnant women and women of childbearing potential that use of phenytoin sodium during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using phenytoin sodium, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)]. Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2)] . Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)] . 

{ "type": "p", "children": [], "text": "\n\n Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions \n \n\n Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician's advice\n \n [\n \n Drug Interactions (7.1,\n \n 7.2)]\n \n . \n \n Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John's wort) can alter their phenytoin levels. \n \n\n Hyperglycemia \n \n\n Advise patients that phenytoin sodium may cause an increase in blood glucose levels\n \n [see\n \n Warnings and Precautions (5.14)]\n \n . \n \n\n Gingival Hyperplasia \n \n\n Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications. \n \n\n Neurologic Effects \n \n\n Counsel patients that phenytoin sodium may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin sodium not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin sodium. \n \n\n Use in Pregnancy \n \n\n Inform pregnant women and women of childbearing potential that use of phenytoin sodium during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using phenytoin sodium, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy\n \n [see\n \n Drug Interactions (7.2)]. \n \n\n Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy\n \n [see\n \n Use in Specific Populations (8.1,\n \n 8.2)]\n \n . \n \n Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy\n \n [see\n \n Use in Specific Populations (8.1)]\n \n . \n\n " }

Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides

{ "type": "p", "children": [], "text": "\nDispense with Medication Guide available at:\n \n www.aurobindousa.com/medication-guides\n" }

Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 09/2023 Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides

{ "type": "p", "children": [], "text": "Distributed by: \n \nAurobindo Pharma USA, Inc. \n \n279 Princeton-Hightstown Road \n East Windsor, NJ 08520 \n \n Manufactured by: \n \nAurobindo Pharma Limited \n \nHyderabad-500 032, India \n \n Revised: 09/2023 \n \n\n Dispense with Medication Guide available at:\n \n www.aurobindousa.com/medication-guides\n" }

Extended Phenytoin Sodium Capsules USP

{ "type": "p", "children": [], "text": "\nExtended Phenytoin Sodium Capsules USP\n" }

(fen' i toyn soe' dee um)

{ "type": "p", "children": [], "text": "\n(fen' i toyn soe' dee um)\n" }

What is the most important information I should know about extended phenytoin sodium capsules?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about extended phenytoin sodium capsules?\n" }

1. Do not stop taking extended phenytoin sodium capsules without first talking to your healthcare provider.

{ "type": "p", "children": [], "text": "\n1. Do not stop taking extended phenytoin sodium capsules without first talking to your healthcare provider.\n" }

{ "type": "ul", "children": [ "Stopping extended phenytoin sodium capsules suddenly can cause serious problems.", "Stopping a seizure medicine suddenly can cause you to have seizures more often or seizures that will not stop (status epilepticus)." ], "text": "" }

2. Like other antiepileptic drugs, extended phenytoin sodium capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

{ "type": "p", "children": [], "text": "\n2. Like other antiepileptic drugs, extended phenytoin sodium capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:\n" }

{ "type": "ul", "children": [ "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 in activity and talking (mania)", "Other unusual changes in behavior or mood" ], "text": "" }

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.

{ "type": "p", "children": [], "text": "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." }

How can I watch for early symptoms of suicidal thoughts and actions?

{ "type": "p", "children": [], "text": "\nHow can I watch for early symptoms of suicidal thoughts and actions?\n" }

{ "type": "ul", "children": [ "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." ], "text": "" }

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

{ "type": "p", "children": [], "text": "Call your healthcare provider between visits as needed, especially if you are worried about symptoms." }

3. Extended phenytoin sodium capsules can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms:

{ "type": "p", "children": [], "text": "\n3. Extended phenytoin sodium capsules can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms:\n" }

{ "type": "ul", "children": [ "Fever", "Rash", "Swollen lymph glands", "Swelling of your face, eye, lips, or tongue", "Trouble swallowing or breathing", "Sore throat", "Sores in your mouth", "Bruise easily", "Purple or red spots on your skin", "Increase infections", "Not wanting to eat (anorexia)", "Nausea", "Vomiting", "Yellowing of the skin and the white part of your eyes (jaundice)" ], "text": "" }

Call your healthcare provider even if the symptoms are mild or if you have been taking extended phenytoin sodium capsules for an extended period of time. These symptoms can be a sign of a serious allergic reaction. 4. Extended phenytoin sodium capsules can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:

{ "type": "p", "children": [], "text": "Call your healthcare provider even if the symptoms are mild or if you have been taking extended phenytoin sodium capsules for an extended period of time. These symptoms can be a sign of a serious allergic reaction. \n \n\n 4. Extended phenytoin sodium capsules can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:\n \n" }

{ "type": "ul", "children": [ "dizziness", "tiredness", "feeling like your heart is beating slowly or skipping beats", "chest pain" ], "text": "" }

What are extended phenytoin sodium capsules?

{ "type": "p", "children": [], "text": "\nWhat are extended phenytoin sodium capsules?\n" }

Extended phenytoin sodium capsules are a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

{ "type": "p", "children": [], "text": "Extended phenytoin sodium capsules are a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures." }

Do not take extended phenytoin sodium capsules if you:

{ "type": "p", "children": [], "text": "\nDo not take extended phenytoin sodium capsules if you:\n" }

{ "type": "ul", "children": [ "Are allergic to phenytoin or any of the ingredients in extended phenytoin sodium capsules. See the end of this leaflet for a complete list of ingredients in extended phenytoin sodium capsules.", "Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).", "Have had liver problems from taking phenytoin.", "Take delavirdine." ], "text": "" }

Before taking extended phenytoin sodium capsules, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "\nBefore taking extended phenytoin sodium capsules, tell your healthcare provider about all of your medical conditions, including if you: \n \n\n\n" }

{ "type": "ul", "children": [ "Have or have had depression, mood problems, or suicidal thoughts or behavior", "Have had an allergic reaction to a medicine similar to extended phenytoin sodium capsules called carboxamides, barbiturates, succinimides, and oxazolidinediones", "Have or had liver or kidney problems", "Have or had an enzyme problem called porphyria", "Have or had high blood sugar (hyperglycemia)", "Drink alcohol", "Are pregnant or plan to become pregnant. Extended phenytoin sodium capsules may harm your unborn baby.\n \n \nIf you take extended phenytoin sodium capsules during pregnancy, your baby is at risk for serious birth defects.\nIf you become pregnant while taking extended phenytoin sodium capsules, the level of extended phenytoin sodium capsules in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of extended phenytoin sodium capsules.\nIf you take extended phenytoin sodium capsules 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.\nAll women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of extended phenytoin sodium capsules.\nIf you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking extended phenytoin sodium capsules.\n\nPregnancy Registry:If you become pregnant while taking extended phenytoin sodium capsules, 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.\n \n \nAre breastfeeding or plan to breastfeed. Phenytoin sodium can pass into breast milk. You and your healthcare provider should decide if you will take extended phenytoin sodium capsules while you are breastfeeding.\n\n" ], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of extended phenytoin sodium capsules in your blood.

{ "type": "p", "children": [], "text": "Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of extended phenytoin sodium capsules in your blood." }

Taking extended phenytoin sodium capsules with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

{ "type": "p", "children": [], "text": "Taking extended phenytoin sodium capsules with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider." }

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine." }

How should I take extended phenytoin sodium capsules?

{ "type": "p", "children": [], "text": "\nHow should I take extended phenytoin sodium capsules?\n" }

{ "type": "ul", "children": [ "Take extended phenytoin sodium capsules exactly as your healthcare provider tells you.", "Your healthcare provider will tell you how much extended phenytoin sodium capsules to take and when to take it.", "Your healthcare provider may change your dose if needed. Do not change your dose of extended phenytoin sodium capsules without talking to your healthcare provider.", "Do not stop taking extended phenytoin sodium capsules without first talking to your healthcare provider. Stopping extended phenytoin sodium capsules suddenly can cause serious problems." ], "text": "" }

What should I avoid while taking extended phenytoin sodium capsules?

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking extended phenytoin sodium capsules?\n" }

{ "type": "ul", "children": [ "Do not drink alcohol while you take extended phenytoin sodium capsules without first talking to your healthcare provider. Drinking alcohol while taking extended phenytoin sodium capsules may change your blood levels of extended phenytoin sodium capsules which can cause serious problems.", "Do not drive, operate heavy machinery, or do other dangerous activities until you know how extended phenytoin sodium capsules affects you. Extended phenytoin sodium capsules can slow your thinking and motor skills." ], "text": "" }

What are the possible side effects of extended phenytoin sodium capsules?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of extended phenytoin sodium capsules?\n" }

See " What is the most important information I should know about extended phenytoin sodium capsules?"

{ "type": "p", "children": [], "text": "See \"\n \n What is the most important information I should know about extended phenytoin sodium capsules?\"\n" }

Extended phenytoin sodium capsules may cause other serious side effects including:

{ "type": "p", "children": [], "text": "\nExtended phenytoin sodium capsules may cause other serious side effects including:\n" }

{ "type": "ul", "children": [ "Liver problems.", "Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue", "Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures).", "High blood sugar (hyperglycemia).", "High levels of extended phenytoin sodium capsules in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy)." ], "text": "" }

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

{ "type": "p", "children": [], "text": "Call your healthcare provider right away, if you have any of the symptoms listed above." }

The most common side effects of extended phenytoin sodium capsules include:

{ "type": "p", "children": [], "text": "The most common side effects of extended phenytoin sodium capsules include:" }

{ "type": "ul", "children": [ "Irregular movement of the eye (nystagmus)", "Problems with movement and balance (ataxia)", "Slurred speech", "Decrease in coordination", "Drowsiness (somnolence)", "Confusion" ], "text": "" }

Extended phenytoin sodium capsules can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking extended phenytoin sodium capsules can help prevent this from happening.

{ "type": "p", "children": [], "text": "Extended phenytoin sodium capsules can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking extended phenytoin sodium capsules can help prevent this from happening." }

These are not all of the possible side effects of extended phenytoin sodium capsules.

{ "type": "p", "children": [], "text": "These are not all of the possible side effects of extended phenytoin sodium capsules." }

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

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store extended phenytoin sodium capsules?

{ "type": "p", "children": [], "text": "\nHow should I store extended phenytoin sodium capsules?\n" }

{ "type": "ul", "children": [ "Store extended phenytoin sodium capsules at room temperature between 20° to 25°C (68° to 77°F).", "Store in tight, light-resistant containers.", "Protect from moisture." ], "text": "" }

Keep extended phenytoin sodium capsules and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep extended phenytoin sodium capsules and all medicines out of the reach of children.\n" }

General information about the safe and effective use of extended phenytoin sodium capsules.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of extended phenytoin sodium capsules.\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use extended phenytoin sodium capsules for a condition for which it was not prescribed. Do not give extended phenytoin sodium capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about extended phenytoin sodium capsules that is written for health professionals. What are the ingredients in extended phenytoin sodium capsules? Active ingredient:phenytoin sodium

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use extended phenytoin sodium capsules for a condition for which it was not prescribed. Do not give extended phenytoin sodium capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about extended phenytoin sodium capsules that is written for health professionals. \n \n\nWhat are the ingredients in extended phenytoin sodium capsules? \n \n\n\nActive ingredient:phenytoin sodium\n\n " }

Inactive ingredients:confectioner’s sugar, hypromellose, magnesium oxide, magnesium stearate, microcrystalline cellulose, and talc. In addition, the empty hard gelatin capsule shells also contain gelatin, sodium lauryl sulphate, and titanium dioxide. The capsules are imprinted with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac.

{ "type": "p", "children": [], "text": "\nInactive ingredients:confectioner’s sugar, hypromellose, magnesium oxide, magnesium stearate, microcrystalline cellulose, and talc. In addition, the empty hard gelatin capsule shells also contain gelatin, sodium lauryl sulphate, and titanium dioxide. The capsules are imprinted with edible ink containing black iron oxide, potassium hydroxide, propylene glycol and shellac.\n\n " }

For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.

{ "type": "p", "children": [], "text": "For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876." }

This Medication Guide has been approved by the U.S. Food and Drug Administration

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration" }

The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 09/2023

{ "type": "p", "children": [], "text": "The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. \n \n Distributed by: \n \nAurobindo Pharma USA, Inc. \n \n279 Princeton-Hightstown Road \n East Windsor, NJ 08520 \n \n Manufactured by: \n \nAurobindo Pharma Limited \n \nHyderabad-500 032, India \n \n Revised: 09/2023\n\n " }

Phenytoin Sodium 100 mg Capsules #1000

{ "type": "p", "children": [], "text": "Phenytoin Sodium 100 mg Capsules #1000" }

Phenytoin chewable tablets are indicated for the treatment of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

{ "type": "p", "children": [], "text": "Phenytoin chewable tablets are indicated for the treatment of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery." }

NOT FOR ONCE-A-DAY DOSING. Phenytoin chewable tablets can be either chewed thoroughly before being swallowed or swallowed whole.

The recommended starting dosage for adult patients who have received no previous treatment is two 50 mg phenytoin chewable tablets by mouth three times daily. Adjust the dosage to suit individual requirements up to a maximum of twelve phenytoin chewable tablets daily. For most adults, the satisfactory maintenance dosage will be six to eight phenytoin chewable tablets daily.

The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses. A recommended daily maintenance dosage is usually 4 mg/kg/day to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day). If the daily dosage cannot be divided equally, the larger dose should be given before retiring.

Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments. Trough levels provide information about clinically effective serum level range and confirm patient compliance, and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 mcg/mL and 20 mcg/mL (unbound phenytoin concentrations of 1 mcg/mL to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.6)] .

With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

The free acid form of phenytoin is used in phenytoin oral suspension and phenytoin chewable tablets. Extended phenytoin sodium capsules and parenteral phenytoin are formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)] .

Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)] .

Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the phenytoin chewable tablets dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)] . Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

Phenytoin chewable tablets are available as 50 mg phenytoin yellow, round, scored chewable tablets.

{ "type": "p", "children": [], "text": "Phenytoin chewable tablets are available as 50 mg phenytoin yellow, round, scored chewable tablets." }

Phenytoin chewable tablets are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Phenytoin chewable tablets are contraindicated in patients with:" }

{ "type": "ul", "children": [ "A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins \n \n \n [see \n \n \n Warnings and Precautions (5.5)]\n \n \n . Reactions have included angioedema.\n \n \n ", "A history of prior acute hepatotoxicity attributable to phenytoin \n \n \n [see \n \n \n Warnings and Precautions (5.8)]\n \n \n .\n \n \n ", "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." ], "text": "" }

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class.

Antiepileptic drugs (AEDs), including phenytoin chewable tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 1 Risk by indication for antiepileptic drugs in the pooled analysis</span> </caption> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="18%"/> <col align="left" valign="top" width="18%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="24%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Indication</th><th align="left" class="Rrule">Placebo Patients with Events Per 1000 Patients</th><th align="left" class="Rrule">Drug Patients with Events Per 1000 Patients</th><th align="left" class="Rrule">Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients</th><th align="left" class="Rrule">Risk Difference: Additional Drug Patients with Events Per 1000 Patients</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Epilepsy</td><td align="left" class="Rrule">1.0</td><td align="left" class="Rrule">3.4</td><td align="left" class="Rrule">3.5</td><td align="left" class="Rrule">2.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric</td><td align="left" class="Rrule">5.7</td><td align="left" class="Rrule">8.5</td><td align="left" class="Rrule">1.5</td><td align="left" class="Rrule">2.9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="left" class="Rrule">1.0</td><td align="left" class="Rrule">1.8</td><td align="left" class="Rrule">1.9</td><td align="left" class="Rrule">0.9</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Total</td><td align="left" class="Rrule">2.4</td><td align="left" class="Rrule">4.3</td><td align="left" class="Rrule">1.8</td><td align="left" class="Rrule">1.9</td> </tr> </tbody> </table></div>

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing phenytoin chewable tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Phenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)]. The onset of symptoms is usually within 28 days, but can occur later. Phenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a severe cutaneous adverse reaction, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of SCARs.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding phenytoin as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.5)] .

The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.7)] . Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to phenytoin.

Cases of bradycardia and cardiac arrest have been reported in phenytoin-treated patients, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity [see Overdosage (10)]. Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.

Angioedema has been reported in patients treated with phenytoin in the postmarketing setting. Phenytoin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Phenytoin should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4)] . Other common 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. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not readministered.

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS [see Warnings and Precautions (5.4)] .

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Phenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes [see Use in Specific Populations (8.1)] .

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma.

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.

Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.

The following serious adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are described elsewhere in the labeling:" }

{ "type": "ul", "children": [ "Withdrawal Precipitated Seizure, Status Epilepticus \n \n \n [see \n \n \n Warnings and Precautions (5.1)]\n \n \n \n", "Suicidal Behavior and Ideation \n \n \n [see \n \n \n Warnings and Precautions (5.2)]\n \n \n \n", "Serious Dermatologic Reactions \n \n \n [see \n \n \n Warnings and Precautions (5.3)]\n \n \n \n", "Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity \n \n \n [see \n \n \n Warnings and Precautions (5.4)]\n \n \n \n", "Hypersensitivity \n \n \n [see \n \n \n Warnings and Precautions (5.5)]\n \n \n \n", "Cardiac Effects \n \n \n [see \n \n \n Warnings and Precautions (5.6)]\n \n \n \n", "Angioedema \n \n \n [see \n \n \n Warnings and Precautions (5.7)]\n \n \n \n", "Hepatic Injury \n \n \n [see \n \n \n Warnings and Precautions (5.8)]\n \n \n \n", "Hematopoietic Complications \n \n \n [see \n \n \n Warnings and Precautions (5.9)]\n \n \n \n", "Effects on Vitamin D and Bone \n \n \n [see \n \n \n Warnings and Precautions (5.10)]\n \n \n \n", "Exacerbation of Porphyria \n \n \n [see \n \n \n Warnings and Precautions (5.12)]\n \n \n \n", "Teratogenicity and Other Harm to the Newborn \n \n \n [see \n \n \n Warnings and Precautions (5.13)]\n \n \n \n", "Hyperglycemia \n \n \n [see \n \n \n Warnings and Precautions (5.14)]\n \n \n \n" ], "text": "" }

The following adverse reactions associated with the use of phenytoin were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "The following adverse reactions associated with the use of phenytoin were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure." }

Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema [see Warnings and Precautions (5.3, 5.4, 5.7)] . Anaphylaxis has also been reported.

{ "type": "p", "children": [], "text": "\nBody as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema \n \n \n [see \n \n \n Warnings and Precautions (5.3, \n \n \n 5.4, \n \n \n 5.7)]\n \n \n . Anaphylaxis has also been reported.\n \n\n " }

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.

{ "type": "p", "children": [], "text": "There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities." }

Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.

{ "type": "p", "children": [], "text": "\nDigestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.\n \n\n " }

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported [see Warnings and Precautions (5.9)] . Pure red cell aplasia has also been reported.

{ "type": "p", "children": [], "text": "\nHematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported \n \n \n [see \n \n \n Warnings and Precautions (5.9)]\n \n \n . Pure red cell aplasia has also been reported.\n \n\n " }

Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose [see Warnings and Precautions (5.14)], alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

{ "type": "p", "children": [], "text": "\nLaboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose \n \n \n [see \n \n \n Warnings and Precautions (5.14)],\n \n \n alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). \n \n\n " }

Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.15)] .

{ "type": "p", "children": [], "text": "\nNervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use \n \n \n [see \n \n \n Warnings and Precautions (5.15)]\n \n \n .\n \n\n " }

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

{ "type": "p", "children": [], "text": "A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy." }

Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)] . There have also been reports of hypertrichosis and urticaria.

{ "type": "p", "children": [], "text": "\nSkin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis \n \n \n [see \n \n \n Warnings and Precautions (5.3)]\n \n \n . There have also been reports of hypertrichosis and urticaria.\n \n\n " }

Special Senses: Altered taste sensation including metallic taste.

{ "type": "p", "children": [], "text": "\nSpecial Senses: Altered taste sensation including metallic taste.\n \n\n " }

Urogenital: Peyronie's disease

{ "type": "p", "children": [], "text": "\nUrogenital: Peyronie's disease\n \n\n " }

Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.

The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2: Drugs That Affect Phenytoin Concentrations</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="left" valign="middle" width="70%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Interacting Agent</th><th align="left" class="Rrule">Examples</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Antacids may affect absorption of phenytoin.</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>The induction potency of St. John's wort may vary widely based on preparation.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Valproate sodium and valproic acid are similar medications. The term valproate has been used to represent these medications.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs that may increase phenytoin serum levels</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antiepileptic drugs</td><td align="left" class="Rrule">Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Azoles</td><td align="left" class="Rrule">Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antineoplastic agents</td><td align="left" class="Rrule">Capecitabine, fluorouracil</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antidepressants</td><td align="left" class="Rrule">Fluoxetine, fluvoxamine, sertraline</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Gastric acid reducing agents</td><td align="left" class="Rrule">H <span class="Sub">2</span> antagonists (cimetidine), omeprazole </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Sulfonamides</td><td align="left" class="Rrule">Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other</td><td align="left" class="Rrule">Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs that may decrease phenytoin serum levels</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antacids <a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="left" class="Rrule">Calcium carbonate, aluminum hydroxide, magnesium hydroxide <br/>   <span class="Italics"><span class="Underline">Prevention or Management:</span></span> Phenytoin and antacids should not be taken at the same time of day </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antineoplastic agents <br/> (usually in combination) </td><td align="left" class="Rrule">Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antiviral agents</td><td align="left" class="Rrule">Fosamprenavir, nelfinavir, ritonavir</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antiepileptic drugs</td><td align="left" class="Rrule">Carbamazepine, vigabatrin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other</td><td align="left" class="Rrule">Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort <a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a>, sucralfate, theophylline </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs that may either increase or decrease phenytoin serum levels</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Antiepileptic drugs</td><td align="left" class="Rrule">Phenobarbital, valproate sodium <a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a>, valproic acid <a class="Sup" href="#footnote-3">‡</a></td> </tr> </tbody> </table></div>

Table 3 includes commonly occurring drug interactions affected by phenytoin. However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3: Drugs Affected by Phenytoin</span> </caption> <col align="left" valign="middle" width="30%"/> <col align="left" valign="middle" width="70%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Interacting Agent</th><th align="left" class="Rrule">Examples</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs whose efficacy is impaired by phenytoin</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Azoles</td><td align="left" class="Rrule">Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antineoplastic agents</td><td align="left" class="Rrule">Irinotecan, paclitaxel, teniposide</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Delavirdine</td><td align="left" class="Rrule">Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance <span class="Italics">[see <a href="#S4">Contraindications (4)</a>]. </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Neuromuscular blocking agents</td><td align="left" class="Rrule">Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. <br/>   <span class="Italics"><span class="Underline">Prevention or Management:</span></span> Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Warfarin</td><td align="left" class="Rrule">Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other</td><td align="left" class="Rrule">Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs whose level is decreased by phenytoin</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anticoagulants</td><td align="left" class="Rrule">Apixaban, dabigatran, edoxaban, rivaroxaban</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antiepileptic drugs <a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></td><td align="left" class="Rrule">Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antilipidemic agents</td><td align="left" class="Rrule">Atorvastatin, fluvastatin, simvastatin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antiplatelets</td><td align="left" class="Rrule">Ticagrelor</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Antiviral agents</td><td align="left" class="Rrule">Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir <br/>Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Calcium channel blockers</td><td align="left" class="Rrule">Nifedipine, nimodipine, nisoldipine, verapamil</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Other</td><td align="left" class="Rrule">Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine</td> </tr> </tbody> </table></div>

Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia. Patients treated concomitantly with these two drugs should be monitored for signs and symptoms of hyperammonemia.

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin serum levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients.

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as phenytoin, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Risk Summary

In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data] . There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data] .

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-associated maternal risk

An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.4, 2.8)] . However, postpartum restoration of the original dosage will probably be indicated [see Clinical Pharmacology (12.3)] .

Fetal/Neonatal Adverse Reactions

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Data

Human Data

Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.

Animal Data

Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100 mg/kg, 75 mg/kg, and 12.5 mg/kg, respectively.

Risk Summary

Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for phenytoin and any potential adverse effects on the breastfed infant from phenytoin or from the underlying maternal condition.

Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 mg/kg to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see Dosage and Administration (2.3)] .

Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3)] . Lower or less frequent dosing may be required [see Dosage and Administration (2.7)] .

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

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)].

Treatment: Treatment is nonspecific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Phenytoin is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula:

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Each phenytoin chewable tablet, USP for oral administration, contains 50 mg phenytoin, USP. Also contains: Artificial banana flavor, compressible sugar, D&C yellow No. 10 aluminum lake, FD&C yellow No. 6 aluminum lake, hypromellose 2208, lactose monohydrate, magnesium stearate, saccharin sodium, and talc.

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The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

Absorption

For phenytoin chewable tablets, peak levels occur 1½ to 3 hours after administration. Steady-state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5 to 7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved.

Clinical studies show that chewed and unchewed phenytoin chewable tablets are bioequivalent, yield approximately equivalent serum levels, and are more rapidly absorbed than 100 mg extended phenytoin sodium capsules.

Distribution

Phenytoin is extensively bound to serum plasma proteins.

Elimination

Clinical studies using phenytoin chewable tablets have shown an average plasma half-life of 14 hours with a range of 7 to 29 hours.

Metabolism

Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high serum levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin serum levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

Excretion

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion.

Specific Populations

Age: Geriatric Population:

Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration (2.7)] .

Sex/Race:

Gender and race have no significant impact on phenytoin pharmacokinetics.

Renal or Hepatic Impairment:

Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported.

Pregnancy:

It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery.

Drug Interaction Studies

Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzymes CYP2C9 and to a lesser extent by CYP2C19.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)] .

CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11).

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in the White population, 0.5 to 4% in the Asian population, and <1% in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15 to 36% in the Asian population [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)] .

Carcinogenesis [see Warnings and Precautions (5.9)]

In carcinogenicity studies, phenytoin was administered in the diet to mice (10 mg/kg/day, 25 mg/kg/day, or 45 mg/kg/day) and rats (25 mg/kg/day, 50 mg/kg/day, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations.

In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 160 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats.

Mutagenesis

Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells.

In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells.

Fertility

Phenytoin has not been adequately assessed for effects on male or female fertility.

Phenytoin Chewable Tablets USP, 50 mg are yellow, uniform to slightly mottled, round normal convex tablets, scored and engraved with "T" above the score and "50" below the score on one side and plain on the other side. The tablets are banana flavored. They are supplied as follows:

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NDC: 70518-0841-00

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NDC: 70518-0841-01

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NDC: 70518-0841-02

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PACKAGING: 30 in 1 BLISTER PACK

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PACKAGING: 100 in 1 BOX

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PACKAGING: 1 in 1 POUCH

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Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

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Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "Repackaged and Distributed By:" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "Remedy Repack, Inc." }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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Administration Information

Advise patients taking phenytoin 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 orally as prescribed, e.g., surgery, etc.

Withdrawal of Antiepileptic Drugs

Advise patients not to discontinue use of phenytoin without consulting with their healthcare provider. Phenytoin should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.1)] .

Suicidal Ideation and Behavior

Counsel patients, their caregivers, and families that AEDs, including phenytoin chewable tablets, may increase the risk of suicidal thoughts and behavior and advise them 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, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.2)] .

Serious Dermatologic Reactions

Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.3)] .

Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions

Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.8, 5.9)] .

Cardiac Effects

Counsel patients that cases of bradycardia and cardiac arrest have been reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity. Patients should report cardiac signs or symptoms to their healthcare provider [see Warnings and Precautions (5.6) and Overdosage (10)] .

Angioedema

Advise patients to discontinue phenytoin and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling [see Warnings and Precautions (5.7)] .

Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions

Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician's advice [see Drug Interactions (7.1, 7.2)].

Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John's wort) can alter their phenytoin levels.

Hyperglycemia

Advise patients that phenytoin may cause an increase in blood glucose levels [see Warnings and Precautions (5.14)] .

Gingival Hyperplasia

Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.

Neurologic Effects

Counsel patients that phenytoin may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin.

Use in Pregnancy

Inform pregnant women and women of childbearing potential that use of phenytoin during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using phenytoin, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)] .

Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2)] .

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)] .

Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "Repackaged and Distributed By:" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "Remedy Repack, Inc." }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

{ "type": "p", "children": [], "text": "625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="4%"/> <col align="left" valign="top" width="16%"/> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td align="right" valign="top">Revised: June 2022</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule" colspan="6"><span class="Italics">Dispense with Medication Guide available at: https://www.taro.com/usa-medication-guides</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="6"><span class="Bold">MEDICATION GUIDE <br/> <br/> Phenytoin (fen´ i toin) chewable tablets </span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">What is the most important information I should know about phenytoin chewable tablets?</span> <ul> <li> <span class="Bold">Do not stop taking phenytoin chewable tablets without first talking to your healthcare provider.</span> <ul class="Disc"> <li>Stopping phenytoin chewable tablets suddenly can cause serious problems.</li> <li>Stopping a seizure medicine suddenly can cause you to have seizures more often or seizures that will not stop (status epilepticus).</li> </ul> </li> <li> <span class="Bold">Like other antiepileptic drugs, phenytoin chewable tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Disc"> <li>Thoughts about suicide or dying</li> <li>Attempts to commit suicide</li> <li>New or worse depression</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>New or worse anxiety</li> <li>Feeling agitated or restless</li> <li>Panic attacks</li> </ul> </td><td align="left"> <ul> <li>Trouble sleeping (insomnia)</li> <li>New or worse irritability</li> <li>Acting aggressive, being angry, or violent</li> </ul> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>Acting on dangerous impulses</li> <li>An extreme increase in activity and talking (mania)</li> <li>Other unusual changes in behavior or mood</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="6">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. <br/> <br/> <span class="Bold">How can I watch for early symptoms of suicidal thoughts and actions?</span> <ul class="Disc"> <li>Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.</li> <li>Keep all follow-up visits with your healthcare provider as scheduled.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="6">Call your healthcare provider between visits as needed, especially if you are worried about symptoms. <ul> <li> <span class="Bold">Phenytoin chewable tablets can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul class="Disc"> <li>Fever</li> <li>Rash</li> <li>Swollen lymph glands</li> <li>Swelling of your face, eye, lips, or tongue</li> <li>Trouble swallowing or breathing</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>Sore throat</li> <li>Sores in your mouth</li> <li>Bruise easily</li> <li>Purple or red spots on your skin</li> <li>Increase infections</li> </ul> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>Not wanting to eat (anorexia)</li> <li>Nausea</li> <li>Vomiting</li> <li>Yellowing of the skin and the white part of your eyes (jaundice)</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6">Call your healthcare provider even if the symptoms are mild or if you have been taking phenytoin for an extended period of time. These symptoms can be a sign of a serious allergic reaction. <ul> <li> <span class="Bold">Phenytoin chewable tablets can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:</span> <ul class="Disc"> <li>dizziness</li> <li>tiredness</li> <li>feeling like your heart is beating slowly or skipping beats</li> <li>chest pain</li> </ul> </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">What are phenytoin chewable tablets?</span> <br/> <br/> Phenytoin chewable tablets is a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">Do not take phenytoin chewable tablets if you:</span> <ul class="Disc"> <li>Are allergic to phenytoin or any of the ingredients in phenytoin chewable tablets. See the end of this leaflet for a complete list of ingredients in phenytoin chewable tablets.</li> <li>Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).</li> <li>Have had liver problems from taking phenytoin.</li> <li>Take delavirdine.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">Before taking phenytoin chewable tablets, tell your healthcare provider about all of your medical conditions, including if you:</span> <ul class="Disc"> <li>Have or have had depression, mood problems, or suicidal thoughts or behavior</li> <li>Have had an allergic reaction to a medicine similar to phenytoin called carboxamides, barbiturates, succinimides, and oxazolidinediones</li> <li>Have or had liver or kidney problems</li> <li>Have or had an enzyme problem called porphyria</li> <li>Have or had high blood sugar (hyperglycemia)</li> <li>Drink alcohol</li> <li>Are pregnant or plan to become pregnant. Phenytoin chewable tablets may harm your unborn baby. <ul class="Circle"> <li>If you take phenytoin chewable tablets during pregnancy, your baby is at risk for serious birth defects.</li> <li>If you become pregnant while taking phenytoin chewable tablets, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of phenytoin chewable tablets.</li> <li>If you take phenytoin chewable tablets 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.</li> <li>All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin chewable tablets.</li> <li>If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking phenytoin chewable tablets.</li> <li> <span class="Bold">Pregnancy Registry:</span> If you become pregnant while taking phenytoin chewable tablets, 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. </li> </ul> </li> <li>Are breastfeeding or plan to breastfeed. Phenytoin can pass into breast milk. You and your healthcare provider should decide if you will take phenytoin chewable tablets while you are breastfeeding.</li> </ul> Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of phenytoin in your blood. <br/> <br/> Taking phenytoin chewable tablets with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider. <br/> <br/> Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">How should I take phenytoin chewable tablets?</span> <ul class="Disc"> <li>Take phenytoin chewable tablets exactly as your healthcare provider tells you.</li> <li>Your healthcare provider will tell you how much phenytoin chewable tablets to take and when to take it.</li> <li>Your healthcare provider may change your dose if needed. Do not change your dose of phenytoin chewable tablets without talking to your healthcare provider.</li> <li>If your healthcare provider has prescribed phenytoin oral suspension, ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of phenytoin. <span class="Bold">Do not</span> use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way. </li> </ul> Do not stop taking phenytoin chewable tablets without first talking to your healthcare provider. Stopping phenytoin suddenly can cause serious problems. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">What should I avoid while taking phenytoin chewable tablets?</span> <ul class="Disc"> <li>Do not drink alcohol while you take phenytoin chewable tablets without first talking to your healthcare provider. Drinking alcohol while taking phenytoin chewable tablets may change your blood levels of phenytoin which can cause serious problems.</li> </ul> Do not drive, operate heavy machinery, or do other dangerous activities until you know how phenytoin chewable tablets affect you. Phenytoin can slow your thinking and motor skills. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">What are the possible side effects of phenytoin chewable tablets?</span> <br/> <br/> See <span class="Bold">" <a href="#Important">What is the most important information I should know about phenytoin chewable tablets?</a>" <br/> <br/> Phenytoin chewable tablets may cause other serious side effects including: </span> <ul class="Disc"> <li>Liver problems.</li> <li>Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue.</li> <li>Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures).</li> <li>High blood sugar (hyperglycemia).</li> <li>High levels of phenytoin in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy).</li> </ul> Call your healthcare provider right away, if you have any of the symptoms listed above. <br/> <br/> The most common side effects of phenytoin chewable tablets include: </td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>Irregular movement of the eye (nystagmus)</li> <li>Problems with movement and balance (ataxia)</li> </ul> </td><td align="left" colspan="2"> <ul class="Disc"> <li>Slurred speech</li> <li>Decrease in coordination</li> </ul> </td><td align="left" class="Rrule"> <ul class="Disc"> <li>Drowsiness (somnolence)</li> <li>Confusion</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6">Phenytoin can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking phenytoin chewable tablets can help prevent this from happening. <br/> <br/> These are not all of the possible side effects of phenytoin chewable tablets. <br/> <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">How should I store phenytoin chewable tablets?</span> <ul class="Disc"> <li>Store phenytoin chewable tablets at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Protect from moisture.</li> </ul> <span class="Bold">Keep phenytoin chewable tablets and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">General information about the safe and effective use of phenytoin chewable tablets.</span> <br/> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phenytoin chewable tablets for a condition for which it was not prescribed. Do not give phenytoin chewable tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about phenytoin chewable tablets that is written for health professionals. </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="6"><span class="Bold">What are the ingredients in phenytoin chewable tablets?</span> <br/> <br/> <span class="Bold">Active ingredient:</span> 50 mg phenytoin, USP. <br/> <br/> <span class="Bold">Inactive ingredients:</span> Artificial banana flavor, compressible sugar, D&amp;C yellow No. 10 aluminum lake, FD&amp;C yellow No. 6 aluminum lake, hypromellose 2208, lactose monohydrate, magnesium stearate, saccharin sodium, and talc. <br/> <br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"4%\"/>\n<col align=\"left\" valign=\"top\" width=\"16%\"/>\n<col align=\"left\" valign=\"top\" width=\"15%\"/>\n<col align=\"left\" valign=\"top\" width=\"15%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n<col align=\"left\" valign=\"top\" width=\"25%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"5\" valign=\"top\">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td align=\"right\" valign=\"top\">Revised: June 2022</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Italics\">Dispense with Medication Guide available at: https://www.taro.com/usa-medication-guides</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">MEDICATION GUIDE\n <br/>\n<br/>\n\t\t\tPhenytoin (fen´ i toin) chewable tablets \n </span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">What is the most important information I should know about phenytoin chewable tablets?</span>\n<ul>\n<li>\n<span class=\"Bold\">Do not stop taking phenytoin chewable tablets without first talking to your healthcare provider.</span>\n<ul class=\"Disc\">\n<li>Stopping phenytoin chewable tablets suddenly can cause serious problems.</li>\n<li>Stopping a seizure medicine suddenly can cause you to have seizures more often or seizures that will not stop (status epilepticus).</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Like other antiepileptic drugs, phenytoin chewable tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Disc\">\n<li>Thoughts about suicide or dying</li>\n<li>Attempts to commit suicide</li>\n<li>New or worse depression</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>New or worse anxiety</li>\n<li>Feeling agitated or restless</li>\n<li>Panic attacks</li>\n</ul>\n</td><td align=\"left\">\n<ul>\n<li>Trouble sleeping (insomnia)</li>\n<li>New or worse irritability</li>\n<li>Acting aggressive, being angry, or violent</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>Acting on dangerous impulses</li>\n<li>An extreme increase in activity and talking (mania)</li>\n<li>Other unusual changes in behavior or mood</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\">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.\n <br/>\n<br/>\n<span class=\"Bold\">How can I watch for early symptoms of suicidal thoughts and actions?</span>\n<ul class=\"Disc\">\n<li>Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.</li>\n<li>Keep all follow-up visits with your healthcare provider as scheduled.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\">Call your healthcare provider between visits as needed, especially if you are worried about symptoms.\n\t\t\t\n <ul>\n<li>\n<span class=\"Bold\">Phenytoin chewable tablets can cause a type of serious allergic reaction that may affect different parts of the body such as your liver, kidneys, blood, heart, skin or other parts of your body. These can be very serious and cause death. Call your healthcare provider right away if you have any or all of these symptoms:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Fever</li>\n<li>Rash</li>\n<li>Swollen lymph glands</li>\n<li>Swelling of your face, eye, lips, or tongue</li>\n<li>Trouble swallowing or breathing</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Sore throat</li>\n<li>Sores in your mouth</li>\n<li>Bruise easily</li>\n<li>Purple or red spots on your skin</li>\n<li>Increase infections</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>Not wanting to eat (anorexia)</li>\n<li>Nausea</li>\n<li>Vomiting</li>\n<li>Yellowing of the skin and the white part of your eyes (jaundice)</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\">Call your healthcare provider even if the symptoms are mild or if you have been taking phenytoin for an extended period of time. These symptoms can be a sign of a serious allergic reaction.\n\t\t\t\n <ul>\n<li>\n<span class=\"Bold\">Phenytoin chewable tablets can cause problems with your heart, including a slow heartbeat. Let your healthcare provider know right away if you have any of these symptoms:</span>\n<ul class=\"Disc\">\n<li>dizziness</li>\n<li>tiredness</li>\n<li>feeling like your heart is beating slowly or skipping beats</li>\n<li>chest pain</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">What are phenytoin chewable tablets?</span>\n<br/>\n<br/>\n\t\t\tPhenytoin chewable tablets is a prescription medicine used to treat certain types of seizures called tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">Do not take phenytoin chewable tablets if you:</span>\n<ul class=\"Disc\">\n<li>Are allergic to phenytoin or any of the ingredients in phenytoin chewable tablets. See the end of this leaflet for a complete list of ingredients in phenytoin chewable tablets.</li>\n<li>Have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).</li>\n<li>Have had liver problems from taking phenytoin.</li>\n<li>Take delavirdine.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">Before taking phenytoin chewable tablets, tell your healthcare provider about all of your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>Have or have had depression, mood problems, or suicidal thoughts or behavior</li>\n<li>Have had an allergic reaction to a medicine similar to phenytoin called carboxamides, barbiturates, succinimides, and oxazolidinediones</li>\n<li>Have or had liver or kidney problems</li>\n<li>Have or had an enzyme problem called porphyria</li>\n<li>Have or had high blood sugar (hyperglycemia)</li>\n<li>Drink alcohol</li>\n<li>Are pregnant or plan to become pregnant. Phenytoin chewable tablets may harm your unborn baby.\n\t\t\t\t\n <ul class=\"Circle\">\n<li>If you take phenytoin chewable tablets during pregnancy, your baby is at risk for serious birth defects.</li>\n<li>If you become pregnant while taking phenytoin chewable tablets, the level of phenytoin in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of phenytoin chewable tablets.</li>\n<li>If you take phenytoin chewable tablets 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.</li>\n<li>All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of phenytoin chewable tablets.</li>\n<li>If you are of childbearing age and are not planning on getting pregnant, you should use effective birth control (contraception) while taking phenytoin chewable tablets.</li>\n<li>\n<span class=\"Bold\">Pregnancy Registry:</span> If you become pregnant while taking phenytoin chewable tablets, 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.\n </li>\n</ul>\n</li>\n<li>Are breastfeeding or plan to breastfeed. Phenytoin can pass into breast milk. You and your healthcare provider should decide if you will take phenytoin chewable tablets while you are breastfeeding.</li>\n</ul>\n\t\t\tTell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. These medicines can change the levels of phenytoin in your blood.\n <br/>\n<br/>\n\t\t\tTaking phenytoin chewable tablets with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.\n <br/>\n<br/>\n\t\t\tKnow the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">How should I take phenytoin chewable tablets?</span>\n<ul class=\"Disc\">\n<li>Take phenytoin chewable tablets exactly as your healthcare provider tells you.</li>\n<li>Your healthcare provider will tell you how much phenytoin chewable tablets to take and when to take it.</li>\n<li>Your healthcare provider may change your dose if needed. Do not change your dose of phenytoin chewable tablets without talking to your healthcare provider.</li>\n<li>If your healthcare provider has prescribed phenytoin oral suspension, ask your pharmacist for a medicine dropper or medicine cup to help you measure the correct amount of phenytoin. \n <span class=\"Bold\">Do not</span> use a household teaspoon. Ask your pharmacist for instructions on how to use the measuring device the right way.\n </li>\n</ul>\n\t\t\tDo not stop taking phenytoin chewable tablets without first talking to your healthcare provider. Stopping phenytoin suddenly can cause serious problems.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">What should I avoid while taking phenytoin chewable tablets?</span>\n<ul class=\"Disc\">\n<li>Do not drink alcohol while you take phenytoin chewable tablets without first talking to your healthcare provider. Drinking alcohol while taking phenytoin chewable tablets may change your blood levels of phenytoin which can cause serious problems.</li>\n</ul>\n\t\t\tDo not drive, operate heavy machinery, or do other dangerous activities until you know how phenytoin chewable tablets affect you. Phenytoin can slow your thinking and motor skills.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">What are the possible side effects of phenytoin chewable tablets?</span>\n<br/>\n<br/>\n\t\t\tSee \n <span class=\"Bold\">\" \n <a href=\"#Important\">What is the most important information I should know about phenytoin chewable tablets?</a>\"\n <br/>\n<br/>\n\t\t\tPhenytoin chewable tablets may cause other serious side effects including: \n </span>\n<ul class=\"Disc\">\n<li>Liver problems.</li>\n<li>Low blood count which could increase your chance of getting infections, bruising, bleeding and increased fatigue.</li>\n<li>Softening of your bones (osteopenia, osteoporosis, and osteomalacia) can cause your bones to break (fractures).</li>\n<li>High blood sugar (hyperglycemia).</li>\n<li>High levels of phenytoin in your blood that could cause confusion also known as delirium, psychosis or a more serious condition that affects how your brain works (encephalopathy).</li>\n</ul>\n\t\t\tCall your healthcare provider right away, if you have any of the symptoms listed above.\n <br/>\n<br/>\n\t\t\tThe most common side effects of phenytoin chewable tablets include:\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>Irregular movement of the eye (nystagmus)</li>\n<li>Problems with movement and balance (ataxia)</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>Slurred speech</li>\n<li>Decrease in coordination</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Disc\">\n<li>Drowsiness (somnolence)</li>\n<li>Confusion</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\">Phenytoin can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking phenytoin chewable tablets can help prevent this from happening.\n <br/>\n<br/>\n\t\t\tThese are not all of the possible side effects of phenytoin chewable tablets.\n <br/>\n<br/>\n\t\t\tCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">How should I store phenytoin chewable tablets?</span>\n<ul class=\"Disc\">\n<li>Store phenytoin chewable tablets at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Protect from moisture.</li>\n</ul>\n<span class=\"Bold\">Keep phenytoin chewable tablets and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">General information about the safe and effective use of phenytoin chewable tablets.</span>\n<br/>\n<br/>\n\t\t\tMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use phenytoin chewable tablets for a condition for which it was not prescribed. Do not give phenytoin chewable tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about phenytoin chewable tablets that is written for health professionals.\n </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"6\"><span class=\"Bold\">What are the ingredients in phenytoin chewable tablets?</span>\n<br/>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> 50 mg phenytoin, USP.\n <br/>\n<br/>\n<span class=\"Bold\">Inactive ingredients:</span> Artificial banana flavor, compressible sugar, D&amp;C yellow No. 10 aluminum lake, FD&amp;C yellow No. 6 aluminum lake, hypromellose 2208, lactose monohydrate, magnesium stearate, saccharin sodium, and talc.\n <br/>\n<br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Repackaged By / Distributed By: RemedyRepack Inc.

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625 Kolter Drive, Indiana, PA 15701

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(724) 465-8762

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5200701-0622-10

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DRUG: Phenytoin

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GENERIC: Phenytoin

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DOSAGE: TABLET, CHEWABLE

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ADMINSTRATION: ORAL

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NDC: 70518-0841-0

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NDC: 70518-0841-1

{ "type": "p", "children": [], "text": "NDC: 70518-0841-1" }

NDC: 70518-0841-2

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COLOR: yellow

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SHAPE: ROUND

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SCORE: Two even pieces

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SIZE: 11 mm

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IMPRINT: T;50

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PACKAGING: 30 in 1 BLISTER PACK

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PACKAGING: 100 in 1 BOX

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PACKAGING: 1 in 1 POUCH

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ACTIVE INGREDIENT(S):

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INACTIVE INGREDIENT(S):

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{ "type": "ul", "children": [ "Lactose monohydrate", "Saccharin sodium", "D&C Yellow No. 10", "FD&C Yellow No. 6", "aluminum oxide", "Talc", "Magnesium Stearate", "Hypromellose, Unspecified", "Sucrose" ], "text": "" }