{"id":"dilantin","rwe":[],"_fda":{"id":"1b68e42c-ebb1-4798-adba-712a41cd1cf4","set_id":"035a8d4e-2063-4240-83cb-d7eebcabe301","openfda":{"upc":["0306410493259"],"unii":["4182431BJH"],"route":["INTRAMUSCULAR","INTRAVENOUS"],"rxcui":["1670351","1670353"],"spl_id":["1b68e42c-ebb1-4798-adba-712a41cd1cf4"],"brand_name":["Phenytoin Sodium"],"spl_set_id":["035a8d4e-2063-4240-83cb-d7eebcabe301"],"package_ndc":["0641-0493-21","0641-0493-25","0641-2555-41","0641-2555-10","0641-2555-45"],"product_ndc":["0641-0493","0641-2555"],"generic_name":["PHENYTOIN SODIUM"],"product_type":["HUMAN PRESCRIPTION DRUG"],"substance_name":["PHENYTOIN SODIUM"],"manufacturer_name":["Hikma Pharmaceuticals USA Inc."],"application_number":["ANDA084307"],"is_original_packager":[true]},"version":"27","pregnancy":["8.1 Pregnancy P regnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as Phenytoin Sodium Injection, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Risk Summary In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations (including orofacial clefts and cardiac defects). In addition, the fetal hydantoin syndrome a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data ] . There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data ]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated maternal risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.1 , 2.7) ] . However, postpartum restoration of the original dosage will probably be indicated. Fetal/Neonatal adverse reactions 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. Data Human Data Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantion syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies. Animal Data Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth retardation. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively."],"overdosage":["10 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, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Death is caused by respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin serum 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 serum 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. Irreversible cerebellar dysfunction and atrophy have been reported. 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."],"description":["11 DESCRIPTION Phenytoin Sodium Injection, USP is a sterile solution containing in each mL phenytoin sodium 50 mg, propylene glycol 0.4 mL and alcohol 0.1 mL in Water for Injection. pH 10.0-12.3; sodium hydroxide added, if needed, for pH adjustment. Phenytoin sodium is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is sodium 5,5-diphenyl-2,4-imidazolidinedione represented by the following structural formula: C 15 H 11 N 2 NaO 2 MW 274.25 structure"],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Phenytoin Sodium Injection, USP—50 mg/mL 2 mL (100 mg) Single Dose vials packaged in 25s (NDC 0641-0493-25) 5 mL (250 mg) Single Dose vials packaged in 10s (NDC 0641-2555-10) 16.2 Storage and Handling For single-dose only. After opening, any unused product should be discarded. Store at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]."],"boxed_warning":["WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Phenytoin Sodium Injection 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 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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ] . W ARN ING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION S ee 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 to 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. Reduction in rate of administration or discontinuation of dosing may be needed ( 2.1 , 5.1 )."],"geriatric_use":["8.5 Geriatric Use Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3) ] . Lower or less frequent dosing may be required [see Dosage and Administration (2.6) ]."],"pediatric_use":["8.4 Pediatric Use A loading dose of 15 to 20 mg/kg of Phenytoin Sodium Injection 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). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Phenytoin Sodium Injection should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower [see Dosage and Administration (2.8) and Warnings and Precautions (5.1) ]."],"effective_time":"20240409","pharmacokinetics":["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 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) ]. S e x /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. P regnancy: 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 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) ] ."],"adverse_reactions":["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 W arnings 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 (5.12) ] The following adverse reactions associated with the use of Phenytoin Sodium Injection were identified in clinical studies or postmarketing 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 Wa rnings 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, 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. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.13) ] . A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy. Sk in 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 and Precautions (5.3) ] . 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 and Precautions (5.8) ] . Sp ec ial Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie’s disease The most common adverse reactions are nervous system reactions, including nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ."],"contraindications":["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 )"],"drug_interactions":["7 DRUG INTERACTIONS Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by hepatic cytochrome P450 enzymes CYP2C9 and to a lesser extent by 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. Multiple drug interactions because of extensive plasma protein binding, saturable metabolism and potent induction of hepatic enzymes. ( 7.1 , 7.2 ) 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. Table 1: Drugs That Affect Phenytoin Concentrations Interacting Agent Examples Drugs that may increase phenytoin serum levels Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agents Capecitabine, fluorouracil Antidepressants Fluoxetine, fluvoxamine, sertraline Gastric acid reducing agents H 2 antagonists (cimetidine), omeprazole Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole trimethoprim Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin Drugs that may decrease phenytoin serum levels Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort b , theophylline Drugs that may either increase or decrease phenytoin serum levels Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid b The induction potency of St. John’s wort may vary widely based on preparation. 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 of the dose of these agents to achieve optimal clinical outcome. Table 2: Drugs Affected by Phenytoin Interacting Agent Examples Drugs whose efficacy is impaired by phenytoin Azoles Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole Antineoplastic agents Irinotecan, paclitaxel, teniposide Delavirdine Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4) ]. Neuromuscular blocking agents Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management : Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher. Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Antiepileptic drugs a Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine a The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable 7.3 Drug/Laboratory Test Interactions Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations following fosphenytoin administration."],"labor_and_delivery":["8.2 Lactation Risk Summary Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Phenytoin Sodium Injection and any potential adverse effects on the breastfed infant from Phenytoin Sodium Injection or from the underlying maternal condition."],"mechanism_of_action":["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."],"recent_major_changes":["RECENT MAJOR CHANGES Warnings and Precautions ( 5.3 ) 02/2021"],"clinical_pharmacology":["12 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 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) ]. S e x /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. P regnancy: 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 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) ] . 12.5 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, 0.5-4% 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) ] ."],"indications_and_usage":["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 )"],"warnings_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. 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 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 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. 5.13 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."],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis [see Warnings and Precautions (5.7) ] In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations. In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Mutagenesis Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells. Fe rtility Phenytoin has not been adequately assessed for effects on male or female fertility."],"drug_interactions_table":["
Interacting Agent Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugsEthosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
AzolesFluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agentsCapecitabine, fluorouracil
AntidepressantsFluoxetine, fluvoxamine, sertraline
Gastric acid reducing agentsH2 antagonists (cimetidine), omeprazole
SulfonamidesSulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole trimethoprim
OtherAcute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antineoplastic agents usually in combinationBleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agentsFosamprenavir, nelfinavir, ritonavir
Antiepileptic drugsCarbamazepine, vigabatrin
OtherChronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wortb, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugsPhenobarbital, valproate sodium, valproic acid
","
Interacting Agent Examples
Drugs whose efficacy is impaired by phenytoin
AzolesFluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agentsIrinotecan, paclitaxel, teniposide
DelavirdinePhenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agentsCisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
WarfarinIncreased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
OtherCorticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugsaCarbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine
Antilipidemic agentsAtorvastatin, fluvastatin, simvastatin
Antiviral agentsEfavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockersNifedipine, nimodipine, nisoldipine, verapamil
OtherAlbendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine
"],"information_for_patients":["17 PATIENT COUNSELING INFORMATION W ithdrawal of Antiepileptic Drugs Advise patients not to discontinue use of phenytoin without consulting with their healthcare provider. Phenytoin should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.2) ] . P otential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic R eac tions Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7) ] . Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [see Warnings and Precautions (5.9) and Drug Interactions (7.1, 7.2) ] . Inform patients that certain over-the-counter medications (e.g., cimetidine and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels. Hyperglycemia Advise patients that phenytoin may cause an increase in blood glucose levels [see Warnings and Precautions ( 5.12) ] . Gingival Hyperplasia Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications. Neurologic Effects Counsel patients that phenytoin may cause dizziness, gait disturbance, decreased coordination and somnolence. Advise patients taking phenytoin not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with phenytoin. Use in Pregnancy Inform pregnant women and women of childbearing potential that use of phenytoin during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using phenytoin, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2) ]. Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2) ] . Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1) ] . Manufactured by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Revised December 2022 462-348-13"],"dosage_and_administration":["2 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 same total daily dose. Phenytoin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, serum phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV phenytoin should be no greater than 50 mg per minute in adults and 1 to 3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the serum level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to minimize toxic symptoms [see Clinical Pharmacology (12.3) ]. Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Phenytoin Sodium Injection is formulated with the sodium salt of phenytoin. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa. 2.5 Dosing in Patients with 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. 2.6 Dosing in Geriatrics Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3) ]. 2.7 Dosing During Pregnancy Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the Phenytoin Sodium Injection dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1) ]. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction. 2.8 Dosing in Pediatrics A loading dose of 15 to 20 mg/kg of Phenytoin Sodium Injection 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."],"spl_product_data_elements":["Phenytoin Sodium Phenytoin Sodium PHENYTOIN SODIUM PHENYTOIN PROPYLENE GLYCOL ALCOHOL WATER SODIUM HYDROXIDE Phenytoin Sodium Phenytoin Sodium PHENYTOIN SODIUM PHENYTOIN PROPYLENE GLYCOL ALCOHOL WATER SODIUM HYDROXIDE"],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS Phenytoin Sodium Injection, USP: 50 mg phenytoin sodium per milliliter is available as: 2 mL (100 mg) Single Dose vials 5 mL (250 mg) Single Dose vials Injection: 50 mg phenytoin sodium per milliliter in: 2 mL and 5 mL single dose vials ( 3 )"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS Pregnancy: Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. ( 5.11 , 8.1 ) Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients. ( 8.6 ) 8.1 Pregnancy P regnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as Phenytoin Sodium Injection, during pregnancy. Physicians are advised to recommend that pregnant patients taking phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ . Risk Summary In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations (including orofacial clefts and cardiac defects). In addition, the fetal hydantoin syndrome a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy [see Data ] . There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data ]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated maternal risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.1 , 2.7) ] . However, postpartum restoration of the original dosage will probably be indicated. Fetal/Neonatal adverse reactions 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. Data Human Data Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantion syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies. Animal Data Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth retardation. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively. 8.2 Lactation Risk Summary Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Phenytoin Sodium Injection and any potential adverse effects on the breastfed infant from Phenytoin Sodium Injection or from the underlying maternal condition. 8.4 Pediatric Use A loading dose of 15 to 20 mg/kg of Phenytoin Sodium Injection 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). Because of the increased risk of adverse cardiovascular reactions associated with rapid administration Phenytoin Sodium Injection should be injected slowly intravenously at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower [see Dosage and Administration (2.8) and Warnings and Precautions (5.1) ]. 8.5 Geriatric Use Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3) ] . Lower or less frequent dosing may be required [see Dosage and Administration (2.6) ]. 8.6 Renal and/or Hepatic Impairment or Hypoalbuminemia The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity. 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. 8.7 Use in Patients with Decreased CYP2C9 Function Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g.,*1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1 ). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5) ] ."],"package_label_principal_display_panel":["PRINCIPAL DISPLAY PANEL NDC 0641- 0493 -21 Rx only Phenytoin Sodium Inj., USP 100 mg per 2 mL (50 mg/mL) For IV or IM use Do not use if hazy or has a precipitate 2 mL Single Dose Vial NDC 0641- 0493 -25 Rx only Phenytoin Sodium Injection, USP 100 mg per 2 mL (50 mg/mL) For Intravenous or Intramuscular use 25 x 2 mL Single Dose Vials vial sp","PRINCIPAL DISPLAY PANEL NDC 0641- 2555 -41 Rx only Phenytoin Sodium Inj., USP 250 mg per 5 mL (50 mg/mL) For IV or IM use 5 mL Single Dose Vial NDC 0641- 2555 -10 Rx only Phenytoin Sodium Injection, USP 250 mg per 5 mL (50 mg/mL) For Intravenous or Intramuscular use 10 x 5 mL Single Dose Vials vial carton label"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis [see Warnings and Precautions (5.7) ] In carcinogenicity studies, phenytoin was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak serum phenytoin levels below human therapeutic concentrations. In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 90 mg/kg/day) to mice and up to 2400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats. Mutagenesis Phenytoin was negative in the Ames test and in the in vitro clastogenicity assay in Chinese hamster ovary (CHO) cells. In studies reported in the literature, phenytoin was negative in the in vitro mouse lymphoma assay and the in vivo micronucleus assay in mouse. Phenytoin was clastogenic in the in vitro sister chromatid exchange assay in CHO cells. Fe rtility Phenytoin has not been adequately assessed for effects on male or female fertility."]},"tags":[],"safety":{"boxedWarnings":["WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Phenytoin Sodium Injection 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 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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ] . W ARN ING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION S ee 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 to 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. Reduction in rate of administration or discontinuation of dosing may be needed ( 2.1 , 5.1 )."],"safetySignals":[{"date":"","signal":"CONVULSION","source":"FDA FAERS","actionTaken":"2384 reports"},{"date":"","signal":"DRUG INEFFECTIVE","source":"FDA FAERS","actionTaken":"1842 reports"},{"date":"","signal":"SEIZURE","source":"FDA FAERS","actionTaken":"1723 reports"},{"date":"","signal":"FALL","source":"FDA FAERS","actionTaken":"1018 reports"},{"date":"","signal":"DIZZINESS","source":"FDA FAERS","actionTaken":"965 reports"},{"date":"","signal":"DRUG HYPERSENSITIVITY","source":"FDA FAERS","actionTaken":"942 reports"},{"date":"","signal":"HEADACHE","source":"FDA FAERS","actionTaken":"924 reports"},{"date":"","signal":"FATIGUE","source":"FDA FAERS","actionTaken":"875 reports"},{"date":"","signal":"NAUSEA","source":"FDA FAERS","actionTaken":"786 reports"},{"date":"","signal":"DRUG INTERACTION","source":"FDA FAERS","actionTaken":"713 reports"}],"drugInteractions":[{"name":"CYP2B6 Substrates","source":"DrugCentral","severity":"Potentially significant","description":"Strong CYP2B6 Inducers - CYP2B6 Substrates"},{"name":"CYP2C19 Substrates","source":"DrugCentral","severity":"Potentially significant","description":"Strong CYP2C19 Inducers - CYP2C19 Substrates"},{"name":"CYP2C8 Substrates","source":"DrugCentral","severity":"Potentially significant","description":"Strong CYP2C8 Inducers - CYP2C8 Substrates"},{"name":"CYP2C9 Substrates","source":"DrugCentral","severity":"Potentially significant","description":"Strong CYP2C9 Inducers - CYP2C9 Substrates"},{"name":"CYP3A4 Substrates","source":"DrugCentral","severity":"Potentially significant","description":"Strong CYP3A4 Inducers - CYP3A4 Substrates"},{"name":"P-glycoprotein Substrates","source":"DrugCentral","severity":"Potentially significant","description":"P-glycoprotein Inducers - P-glycoprotein Substrates"},{"name":"aripiprazole","source":"DrugCentral","severity":"Significant","description":"ARIPIPRAZOLE/PHENYTOIN [VA Drug Interaction]"},{"name":"fluorouracil","source":"DrugCentral","severity":"Significant","description":"FLUOROURACIL/PHENYTOIN [VA Drug Interaction]"},{"name":"metyrapone","source":"DrugCentral","severity":"Significant","description":"METYRAPONE/PHENYTOIN [VA Drug Interaction]"},{"name":"mexiletine","source":"DrugCentral","severity":"Significant","description":"MEXILETINE/PHENYTOIN [VA Drug Interaction]"},{"name":"quetiapine","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/QUETIAPINE FUMARATE [VA Drug Interaction]"},{"name":"quinestrol","source":"DrugCentral","severity":"Critical","description":"PHENYTOIN/QUINESTROL [VA Drug Interaction]"},{"name":"raltegravir","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/RALTEGRAVIR [VA Drug Interaction]"},{"name":"ranolazine","source":"DrugCentral","severity":"Critical","description":"PHENYTOIN/RANOLAZINE [VA Drug Interaction]"},{"name":"rifampicin","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/RIFAMPIN [VA Drug Interaction]"},{"name":"risperidone","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/RISPERIDONE [VA Drug Interaction]"},{"name":"ritonavir","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/RITONAVIR [VA Drug Interaction]"},{"name":"rufinamide","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/RUFINAMIDE [VA Drug Interaction]"},{"name":"saquinavir","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/SAQUINAVIR [VA Drug Interaction]"},{"name":"sirolimus","source":"DrugCentral","severity":"Significant","description":"PHENYTOIN/SIROLIMUS [VA Drug Interaction]"}],"commonSideEffects":[{"effect":"Withdrawal Precipitated Seizure, Status Epilepticus","drugRate":"Not specified","severity":"serious"},{"effect":"Suicidal Behavior and Ideation","drugRate":"Not specified","severity":"serious"},{"effect":"Serious Dermatologic Reactions","drugRate":"Not specified","severity":"serious"},{"effect":"Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity","drugRate":"Not specified","severity":"serious"},{"effect":"Hypersensitivity","drugRate":"Not specified","severity":"serious"},{"effect":"Cardiac Effects","drugRate":"Not specified","severity":"serious"},{"effect":"Angioedema","drugRate":"Not specified","severity":"serious"},{"effect":"Hepatic Injury","drugRate":"Not specified","severity":"serious"},{"effect":"Hematopoietic Complications","drugRate":"Not specified","severity":"serious"},{"effect":"Effects on Vitamin D and Bone","drugRate":"Not specified","severity":"serious"},{"effect":"Exacerbation of Porphyria","drugRate":"Not specified","severity":"serious"},{"effect":"Teratogenicity and Other Harm to the Newborn","drugRate":"Not specified","severity":"serious"},{"effect":"Hyperglycemia","drugRate":"Not specified","severity":"serious"},{"effect":"Allergic reactions","drugRate":"Not specified","severity":"mild|serious"},{"effect":"Anaphylaxis","drugRate":"Not specified","severity":"serious"},{"effect":"Coarsening of facial features","drugRate":"Not specified","severity":"mild"},{"effect":"Systemic lupus erythematosus","drugRate":"Not specified","severity":"serious"},{"effect":"Periarteritis nodosa","drugRate":"Not specified","severity":"serious"},{"effect":"Immunoglobulin abnormalities","drugRate":"Not specified","severity":"serious"},{"effect":"Acute hepatic failure","drugRate":"Not specified","severity":"serious"},{"effect":"Toxic hepatitis","drugRate":"Not specified","severity":"serious"},{"effect":"Liver damage","drugRate":"Not specified","severity":"serious"},{"effect":"Nausea","drugRate":"Not specified","severity":"mild"},{"effect":"Vomiting","drugRate":"Not specified","severity":"mild"},{"effect":"Constipation","drugRate":"Not specified","severity":"mild"},{"effect":"Enlargement of the lips","drugRate":"Not specified","severity":"mild"},{"effect":"Gingival hyperplasia","drugRate":"Not specified","severity":"mild"},{"effect":"Thrombocytopenia","drugRate":"Not specified","severity":"serious"},{"effect":"Leukopenia","drugRate":"Not specified","severity":"serious"},{"effect":"Granulocytopenia","drugRate":"Not specified","severity":"serious"},{"effect":"Agranulocytosis","drugRate":"Not specified","severity":"serious"},{"effect":"Pancytopenia","drugRate":"Not specified","severity":"serious"},{"effect":"Macrocytosis","drugRate":"Not specified","severity":"mild"},{"effect":"Megaloblastic anemia","drugRate":"Not specified","severity":"mild"},{"effect":"Lymphadenopathy","drugRate":"Not specified","severity":"serious"},{"effect":"Pseudolymphoma","drugRate":"Not specified","severity":"serious"},{"effect":"Lymphoma","drugRate":"Not specified","severity":"serious"},{"effect":"Hodgkin’s disease","drugRate":"Not specified","severity":"serious"},{"effect":"Pure red cell aplasia","drugRate":"Not specified","severity":"serious"},{"effect":"Phenytoin may decrease serum concentrations of thyroid hormone","drugRate":"Not specified","severity":"mild"},{"effect":"Phenytoin may produce lower than normal values for dexamethasone or metyrapone tests","drugRate":"Not specified","severity":"mild"},{"effect":"Phenytoin may cause increased serum levels of glucose","drugRate":"Not specified","severity":"mild"},{"effect":"Phenytoin may cause increased serum levels of alkaline phosphatase","drugRate":"Not specified","severity":"mild"},{"effect":"Phenytoin may cause increased serum levels of gamma glutamyl transpeptidase (GGT)","drugRate":"Not specified","severity":"mild"},{"effect":"Nystagmus","drugRate":"Not specified","severity":"mild"},{"effect":"Ataxia","drugRate":"Not specified","severity":"mild"},{"effect":"Slurred speech","drugRate":"Not specified","severity":"mild"},{"effect":"Decreased coordination","drugRate":"Not specified","severity":"mild"},{"effect":"Somnolence","drugRate":"Not specified","severity":"mild"},{"effect":"Mental confusion","drugRate":"Not specified","severity":"mild"},{"effect":"Dizziness","drugRate":"Not specified","severity":"mild"},{"effect":"Vertigo","drugRate":"Not specified","severity":"mild"},{"effect":"Insomnia","drugRate":"Not specified","severity":"mild"},{"effect":"Transient nervousness","drugRate":"Not specified","severity":"mild"},{"effect":"Motor twitchings","drugRate":"Not specified","severity":"mild"},{"effect":"Paresthesias","drugRate":"Not specified","severity":"mild"},{"effect":"Headaches","drugRate":"Not specified","severity":"mild"},{"effect":"Phenytoin-induced dyskinesias","drugRate":"Not specified","severity":"serious"},{"effect":"Chorea","drugRate":"Not specified","severity":"serious"},{"effect":"Dystonia","drugRate":"Not specified","severity":"serious"},{"effect":"Tremor","drugRate":"Not specified","severity":"serious"},{"effect":"Asterixis","drugRate":"Not specified","severity":"serious"},{"effect":"Cerebellar atrophy","drugRate":"Not specified","severity":"serious"},{"effect":"Peripheral polyneuropathy","drugRate":"Not specified","severity":"serious"},{"effect":"Scarlatiniform or morbilliform rashes","drugRate":"Not specified","severity":"mild"},{"effect":"Bullous, exfoliative or purpuric dermatitis","drugRate":"Not specified","severity":"serious"},{"effect":"Acute generalized exanthematous pustulosis","drugRate":"Not specified","severity":"serious"},{"effect":"Stevens-Johnson syndrome","drugRate":"Not specified","severity":"serious"},{"effect":"Toxic epidermal necrolysis","drugRate":"Not specified","severity":"serious"},{"effect":"Hypertrichosis","drugRate":"Not specified","severity":"mild"},{"effect":"Urticaria","drugRate":"Not specified","severity":"mild"},{"effect":"Altered taste sensation","drugRate":"Not specified","severity":"mild"},{"effect":"Metallic taste","drugRate":"Not specified","severity":"mild"},{"effect":"Peyronie’s disease","drugRate":"Not specified","severity":"serious"}],"contraindications":["Acute nephropathy","Agranulocytosis","Alcohol intoxication","Alcoholism","Anemia","Aplastic anemia","Breastfeeding (mother)","Complete atrioventricular block","Conduction disorder of the heart","Congenital long QT syndrome","Decompensated cardiac failure","Decreased respiratory function","Depressive disorder","Diabetes mellitus","Disease of liver","Disorder of thyroid gland","Dyspnea","Fever greater than 100.4 Fahrenheit","Granulocytopenic disorder","HLA-B 1502 Positive Status"],"specialPopulations":{"Pregnancy":"Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. The fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported.","Geriatric use":"Phenytoin clearance tends to decrease with increasing age. Lower or less frequent dosing may be required.","Paediatric use":"Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).","Renal impairment":"The monitoring of phenytoin serum levels should be based on the unbound fraction in patients with renal impairment.","Hepatic impairment":"The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function may show early signs of toxicity. The monitoring of phenytoin serum levels should be based on the unbound fraction in patients with hepatic impairment."}},"trials":[],"aliases":[],"company":"Pfizer","patents":[],"pricing":[{"market":"United States","source":"CMS National Average Drug Acquisition Cost (NADAC)","asOfDate":"2024-01-03","unitCost":"$0.0662/ML","priceType":"NADAC","sourceUrl":"https://data.medicaid.gov/dataset/4j6z-xnwq","annualCost":"$24","description":"PHENYTOIN 125 MG/5 ML SUSP","retrievedDate":"2026-04-07"}],"_fixedAt":"2026-03-30T15:17:31.399173","_recalls":[{"date":"20230621","reason":"Failed Dissolution Specifications: Out-of-specification results for dissolution (above specification)","classification":"Class II"},{"date":"20140129","reason":"Labeling: Label Mixup: PHENYTOIN SODIUM ER, Capsule, 30 mg may have potentially been mislabeled as the following drug: LITHIUM CARBONATE ER, Tablet, 450 mg, NDC 00054002025, Pedigree: W003327, EXP: 6/19/2014.","classification":"Class II"},{"date":"20140716","reason":"Presence of Particular Matter: Potential glass delamination and consistent with glass particulates observed in sample vials.","classification":"Class II"},{"date":"20221130","reason":"Labeling: Not elsewhere classified; the product is being recalled because of customer complaints that the primary vial label was missing a barcode.","classification":"Class III"},{"date":"20231115","reason":"Failed Dissolution Specifications","classification":"Class II"}],"_sources":{"trials":{"url":"https://clinicaltrials.gov/search?intr=Phenytoin Sodium","method":"api_direct","source":"ClinicalTrials.gov","rawText":"","confidence":1,"sourceType":"ctgov","retrievedAt":"2026-04-19T23:32:44.207833+00:00"},"timeline":{"url":"https://en.wikipedia.org/wiki/Phenytoin Sodium","method":"deterministic","source":"Wikipedia","rawText":"","confidence":0.8,"sourceType":"wikipedia","retrievedAt":"2026-04-19T23:32:52.342658+00:00"},"regulatory.ca":{"url":"","method":"api_direct","source":"Health Canada DPD","rawText":"","confidence":1,"sourceType":"health_canada_dpd","retrievedAt":"2026-04-19T23:32:49.949639+00:00"},"regulatory.eu":{"url":"","method":"api_direct","source":"European Medicines Agency","rawText":"","confidence":1,"sourceType":"ema_api","retrievedAt":"2026-04-19T23:32:44.279244+00:00"},"regulatory.us":{"url":"","method":"api_direct","source":"FDA Drugs@FDA","rawText":"","confidence":1,"sourceType":"fda_drugsfda","retrievedAt":"2026-04-19T23:32:43.309108+00:00"},"publicationCount":{"url":"https://pubmed.ncbi.nlm.nih.gov/?term=Phenytoin Sodium","method":"api_direct","source":"PubMed/NCBI","rawText":"","confidence":1,"sourceType":"pubmed","retrievedAt":"2026-04-19T23:32:50.280621+00:00"},"administration.route":{"url":"","method":"deterministic","source":"FDA Label","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-19T23:32:36.013967+00:00"},"safety.boxedWarnings":{"url":"","method":"deterministic","source":"FDA Label (boxed_warning)","rawText":"WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION The rate of intravenous Phenytoin Sodium Injection 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 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","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-19T23:32:36.013992+00:00"},"safety.safetySignals":{"url":"https://api.fda.gov/drug/event.json","method":"api_direct","source":"FDA FAERS","rawText":"","confidence":1,"sourceType":"fda_faers","retrievedAt":"2026-04-19T23:32:52.816551+00:00"},"mechanism.target_chembl":{"url":"","method":"api_direct","source":"ChEMBL mechanism: Sodium channel alpha subunit blocker","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-19T23:32:52.342601+00:00"},"crossReferences.chemblId":{"url":"https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL1611/","method":"api_direct","source":"ChEMBL (EMBL-EBI)","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-19T23:32:51.992706+00:00"},"regulatory.fda_application":{"url":"","method":"deterministic","source":"FDA Label","rawText":"ANDA084307","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-19T23:32:36.013996+00:00"}},"offLabel":[],"synonyms":["fenitoin","sodium diphenylhydantoinate","phenytoin","diphantoin","diphenylan","diphenylhydantoin","phenytoine","phenytoinum","phenytoin sodium"],"timeline":[{"date":"1908-01-01","type":"neutral","_source":"Wikipedia","milestone":"Phenytoin synthesized by Heinrich Biltz","regulator":"none"},{"date":"1938-01-01","type":"positive","_source":"Wikipedia","milestone":"Phenytoin's usefulness for controlling seizures discovered","regulator":"none"},{"date":"1953-01-01","type":"positive","_source":"Wikipedia","milestone":"Phenytoin approved by the FDA","regulator":"FDA"},{"date":"1953-01-06","type":"positive","_source":"FDA NDA008762","milestone":"FDA ORIG — VIATRIS","regulator":"FDA","description":""},{"date":"1975-03-18","type":"positive","_source":"FDA NDA008762","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1975-07-16","type":"positive","_source":"FDA ANDA084307","milestone":"FDA ORIG — HIKMA","regulator":"FDA","description":""},{"date":"1976-08-27","type":"positive","_source":"FDA ANDA084349","milestone":"FDA ORIG — VIATRIS","regulator":"FDA","description":""},{"date":"1978-02-23","type":"positive","_source":"FDA NDA008762","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1979-02-26","type":"positive","_source":"FDA ANDA084427","milestone":"FDA ORIG — PHARMACIA","regulator":"FDA","description":""},{"date":"1979-08-16","type":"positive","_source":"FDA NDA008762","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1980-12-08","type":"positive","_source":"FDA NDA008762","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1981-06-22","type":"positive","_source":"FDA ANDA084427","milestone":"FDA SUPPL — PHARMACIA","regulator":"FDA","description":""},{"date":"1982-05-17","type":"positive","_source":"FDA ANDA084427","milestone":"FDA SUPPL — PHARMACIA","regulator":"FDA","description":""},{"date":"1982-05-18","type":"positive","_source":"FDA ANDA084349","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1983-02-14","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1984-04-09","type":"positive","_source":"FDA ANDA084349","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1984-05-01","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1985-04-18","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1986-02-11","type":"positive","_source":"FDA ANDA084349","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1987-10-02","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1988-08-10","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1988-08-25","type":"positive","_source":"FDA ANDA084349","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1989-07-24","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1990-03-22","type":"positive","_source":"FDA ANDA084349","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1990-05-02","type":"positive","_source":"FDA ANDA084427","milestone":"FDA SUPPL — PHARMACIA","regulator":"FDA","description":""},{"date":"1990-05-18","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1991-07-31","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1991-11-12","type":"positive","_source":"FDA ANDA084427","milestone":"FDA SUPPL — PHARMACIA","regulator":"FDA","description":""},{"date":"1993-11-15","type":"positive","_source":"FDA ANDA084349","milestone":"FDA SUPPL — VIATRIS","regulator":"FDA","description":""},{"date":"1993-11-18","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1995-04-06","type":"positive","_source":"FDA ANDA084427","milestone":"FDA SUPPL — PHARMACIA","regulator":"FDA","description":""},{"date":"1995-11-27","type":"positive","_source":"FDA ANDA084307","milestone":"FDA SUPPL — HIKMA","regulator":"FDA","description":""},{"date":"1996-02-22","type":"positive","_source":"FDA NDA008762","milestone":"FDA SUPPL — 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It works by blocking sodium channels in the brain. It's used to prevent tonic-clonic and focal seizures, but not absence seizures. The intravenous form is used for status epilepticus and certain heart arrhythmias. It can be taken intravenously or orally. Dilantin is a significant commercial product with $63.6B revenue and 414 publications.","brandName":"Dilantin","ecosystem":[],"isGeneric":true,"mechanism":{"target":"Nuclear receptor subfamily 1 group I member 3","novelty":"best-in-class","targets":[{"gene":"NR1I3","source":"DrugCentral","target":"Nuclear receptor subfamily 1 group I member 3","protein":"Nuclear receptor subfamily 1 group I member 3","activityType":""},{"gene":"SCN1A","source":"DrugCentral","target":"Sodium channel protein type 1 subunit alpha","protein":"Sodium channel protein type 1 subunit alpha","activityType":""},{"gene":"SCN2A","source":"DrugCentral","target":"Sodium channel protein type 2 subunit alpha","protein":"Sodium channel protein type 2 subunit alpha","activityType":"IC50"},{"gene":"SCN3A","source":"DrugCentral","target":"Sodium channel protein type 3 subunit alpha","protein":"Sodium channel protein type 3 subunit alpha","activityType":""},{"gene":"SCN4A","source":"DrugCentral","target":"Sodium channel protein type 4 subunit alpha","protein":"Sodium channel protein type 4 subunit alpha","activityType":"Ki"},{"gene":"SCN5A","source":"DrugCentral","target":"Sodium channel protein type 5 subunit alpha","protein":"Sodium channel protein type 5 subunit alpha","activityType":""},{"gene":"SCN8A","source":"DrugCentral","target":"Sodium channel protein type 8 subunit alpha","protein":"Sodium channel protein type 8 subunit alpha","activityType":""},{"gene":"SCN9A","source":"DrugCentral","target":"Sodium channel protein type 9 subunit alpha","protein":"Sodium channel protein type 9 subunit alpha","activityType":""}],"modality":"small molecule","drugClass":"phenytoin","explanation":"The precise mechanism of action of phenytoin is not fully understood, but it's thought to involve the blockade of sodium channels in the brain. This blockade reduces sustained high-frequency neuronal discharges, which are associated with seizures. By reducing these discharges, phenytoin helps to prevent seizures.","oneSentence":"Phenytoin exerts its therapeutic effect by voltage-dependent blockade of membrane sodium channels.","technicalDetail":"Phenytoin's mechanism of action involves the voltage-dependent blockade of membrane sodium channels, resulting in a reduction in sustained high-frequency neuronal discharges. This is thought to be the primary mechanism by which phenytoin exerts its therapeutic effect. The blockade of sodium channels is believed to be the key to phenytoin's ability to prevent seizures.","_target_confidence":0.5},"_companyIR":{"url":"https://www.pfizer.com/investors","revenueRefs":[],"pipelineRefs":[]},"_wikipedia":{"title":"Phenytoin","extract":"Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures and focal seizures, but not absence seizures. The intravenous form, fosphenytoin, is used for status epilepticus that does not improve with benzodiazepines. It may also be used for certain heart arrhythmias or neuropathic pain. It can be taken intravenously or by mouth. The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours. Blood levels can be measured to determine the proper dose.","wiki_history":"==History==\nPhenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908.\nBiltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, other physicians, including H. Houston Merritt and Tracy Putnam, discovered phenytoin's usefulness for controlling seizures, without the sedative effects associated with phenobarbital.\n\nAccording to Goodman and Gilman's Pharmacological Basis of Therapeutics:\n\n
In contrast to the earlier accidental discovery of the antiseizure properties of potassium bromide and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals.
\n\nIt was approved by the FDA in 1953 for use in seizures.\n\nJack Dreyfus, founder of the Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and depression when he received a prescription for Dilantin in 1966. He has claimed to have supplied large amounts of the drug to Richard Nixon throughout the late 1960s and early 1970s, although this is disputed by former White House aides and Presidential historians.\nDreyfus' experience with phenytoin is outlined in his book, A Remarkable Medicine Has Been Overlooked. Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community. Thi","wiki_medical_uses":"==Medical uses==\n\n===Seizures===\n* Tonic-clonic seizures: Mainly used in the prophylactic management of tonic-clonic seizures with complex symptomatology (psychomotor seizures). A period of 5–10 days of dosing may be required to achieve anticonvulsant effects.\n* Focal seizures: Mainly used to protect against the development of focal seizures with complex symptomatology (psychomotor and temporal lobe seizures). Also effective in controlling focal seizures with autonomic symptoms.\n* Absence seizures: Not used in treatment of pure absence seizures due to risk for increasing frequency of seizures. However, can be used in combination with other anticonvulsants during combined absence and tonic-clonic seizures.\n* Seizures during surgery: A 2018 meta-analysis found that early antiepileptic treatment with either phenytoin or phenobarbital reduced the risk of seizure in the first week after neurosurgery for brain tumors.\n* Status epilepticus: Considered after failed treatment using a benzodiazepine due to slow onset of action.\nThough phenytoin has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Due to the lack of a comparison group, the evidence is inconclusive.\n\n===Other===\n* Abnormal heart rhythms: may be used in the treatment of ventricular tachycardia and sudden episodes of atrial tachycardia after other antiarrhythmic medications or cardioversion has failed. It is a class Ib antiarrhythmic.\n* Digoxin t","wiki_society_and_culture":"==Society and culture==\n\n===Economics===\nPhenytoin is available as a generic medication. The capsules are still made by Pfizer's Goedecke subsidiary's plant in Freiburg, Germany, and they still have Epanutin printed on them. After Pfizer's sale of the UK marketing licence to Flynn Pharma, the price of a 28-pack of 25 mg phenytoin sodium capsules marked Epanutin rose from 66p (about $0.88) to (about $25.06). Capsules of other strengths also went up in price by the same factor—2,384%, costing the UK's National Health Service an extra (about $68.44 million) a year. The companies were referred to the Competition and Markets Authority (CMA) who found that they had exploited their dominant position in the market to charge \"excessive and unfair\" prices.\n\nThe CMA imposed a record fine on the manufacturer Pfizer, and a fine on the distributor Flynn Pharma and ordered the companies to reduce their prices.\n\n===Brand names===\nPhenytoin is marketed under many brand names worldwide.\n\nIn the US, Dilantin is marketed by Viatris after Upjohn was spun off from Pfizer."},"commercial":{"yoyGrowth":"7%","launchDate":"1953","annualCostUS":"$80,000/yr","_launchSource":"DrugCentral (FDA 1953-01-06, PARKE DAVIS)","genericStatus":"Generic — off-patent","currentRevenue":"","manufacturerCount":"10 approved manufacturers","patientPopulation":"Generic — multiple 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GuideSign Up\nSAVINGS\nTerms and conditions apply.\nABOUT\nSAVINGS\nFAQs\nCAPTURE THE MOMENT WITH BRAND-NAME DILANTIN\n\nBacked by over 70 years of clinical experience\n\n \n\nProven to help treat tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery\n\n \n\nOngoing commitment to product quality and safety monitoring\n\nLEARN MORE\n3 TIPS TO GET BRAND-NAME DILANTIN\nAsk your Doctor:\n\nAsk your doctor to prescribe brand-name DILANTIN and to indicate \"DAW\" (Dispense As Written), if appropriate, on all your DILANTIN prescriptions.*\n\n*Language and requirements may vary based on your state’s law.\n\nGet a Savings Card:\n\nTell the pharmacist that you want brand-name DILANTIN—and be sure to use the DILANTIN Savings Card, if eligible.\n\nCheck Your Pills:\n\nCheck your pills to be sure they're brand-name DILANTIN—not the generic—and also check that you've saved on your prescription, if eligible.\n\nMAKE SURE YOU HAVE BRAND-NAME DILANTIN\n\nLook for the distinctive shape and marking of DILANTIN, so you get the brand-name medication you want.\n\nChoose dosage from the drop down\n\n30 mg\n100 mg\n\nPill not actual size.\n\nSAVINGS\nTerms and conditions apply.\nIMPORTANT SAFETY INFORMATION AND INDICATIONS\n\nDo not take DILANTIN if you:\n\nAre allergic to phenytoin or its inactive ingredients or other anticonvulsants such as CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin)\nHave had liver problems from taking phenytoin\nTake delavirdine (a drug which may be prescribed to you when you suffer from an HIV infection) since DILANTIN modifies its effect\n\nDo not stop taking DILANTIN without first talking to your healthcare provider. 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Post-Traumatic Epilepsy","status":"COMPLETED","sponsor":"Pavel Klein","startDate":"2005-04","conditions":"Epilepsy, Post-traumatic Epilepsy","enrollment":126},{"nctId":"NCT02409433","phase":"PHASE4","title":"Comparative Trial of IV Lacosamide Versus Phenytoin for Seizure Management","status":"TERMINATED","sponsor":"London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's","startDate":"2014-08","conditions":"Seizures","enrollment":3},{"nctId":"NCT01451593","phase":"PHASE2","title":"Neuroprotection With Phenytoin in Optic Neuritis","status":"COMPLETED","sponsor":"University College, London","startDate":"2011-11","conditions":"Optic Neuritis, Multiple Sclerosis","enrollment":92},{"nctId":"NCT00591006","phase":"PHASE3","title":"Phenytoin as a Neuroprotective Agent Against Corticosteroid-induced Functional Imaging Changes","status":"COMPLETED","sponsor":"University of Texas Southwestern Medical Center","startDate":"2008-01","conditions":"Healthy","enrollment":17},{"nctId":"NCT02413658","phase":"PHASE2","title":"Phenytoin in the Healing of Clean Surgical Wounds","status":"UNKNOWN","sponsor":"Children's Surgical Center, Cambodia","startDate":"2015-03","conditions":"Wound, Re-Epithelialization","enrollment":100},{"nctId":"NCT00004403","phase":"NA","title":"Randomized Study of Albendazole in Patients With Epilepsy Due to Neurocysticercosis","status":"COMPLETED","sponsor":"Johns Hopkins University","startDate":"2000-05","conditions":"Epilepsy, Cysticercosis","enrollment":120},{"nctId":"NCT00068770","phase":"PHASE2","title":"Celecoxib in Patients With Newly Diagnosed GBM Who Are Receiving Anticonvulsant Drugs and Undergoing RT","status":"TERMINATED","sponsor":"Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins","startDate":"2003-10","conditions":"Brain and Central Nervous System Tumors","enrollment":35},{"nctId":"NCT02283827","phase":"PHASE1","title":"Open-label Drug Interaction Study Between Eslicarbazepine Acetate and Phenytoin.","status":"COMPLETED","sponsor":"Bial - Portela C S.A.","startDate":"2007-01","conditions":"Epilepsy","enrollment":32},{"nctId":"NCT00823264","phase":"NA","title":"Phenytoin and Multidose Activated Charcoal","status":"COMPLETED","sponsor":"Emory University","startDate":"2008-08","conditions":"Phenytoin Toxicity","enrollment":17},{"nctId":"NCT01584765","phase":"","title":"Rechallenge, Potential Drug Induced Liver Injury (Kaiser)","status":"COMPLETED","sponsor":"GlaxoSmithKline","startDate":"2012-02","conditions":"Drug-induced Liver Injury","enrollment":1},{"nctId":"NCT01110187","phase":"NA","title":"A Pilot Study of NSICU Assessment of Seizure Prophylaxis With Lacosamide","status":"TERMINATED","sponsor":"University of Alabama at Birmingham","startDate":"2010-05","conditions":"Traumatic Brain Injury","enrollment":11},{"nctId":"NCT00618436","phase":"PHASE4","title":"Assess Safety and Efficacy of Levetiracetam(LEV;Keppra)for Seizure Prevention","status":"COMPLETED","sponsor":"University of Cincinnati","startDate":"2007-08","conditions":"Traumatic Brain Injury, Subarachnoid Hemorrhage","enrollment":52},{"nctId":"NCT01878578","phase":"PHASE1","title":"The Effect of BIA 2-093 on the Steady-state Pharmacokinetic Profile of Phenytoin in Patients","status":"TERMINATED","sponsor":"Bial - Portela C S.A.","startDate":"2002-11","conditions":"Epilepsy","enrollment":4},{"nctId":"NCT00510783","phase":"PHASE4","title":"IV Keppra in the Emergency Department for Prevention of Early Recurrent Seizures","status":"COMPLETED","sponsor":"Emory University","startDate":"2007-07","conditions":"Tonic-clonic Seizure","enrollment":158},{"nctId":"NCT00021866","phase":"","title":"Developmental Effects On Children Of Women Who Take Antiepileptic Drugs During Pregnancy","status":"COMPLETED","sponsor":"Emory University","startDate":"2000-09","conditions":"Epilepsy, Seizure, Cognition Disorders","enrollment":331},{"nctId":"NCT01635829","phase":"PHASE1","title":"A Study to Investigate the Potential Pharmacokinetic Interactions Between Phenytoin or Carbamazepine and Telaprevir","status":"COMPLETED","sponsor":"Janssen Infectious Diseases BVBA","startDate":"2012-05","conditions":"Healthy Participants","enrollment":24},{"nctId":"NCT00610532","phase":"PHASE4","title":"Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy","status":"TERMINATED","sponsor":"Jim McAuley","startDate":"2006-03","conditions":"Epilepsy","enrollment":8},{"nctId":"NCT01586208","phase":"PHASE3","title":"Refractory Status Epilepticus Treatment Study","status":"COMPLETED","sponsor":"Hospital Universitari de Bellvitge","startDate":"2010-01","conditions":"Grand Mal Status Epilepticus, Non-convulsive Status Epilepticus","enrollment":5},{"nctId":"NCT00612651","phase":"PHASE1","title":"PH I Addition of Farnesyl Transferase Inhibitor to Temozolomide for Pts w Gr 3 & 4 Malignant Gliomas","status":"COMPLETED","sponsor":"Duke University","startDate":"2005-10","conditions":"Gliosarcoma, Glioblastoma, Anaplastic Astrocytoma","enrollment":37}],"_emaApprovals":[{"date":"","name":"Dilantin","status":"Authorised","regulator":"EMA"}],"genericFilers":[],"latestUpdates":[{"url":"https://www.drugpatentwatch.com/p/drug-price/drugname/DILANTIN","date":"2026-04-07","type":"news","title":"Drug prices and trends for DILANTIN","source":"www.drugpatentwatch.com"},{"url":"https://www.drugdiscoverytrends.com/pharma-50-2026-the-top-spot-in-pharma-rarely-lasts-lilly-is-betting-it-can-change-that/","date":"2026-04-07","type":"news","title":"Pharma 50 2026: The top spot in pharma rarely lasts. Lilly is betting ...","source":"www.drugdiscoverytrends.com"},{"url":"https://www.coherentmarketinsights.com/industry-reports/epilepsy-drugs-market","date":"2026-04-07","type":"news","title":"Epilepsy Drugs Market Size, Share and Forecast, 2026-2033","source":"www.coherentmarketinsights.com"},{"url":"https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/008762Orig1s039.pdf","date":"2026-04-07","type":"news","title":"[PDF] Approval Package for: NDA 08-762/S-039 - accessdata.fda.gov","source":"www.accessdata.fda.gov"},{"url":"https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/084427Orig1s031lbl.pdf","date":"2026-04-07","type":"news","title":"[PDF] dilantin - accessdata.fda.gov","source":"www.accessdata.fda.gov"}],"manufacturing":[{"role":"Manufacturer","site":"Viatris Specialty LLC","location":"","operator":"Viatris Specialty LLC"}],"molecularData":{"oral":true,"chemblId":"CHEMBL1611","moleculeType":"Small molecule","molecularWeight":"274.25"},"administration":{"route":"Intramuscular","formulation":"pentobarbital sodium 390 MG/ML / phenytoin sodium 50 MG/ML Injectable Solution [Euthasol]; pentobarbital sodium 390 MG/ML / phenytoin sodium 50 MG/ML Injectable Solution [Euthaphen]; phenytoin sodium 100 MG Extended Release Oral Capsule [Dilantin]","formulations":[{"form":"CAPSULE","route":"ORAL","tradeName":"Dilantin"},{"form":"CAPSULE","route":"ORAL","tradeName":"EXTENDED PHENYTOIN SODIUM"},{"form":"CAPSULE","route":"ORAL","tradeName":"Extended Phenytoin Sodium"},{"form":"CAPSULE","route":"ORAL","tradeName":"PHENYTOIN SODIUM"},{"form":"CAPSULE","route":"ORAL","tradeName":"PHENYTOINER"},{"form":"CAPSULE, EXTENDED RELEASE","route":"ORAL","tradeName":"Dilantin"},{"form":"CAPSULE, EXTENDED RELEASE","route":"ORAL","tradeName":"Extended Phenytoin Sodium"},{"form":"CAPSULE, EXTENDED RELEASE","route":"ORAL","tradeName":"PHENYTOIN SODIUM"},{"form":"CAPSULE, EXTENDED RELEASE","route":"ORAL","tradeName":"Phenytek"},{"form":"CAPSULE, EXTENDED RELEASE","route":"ORAL","tradeName":"Phenytoin Sodium"}]},"_patentsChecked":true,"_warningLetters":[{"date":"03/28/2023","subject":"11/07/2022\tTodos Medical Ltd aka Todos Medical USA Inc\tCenter for Food Safety and Applied Nutrition"},{"date":"03/27/2026","subject":"Feedback form"}],"crossReferences":{"NUI":"N0000146211","MMSL":"1366","NDDF":"001617","UNII":"6158TKW0C5","VUID":"4017856","CHEBI":"CHEBI:8107","VANDF":"4017856","INN_ID":"416","RXNORM":"71227","UMLSCUI":"C0031507","chemblId":"CHEMBL1611","ChEMBL_ID":"CHEMBL16","KEGG_DRUG":"D00512","DRUGBANK_ID":"DB00252","PUBCHEM_CID":"1775","SNOMEDCT_US":"387220006","IUPHAR_LIGAND_ID":"2624","SECONDARY_CAS_RN":"630-93-3","MESH_DESCRIPTOR_UI":"D010672"},"formularyStatus":[],"_offLabelChecked":true,"developmentCodes":[],"ownershipHistory":[{"notes":"","period":"1908","_source":"Wikipedia","companyName":"Heinrich Biltz","relationship":"Originator"},{"notes":"","period":"1938-present","_source":"Wikipedia","companyName":"Parke-Davis","relationship":"Acquirer"},{"notes":"","period":"present","_source":"Wikipedia","companyName":"Pfizer","relationship":"Licensee"}],"pharmacokinetics":{"source":"DrugCentral","halfLife":"16.8 hours","clearance":"0.37 mL/min/kg","bioavailability":"90.0%","fractionUnbound":"0.13%","volumeOfDistribution":"0.43 L/kg"},"publicationCount":415,"therapeuticAreas":["Neuroscience"],"atcClassification":{"source":"DrugCentral","atcCode":"N03AB02","allCodes":["N03AB02","N03AB52"]},"biosimilarFilings":[],"commercialAnalysis":{"text":"**Current Market Position and Revenue Trajectory**\n\nDilantin (Phenytoin Sodium) by Pfizer holds a stable presence in the epilepsy treatment market, with a long history of over 80 years [1]. According to recent data, the average pharmacy cost for Dilantin 100 MG Capsule is $0.13918 per unit, with a slight increase in price over the past few months [2]. However, the exact revenue trajectory of Dilantin is not explicitly stated in the provided sources.\n\n**Competitive Landscape and Threats**\n\nThe competitive landscape of the epilepsy treatment market is dynamic, with various anticonvulsant medications vying for market share. The market share of Dilantin is not explicitly stated in the provided sources, but it is likely to face competition from newer, more effective treatments. The increasing prevalence of epilepsy, particularly among the aging population, may drive growth in the market [3].\n\n**Key Upcoming Catalysts**\n\nThe epilepsy drugs market is expected to experience significant growth due to the increasing prevalence of epilepsy and the approval of new drugs for refractory epilepsy [4]. However, the exact impact of these catalysts on Dilantin's market position is unclear. Additionally, the patent cliff for Dilantin may pose a threat to its market share, although the exact date of the patent expiration is not specified in the provided sources.\n\n**Market Outlook**\n\nThe epilepsy drugs market is expected to reach USD 15.83 Bn by 2032, exhibiting a compound annual growth rate (CAGR) of 5.5% from 2025 to 2032 [5]. However, the exact market outlook for Dilantin is uncertain due to the lack of specific data on its market share and revenue trajectory.\n\nReferences:\n[1] www.drugpatentwatch.com (2026)\n[2] www.drugpatentwatch.com (2026)\n[3] www.coherentmarketinsights.com (2026)\n[4] www.coherentmarketinsights.com (2026)\n[5] www.coherentmarketinsights.com (2026)","model":"llama-3.1-8b (Groq)","sources":[{"url":"https://www.drugpatentwatch.com/p/drug-price/drugname/DILANTIN","date":"","title":"Drug prices and trends for DILANTIN","source":"www.drugpatentwatch.com"},{"url":"https://www.drugdiscoverytrends.com/pharma-50-2026-the-top-spot-in-pharma-rarely-lasts-lilly-is-betting-it-can-change-that/","date":"","title":"Pharma 50 2026: The top spot in pharma rarely lasts. Lilly is betting ...","source":"www.drugdiscoverytrends.com"},{"url":"https://www.coherentmarketinsights.com/industry-reports/epilepsy-drugs-market","date":"","title":"Epilepsy Drugs Market Size, Share and Forecast, 2026-2033","source":"www.coherentmarketinsights.com"}],"disclaimer":"AI-generated analysis based on public sources. Verify with primary sources for investment decisions.","generatedDate":"2026-04-07"},"recentPublications":[{"date":"2026","pmid":"41756778","title":"Evaluation of neurotoxicity of drugs from morphological and electrophysiological endpoints using human iPSC-derived neural cell models.","journal":"Frontiers in cellular and infection microbiology"},{"date":"2025","pmid":"41668863","title":"Analysis of ASMs and male infertility using the FDA adverse event reporting system (FAERS).","journal":"Frontiers in public health"},{"date":"2026","pmid":"41635908","title":"Synthesis, In-silico and In-vivo anticonvulsant activity of substituted 2-Phenyl Indole derivatives.","journal":"In silico pharmacology"},{"date":"2025 Nov 21","pmid":"41269467","title":"Fluvoxamine Attenuates Blood-Brain Barrier Disruption in Drug-Resistance Epilepsy and inhibits Ferroptosis via the Sigma-1 Receptor-TAMM41 signaling in bEnd.3 cells.","journal":"Molecular neurobiology"},{"date":"2025 May 20","pmid":"40964104","title":"[Effect of High-Altitude Hypoxia on the Pharmacokinetics and Brain Distribution of Phenytoin Sodium in Epileptic Rats].","journal":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. 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