Phenytoin (injection)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
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Black Box Warning
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WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION
See full prescribing information for complete Boxed Warning.
The rate of intravenous Phenytoin Sodium Injection 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 Sodium Injection. 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.
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Overview
Phenytoin (injection) is an antiepileptic that is FDA approved for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Parenteral phenytoin should be used only when oral phenytoin administration is not possible. There is a Black Box Warning for this drug as shown here. Common adverse reactions include morbilliform eruption, rash, drug-induced gingival hyperplasia, ataxia, decreased coordination, nystagmus, Slurred speech and confusion.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
Parenteral Phenytoin Sodium Injection is indicated for the control of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Parenteral phenytoin should be used only when oral phenytoin administration is not possible.
Dosage
- 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
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phenytoin (injection) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phenytoin (injection) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Phenytoin (injection) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Phenytoin (injection) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Phenytoin (injection) in pediatric patients.
Contraindications
Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins.
Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome.
Coadministration of phenytoin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.
Warnings
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WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION
See full prescribing information for complete Boxed Warning.
The rate of intravenous Phenytoin Sodium Injection 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 Sodium Injection. 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.
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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 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.
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.
Hypersensitivity 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).
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.
Precations
General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity.
A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined.
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.
Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.
Phenytoin is not effective for absence seizures. If tonic-clonic and absence seizures are present, combined drug therapy is needed.
Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium", "psychosis', or “encephalopathy”, or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended (see WARNINGS).
Laboratory Tests Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL).
Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma 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.
Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It 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).
Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration.
Adverse Reactions
Clinical Trials Experience
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 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.
A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
Digestive System Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.
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 section).
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.
Postmarketing Experience
There is limited information regarding Phenytoin (injection) Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Phenytoin (injection) Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): D 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 orofacial 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Phenytoin (injection) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Phenytoin (injection) during labor and delivery.
Nursing Mothers
Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk.
Pediatric Use
There is no FDA guidance on the use of Phenytoin (injection) in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Phenytoin (injection) in geriatric settings.
Gender
There is no FDA guidance on the use of Phenytoin (injection) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Phenytoin (injection) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Phenytoin (injection) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Phenytoin (injection) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Phenytoin (injection) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Phenytoin (injection) in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Phenytoin (injection) Administration in the drug label.
Monitoring
There is limited information regarding Phenytoin (injection) Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Phenytoin (injection) and IV administrations.
Overdosage
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, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.
There are marked variations among individuals with respect to phenytoin plasma 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 plasma 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.
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.
Pharmacology
There is limited information regarding Phenytoin (injection) Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Phenytoin (injection) Mechanism of Action in the drug label.
Structure
There is limited information regarding Phenytoin (injection) Structure in the drug label.
Pharmacodynamics
There is limited information regarding Phenytoin (injection) Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Phenytoin (injection) Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Phenytoin (injection) Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Phenytoin (injection) Clinical Studies in the drug label.
How Supplied
Phenytoin Sodium Injection, USP—50 mg/mL
2 mL (100 mg) Single Dose vials packaged in 25s (NDC 0641-6138-25)
5 mL (250 mg) Single Dose vials packaged in 25s (NDC 0641-6139-25)
Storage
Store at 20°-25°C (68°-77°F), excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].
Images
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Patient Counseling Information
There is limited information regarding Phenytoin (injection) Patient Counseling Information in the drug label.
Precautions with Alcohol
Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels.
Brand Names
There is limited information regarding Phenytoin (injection) Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Phenytoin (injection) Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.