WARNING AND CAUTIONS

5 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.

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.

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 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.

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.

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.

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.

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.

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)].

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.

5.12 Slow Metabolizers of Phenytoin A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly.

Slow metabolism may be caused by limited enzyme availability and lack of induction; it appears to be genetically determined.

If early signs of dose-related central nervous system (CNS) toxicity develop, serum levels should be checked immediately.

5.13 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.

5.14 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.