FDA label 492a8728-d60f-41ea-bedd-ead7375f3ad5

BOXED WARNING WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Phenytoin administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Phenytoin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed (see WARNINGS and DOSAGE AND ADMINISTRATION).

WARNINGS Cardiovascular Risk Associated with Rapid Infusion 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 1-3 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. Adverse cardiovascular reactions include 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. 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 judgement 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. 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 (see DRESS/Multiorgan hypersensitivity below). 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. Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502. The use of HLA-B*1502 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)/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, and/or lymphadenopathy, 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. Hyersensitivity Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS ). 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. 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. 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. Hematopoietic 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. 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. 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. 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. 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 due to 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 ). Alcohol Use Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. 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. Usage In pregnancy Clinical Risks to Mother An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests ). However, postpartum restoration of the original dosage will probably be indicated. Risks to the Fetus If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. Increased frequencies of major malformations (such as profacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two to three fold that in the general population. However, the relative contribution of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy. Postpartum Period 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. Preclinical Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher(approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.

ADVERSE REACTIONS The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system 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 1-3 mg/ kg/ min (or 50 mg per minute, whichever is slower) in pediatric patients. 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 ) 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 WARNINGS ). Nervous System The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, 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. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Digestive System Nausea, vomiting, constipation, enlargement of the lips, gingival hyperplasia, toxic hepatitis and liver damage. 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 ). 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 ). 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 ). Special Senses Altered taste sensation including metallic taste. Urogenital Peyronie’s disease. To report SUSPECTED ADVERSE REACTIONS, contact X-GEN Pharmaceuticals, Inc. at 1-866-390-4411 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.