FDA label 9d43cbcf-01a4-8984-4dcc-0b7cb4cb9fbe

WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES The rate of intravenous fosphenytoin administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg PE/min, 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 fosphenytoin. 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 ( 2.3 , 2.4 ) and Warnings and Precautions ( 5.2 )] . WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES See full prescribing information for complete boxed warning. The rate of intravenous fosphenytoin administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg PE/min, 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 fosphenytoin sodium injection. Reduction in rate of administration or discontinuation of dosing may be needed ( 2.3 , 2.4 , 5.2 ).

5 WARNINGS AND PRECAUTIONS Dosing Errors: Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial . Ensure the appropriate volume is withdrawn from the vial when preparing for administration. ( 5.1 ) Withdrawal Precipitated Seizure: May precipitate status epilepticus. Dose reductions or discontinuation should be done gradually. ( 5.3 ) Serious Dermatologic Reactions: Discontinue at the first sign of a rash, unless clearly not drug-related. If signs or symptoms suggest SJS/TEN, fosphenytoin should not be resumed; consider alternative therapy. ( 5.4 ) 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. ( 5.5 ) Angioedema: Discontinue immediately if symptoms of angioedema such as facial, perioral, or upper airway swelling occur. ( 5.7 ) Hematopoietic Complications: If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used. ( 5.9 ) 5.1 Dosing Errors Phenytoin Sodium Equivalents (PE) Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial. Doses of fosphenytoin are always expressed in terms of milligrams of phenytoin sodium equivalents (mg PE). 1 mg PE is equivalent to 1 mg phenytoin sodium. Do not, therefore, make any adjustment in the recommended doses when substituting fosphenytoin sodium injection for phenytoin sodium or vice versa. For example, if a patient is receiving 1000 mg PE of fosphenytoin, that is equivalent to 1000 mg of phenytoin sodium. Concentration of 50 mg PE/mL Medication errors associated with fosphenytoin have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium injection is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten-fold overdoses of fosphenytoin sodium injection since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of fosphenytoin should always be expressed in milligrams of phenytoin equivalents (mg PE) [ see Dosage and Administration (2.1) ]. Additionally, when ordering and storing fosphenytoin sodium injection, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg PE/ 10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of fosphenytoin sodium injection is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some fosphenytoin sodium medication errors from occurring. 5.2 Cardiovascular Risk Associated with Rapid Infusion Rapid intravenous administration of fosphenytoin increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, 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. The rate of intravenous fosphenytoin administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Dosage and Administration ( 2.3, 2.4)] . 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, intravenous fosphenytoin should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV fosphenytoin, 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 fosphenytoin. Reduction in rate of administration or discontinuation of dosing may be needed. 5.3 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. 5.4 Serious Dermatologic Reactions Fosphenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin (the active metabolite of fosphenytoin)-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ( 5.5 )]. The onset of symptoms is usually within 28 days but can occur later. Fosphenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest a severe cutaneous adverse reaction, 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 SCARs. 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 Asain 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 fosphenytoin as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or CYP2C9*3 patients. Should fosphenytoin be utilized for CYP2C9*3 carriers, consider starting at the lower end of the dosage range [see Use in Specific Populations ( 8.7 )]. 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. 5.5 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 and fosphenytoin. 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. Fosphenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.6 Hypersensitivity Fosphenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications ( 4 ) and Warnings and Precautions ( 5.7 )] . 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 fosphenytoin. 5.7 Angioedema Angioedema has been reported in patients treated with phenytoin and fosphenytoin in the postmarketing setting. Fosphenytoin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Fosphenytoin should be discontinued permanently if a clear alternative etiology for the reaction cannot be established. 5.8 Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin (the active metabolite of fosphenytoin). These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.5) ]. 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, fosphenytoin should be immediately discontinued and not re-administered. 5.9 Hematopoietic Complications Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin (the active metabolite of fosphenytoin). These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports that have suggested 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 (5.5)]. 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. Macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Pure red cell aplasia has also been reported with phenytoin. 5.10 Sensory Disturbances Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered IV fosphenytoin at a dose of 1200 mg PE at the maximum rate of administration (150 mg PE/min). The severe sensory disturbance lasted from 3 to 50 minutes in 6 of these subjects and for 14 hours in the seventh subject. In some cases, milder sensory disturbances persisted for as long as 24 hours. The location of the discomfort varied among subjects with the groin mentioned most frequently as an area of discomfort. In a separate cohort of 16 normal volunteers (taken from 2 other studies) who were administered IV fosphenytoin at a dose of 1200 mg PE at the maximum rate of administration (150 mg PE/min), none experienced severe disturbances, but most experienced mild to moderate itching or tingling. Patients administered fosphenytoin at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree. The occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion. The effect of continuing infusion unaltered in the presence of these sensations is unknown. No permanent sequelae have been reported thus far. The pharmacologic basis for these positive sensory phenomena is unknown, but other phosphate ester drugs, which deliver smaller phosphate loads, have been associated with burning, itching, and/or tingling predominantly in the groin area. 5.11 Local Toxicity (Including Purple Glove Syndrome) Edema, discoloration, and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous fosphenytoin sodium injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection. 5.12 Phosphate Load The phosphate load provided by fosphenytoin sodium (0.0037 mmol phosphate/mg PE fosphenytoin) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment. 5.13 Renal or Hepatic Disease or Hypoalbuminemia Because the fraction of unbound phenytoin (the active metabolite of fosphenytoin) 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. After IV administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events. 5.14 Exacerbation of Porphyria In view of isolated reports associating phenytoin (the active metabolite of fosphenytoin) with exacerbation of porphyria, caution should be exercised in using fosphenytoin in patients suffering from this disease. 5.15 Teratogenicity and Other Harm to the Newborn Fosphenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin (the active metabolite of fosphenytoin) 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. 5.16 Hyperglycemia Hyperglycemia, resulting from the inhibitory effect of phenytoin (the active metabolite of fosphenytoin) on insulin release, has been reported. Phenytoin may also raise the serum glucose concentrations in diabetic patients. 5.17 Serum Phenytoin Levels above Therapeutic Range Serum levels of phenytoin (the active metabolite of fosphenytoin) 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. Fosphenytoin dose reduction is indicated if serum levels are excessive; if symptoms persist, administration of fosphenytoin should be discontinued.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Cardiovascular Risk Associated with Rapid Infusion [see Warnings and Precautions ( 5.2 )] Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions ( 5.3 )] Serious Dermatologic Reactions [see Warnings and Precautions (5.4) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.5) ] Hypersensitivity [see Warnings and Precautions ( 5.6) ] Angioedema [see Warnings and Precautions ( 5.7 )] Hepatic Injury [ see Warnings and Precautions ( 5.8 )] Hematopoietic Complications [see Warnings and Precautions ( 5.9 )] Sensory Disturbances [see Warnings and Precautions ( 5.10 )] Local Toxicity (Including Purple Glove Syndrome) [see Warnings and Precautions ( 5.11 )] Exacerbation of Porphyria [ see Warnings and Precautions ( 5.14 )] Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions ( 5.15 )] Hyperglycemia [see Warnings and Precautions ( 5.16 )] Most common adverse reactions (incidence ≥10%) are: Adults: pruritus, nystagmus, dizziness, somnolence, and ataxia Pediatrics: vomiting, nystagmus, and ataxia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The more important adverse clinical reactions caused by the IV use of fosphenytoin or phenytoin are cardiovascular collapse and/or CNS depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for fosphenytoin, it should not exceed 150 mg PE/min [see Warnings and Precautions (5.2 )]. The adverse reactions most commonly observed with the use of fosphenytoin in clinical trials were nystagmus, dizziness, pruritus, somnolence, and ataxia. With one exception, these reactions are commonly associated with the administration of IV phenytoin. Pruritus, however, was seen much more often following fosphenytoin administration and occurred more often with IV fosphenytoin administration than with IM fosphenytoin administration. These reactions were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of fosphenytoin infusion. Some patients experienced symptoms for hours. These reactions did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen [see Warnings and Precautions ( 5.10 )] . Approximately 2% of the 859 patients who received fosphenytoin in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%). Dose and Rate Dependency of Adverse Reactions Following IV fosphenytoin: The incidence of adverse reactions tended to increase as both dose and infusion rate increased. In particular, at doses of ≥15mg PE/kg and rates ≥150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates. Incidence in Controlled Clinical Trials All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the tables and listings below with the frequencies representing the proportion of individuals exposed to fosphenytoin or comparative therapy. Incidence in Controlled Clinical Trials - IV Administration to Adult Patients with Epilepsy or Neurosurgical Patients: Table 4 lists adverse reactions that occurred in at least 2% of patients treated with IV fosphenytoin at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and fosphenytoin administration would have resulted in equivalent systemic exposure to phenytoin. TABLE 4. Adverse Reaction Incidence Following IV Administration at the Maximum Dose and Rate to Adult Patients with Epilepsy or Neurosurgical Patients (Events in at Least 2% of Fosphenytoin-Treated Patients) BODY SYSTEM IV FOSPHENYTOIN IV Phenytoin 1 Adverse Event N=90 N=22 BODY AS A WHOLE Pelvic Pain 4 0 Asthenia 2 0 Back Pain 2 0 Headache 2 5 CARDIOVASCULAR Hypotension 8 9 Vasodilatation 6 5 Tachycardia 2 0 DIGESTIVE Nausea 9 14 Tongue Disorder 4 0 Dry Mouth 4 5 Vomiting 2 9 NERVOUS Nystagmus 44 59 Dizziness 31 27 Somnolence 20 27 Ataxia 11 18 Stupor 8 5 Incoordination 4 5 Paresthesia 4 0 Extrapyramidal Syndrome 4 0 Tremor 3 9 Agitation 3 0 Hypesthesia 2 9 Dysarthria 2 0 Vertigo 2 0 Brain Edema 2 5 SKIN AND APPENDAGES Pruritus SPECIAL SENSES 49 5 Tinnitus 9 9 Diplopia 3 0 Taste Perversion 3 0 Amblyopia 2 9 Deafness 2 0 1 The study was not designed to assess comparative safety. Incidence in Clinical Trials - IV Administration to Pediatric Patients with Epilepsy or Neurosurgical Patients: The overall incidence of adverse reactions and the types of adverse reactions seen were similar among children and adults treated with fosphenytoin. In an open-label, safety, tolerability, and pharmacokinetic study of fosphenytoin in pediatric subjects (neonates through age 16), the following adverse reactions occurred at a frequency of at least 5% in 96 subjects treated with intravenous fosphenytoin: vomiting (21%), nystagmus (18%), ataxia (10%), fever (8%), nervousness (7%), pruritus (6%), somnolence (6%), hypotension (5%), and rash (5%). Incidence in Controlled Trials - IM Administration to Adult Patients with Epilepsy: Table 5 lists adverse reactions that occurred in at least 2% of fosphenytoin-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either IM fosphenytoin substituted for oral phenytoin or continuing oral phenytoin. Both treatments were administered for 5 days. TABLE 5. Adverse Reaction Incidence Following Substitution of IM Fosphenytoin for Oral Phenytoin in Adult Patients with Epilepsy (Events in at Least 2% of Fosphenytoin-Treated Patients) BODY SYSTEM IM FOSPHENYTOIN Oral Phenytoin 1 Adverse Event N=179 N=61 BODY AS A WHOLE Headache 9 5 Asthenia 9 3 DIGESTIVE Nausea 5 0 Vomiting 3 0 HEMATOLOGIC AND LYMPHATIC Ecchymosis 7 5 NERVOUS Nystagmus 15 8 Tremor 10 13 Ataxia 8 8 Incoordination 8 5 Somnolence 7 10 Dizziness 5 3 Paresthesia 4 3 Reflexes Decreased 3 5 SKIN AND APPENDAGES Pruritus 3 0 1 The study was not designed to assess comparative safety. Adverse Events During Clinical Trials in Adult and Pediatric Patients Fosphenytoin has been administered to approximately 900 individuals during clinical trials. Adverse events seen at least twice are listed in the following, except those already included in previous tables and listings. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 individuals; infrequent adverse events are those occurring in 1/100 to 1/1000 individuals. Body as a Whole: Frequent: fever, injection-site reaction, infection, chills, face edema, injection-site pain; Infrequent : sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis. Cardiovascular : Frequent: hypertension; Infrequent: cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation, sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly, cerebral infarct, postural hypotension, pulmonary embolus, QT interval prolongation, thrombophlebitis, ventricular extrasystoles, congestive heart failure. Digestive: Frequent: constipation; Infrequent: dyspepsia, diarrhea, anorexia, gastrointestinal hemorrhage, increased salivation, liver function tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis, ileus. Endocrine : Infrequent: diabetes insipidus. Hematologic and Lymphatic: Infrequent: thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia [see Warnings and Precautions ( 5.9 ) ]. Laboratory Test Abnormality: Phenytoin (the active metabolite of fosphenytoin) may cause increased serum levels of glucose and alkaline phosphatase. Metabolic and Nutritional: Frequent: hypokalemia; Infrequent: hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis. Musculoskeletal: Frequent: myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia. Nervous: Frequent: reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness; Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis. Respiratory: Frequent : pneumonia; Infrequent: pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased, epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis. Skin and Appendages: Frequent: rash; Infrequent: maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule. Special Senses: Infrequent : visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss. Urogenital: Infrequent: urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of phenytoin or fosphenytoin. 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. Body as a Whole: Anaphylaxis, angioedema [see Warnings and Precautions ( 5.7 )] Hematologic: Pure red cell aplasia [see Warnings and Precautions ( 5.9 )] Laboratory Test Abnormality: Phenytoin or Fosphenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of gamma glutamyl transpeptidase (GGT). Nervous System Disorders: Dyskinesia

<table width="100%"><caption>TABLE 4. Adverse Reaction Incidence Following IV Administration at the Maximum Dose and Rate to Adult Patients with Epilepsy or Neurosurgical Patients (Events in at Least 2% of Fosphenytoin-Treated Patients)</caption><col align="left" valign="top" width="50%"/><col align="center" valign="top" width="25%"/><col align="center" valign="top" width="25%"/><thead><tr><th>BODY SYSTEM</th><th>IV FOSPHENYTOIN</th><th>IV Phenytoin¹</th></tr><tr><th> Adverse Event </th><th> N=90 </th><th> N=22 </th></tr></thead><tbody><tr align="left"><td colspan="3"><content styleCode="bold">BODY AS A WHOLE</content></td></tr><tr><td align="left"> Pelvic Pain </td><td> 4 </td><td> 0 </td></tr><tr><td align="left"> Asthenia </td><td> 2 </td><td> 0 </td></tr><tr><td align="left"> Back Pain </td><td> 2 </td><td> 0 </td></tr><tr><td align="left"> Headache </td><td> 2 </td><td> 5 </td></tr><tr><td align="left" colspan="3"><content styleCode="bold"> CARDIOVASCULAR</content></td></tr><tr align="center"><td align="left"> Hypotension </td><td> 8 </td><td> 9 </td></tr><tr align="center"><td align="left"> Vasodilatation </td><td> 6 </td><td> 5 </td></tr><tr align="center"><td align="left"> Tachycardia </td><td> 2 </td><td> 0 </td></tr><tr><td align="left" colspan="3"><content styleCode="bold">DIGESTIVE</content></td></tr><tr><td align="left"> Nausea </td><td> 9 </td><td> 14 </td></tr><tr><td align="left"> Tongue Disorder </td><td> 4 </td><td> 0 </td></tr><tr><td align="left"> Dry Mouth </td><td> 4 </td><td> 5 </td></tr><tr><td align="left"> Vomiting </td><td> 2 </td><td> 9 </td></tr><tr><td align="left"><content styleCode="bold">NERVOUS</content></td><td/><td/></tr><tr><td align="left"> Nystagmus </td><td> 44 </td><td> 59 </td></tr><tr><td align="left"> Dizziness </td><td> 31 </td><td> 27 </td></tr><tr><td align="left"> Somnolence </td><td> 20 </td><td> 27 </td></tr><tr><td align="left"> Ataxia </td><td> 11 </td><td> 18 </td></tr><tr><td align="left"> Stupor </td><td> 8 </td><td> 5 </td></tr><tr><td align="left"> Incoordination </td><td> 4 </td><td> 5 </td></tr><tr><td align="left"> Paresthesia </td><td> 4 </td><td> 0 </td></tr><tr><td> Extrapyramidal Syndrome </td><td> 4 </td><td> 0 </td></tr><tr><td align="left"> Tremor </td><td> 3 </td><td> 9 </td></tr><tr><td align="left"> Agitation </td><td> 3 </td><td> 0 </td></tr><tr><td align="left"> Hypesthesia </td><td> 2 </td><td> 9 </td></tr><tr><td align="left"> Dysarthria </td><td> 2 </td><td> 0 </td></tr><tr><td align="left"> Vertigo </td><td> 2 </td><td> 0 </td></tr><tr><td align="left"> Brain Edema </td><td> 2 </td><td> 5 </td></tr><tr><td align="left" colspan="3"><content styleCode="bold"> SKIN AND APPENDAGES</content></td></tr><tr><td align="left" scope="row"> Pruritus <content styleCode="bold"> SPECIAL SENSES</content></td><td> 49 </td><td> 5 </td></tr><tr><td align="left"> Tinnitus </td><td> 9 </td><td> 9 </td></tr><tr><td align="left"> Diplopia </td><td> 3 </td><td> 0 </td></tr><tr><td align="left"> Taste Perversion </td><td> 3 </td><td> 0 </td></tr><tr><td align="left"> Amblyopia </td><td> 2 </td><td> 9 </td></tr><tr><td align="left"> Deafness </td><td> 2 </td><td> 0 </td></tr></tbody></table>

<table width="100%"><caption>TABLE 5. Adverse Reaction Incidence Following Substitution of IM Fosphenytoin for Oral Phenytoin in Adult Patients with Epilepsy (Events in at Least 2% of Fosphenytoin-Treated Patients)</caption><col align="left" valign="top" width="50%"/><col align="center" valign="top" width="25%"/><col align="center" valign="top" width="25%"/><thead><tr><th>BODY SYSTEM</th><th>IM FOSPHENYTOIN</th><th>Oral Phenytoin¹</th></tr><tr><th> Adverse Event </th><th> N=179 </th><th> N=61 </th></tr></thead><tbody><tr><td align="left" colspan="3"><content styleCode="bold">BODY AS A WHOLE </content></td></tr><tr><td align="left"> Headache </td><td> 9 </td><td> 5 </td></tr><tr><td align="left"> Asthenia </td><td> 9 </td><td> 3 </td></tr><tr><td align="left"><content styleCode="bold">DIGESTIVE</content></td><td> </td><td> </td></tr><tr align="center"><td align="left"> Nausea </td><td> 5 </td><td> 0 </td></tr><tr><td align="left"> Vomiting </td><td> 3 </td><td> 0 </td></tr><tr><td align="left" colspan="3"><content styleCode="bold"> HEMATOLOGIC AND LYMPHATIC</content></td></tr><tr><td align="left"> Ecchymosis </td><td> 7 </td><td> 5 </td></tr><tr><td align="left" colspan="3"><content styleCode="bold"> NERVOUS</content></td></tr><tr><td align="left"> Nystagmus </td><td> 15 </td><td> 8 </td></tr><tr><td align="left"> Tremor </td><td> 10 </td><td> 13 </td></tr><tr><td align="left"> Ataxia </td><td> 8 </td><td> 8 </td></tr><tr><td align="left"> Incoordination </td><td> 8 </td><td> 5 </td></tr><tr><td align="left"> Somnolence </td><td> 7 </td><td> 10 </td></tr><tr><td align="left"> Dizziness </td><td> 5 </td><td> 3 </td></tr><tr><td align="left"> Paresthesia </td><td> 4 </td><td> 3 </td></tr><tr><td> Reflexes Decreased </td><td> 3 </td><td> 5 </td></tr><tr><td align="left" colspan="3"><content styleCode="bold"> SKIN AND APPENDAGES</content></td></tr><tr><td align="left"> Pruritus </td><td> 3 </td><td> 0 </td></tr></tbody></table>