PHENYTOIN SODIUM

1 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 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. (1)

2 DOSAGE AND ADMINISTRATION 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 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: 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. 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)]. 2.2 Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be admini…

5 WARNINGS AND PRECAUTIONS 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…

4 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)

7 DRUG INTERACTIONS 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. 7.1 Drugs That Affect Phenytoin Concentrations 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. 7.2 Drugs Affected by Phenytoin 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 Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations following fosphenytoin administration. Multiple drug interactions because of extensive plasma protein binding, saturable metabolism and potent induction of hepatic enzymes. (7.1, 7.2) Image1.jpg Image2.jpg

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Cardiovascular Risk Associated with Rapid Infusion [see Warnings and Precautions (5.1)] • Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.2)] • 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)] • Hypersensitivity [see Warnings and Precautions (5.5)] • Hepatic Injury [see Warnings and Precautions (5.6)] • Hematopoietic Complications [see Warnings and Precautions (5.7)] • Local toxicity (Including Purple Glove Syndrome) [see Warnings and Precautions (5.8)] • Exacerbation of Porphyria [see Warnings and Precautions (5.10)] • Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.11)] • 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. 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. 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)]. 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. 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)]. 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). 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, …