phenytoin 50 MG Chewable Tablet [Dilantin]

INDICATIONS AND USAGE 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 Sodium Injection 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) ]. 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.

DOSAGE AND ADMINISTRATION For Status Epilepticus and Non-emergent Loading Dose: Adult loading dose is 10 to 15 mg/kg at a rate not exceeding 50 mg/min. ( 2.2 ) Pediatric loading dose is 15 to 20 mg/kg at a rate not exceeding 1 to 3 mg/kg/min or 50 mg/min, whichever is slower. ( 2.8 ) Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. ( 2.2 ) Maintenance Dosing: Initial loading dose should be followed by maintenance doses of oral or intravenous Phenytoin Sodium Injection every 6 to 8 hours. ( 2.2 , 2.3 ) Intramuscular Administration: Because of erratic absorption and local toxicity, Phenytoin Sodium Injection should ordinarily not be given intramuscularly. ( 2.2 , 2.3 ) 2.1 General Dosing Information 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. 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. Phenytoin Sodium Injection can be given diluted with normal saline. The addition 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: 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. 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. 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. For single-dose only. After opening, any unused product should be discarded. M onitoring 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 and 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 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 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. 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 epilepticus 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. 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. 2.3 Non-emergent Loading and Maintenance Dosing 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. 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. 2.4 Parenteral Substitution for Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, IV phenytoin can be substituted for oral phenytoin at the

WARNINGS AND PRECAUTIONS Withdrawal Precipitated Seizure : May precipitate status epilepticus. Dose reductions or discontinuation should be done gradually. ( 5.2 ) Serious Dermatologic Reactions : Discontinue phenytoin 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. ( 5.3 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity : If signs or symptoms of hypersensitivity are present, evaluate the patient immediately. Discontinue if an alternative etiology cannot be established. ( 5.4 ) Hematopoietic Complications: If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used. ( 5.7 ) 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. 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. 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. 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. 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) ] . 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. 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. 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. 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. 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. 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 rel

CONTRAINDICATIONS 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)] . • 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)] . • 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. • Hypersensitivity to phenytoin, its ingredients, or other hydantoins (4) • Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome (4) • A history of prior acute hepatotoxicity attributable to phenytoin (4, 5.6) • Coadministration with delavirdine (4)

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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 Absorption 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. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the phenytoin sodium injection IM 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). Distribution Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Elimination The serum half-life in man after intravenous administration ranges from 10 to 15 hours. Metabolism Phenytoin is metabolized by the hepatic cytochrome P450 enzymes CYP2C9 and to a lesser extent by CYP2C19. Excretion 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 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 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 )] . 12.4 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). The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2-3% in the White population, 0.54% 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) ] .