Cerebyx
Fosphenytoin Sodium · Injection, Solution · Intramuscular, Intravenous
Uses
1 INDICATIONS AND USAGE CEREBYX is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. CEREBYX can also be substituted, short-term, for oral phenytoin. CEREBYX should be used only when oral phenytoin administration is not possible [see Dosage and Administration (2.4) and Warnings and Precautions (5.2) ] . CEREBYX is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. CEREBYX can also be substituted, as short-term use, for oral phenytoin. CEREBYX should be used only when oral phenytoin administration is not possible. ( 1 )
Dosage and administration
• The dose, concentration, and infusion rate of CEREBYX should always be expressed as phenytoin sodium equivalents (PE) ( 2.1 )
• For Status Epilepticus: o Adult loading dose is 15 to 20 mg PE/kg at a rate of 100 to 150 mg PE/min ( 2.3 ) o Pediatric loading dose is 15 to 20 mg PE/kg at a rate of 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) ( 2.3 )
• For Non-emergent Loading and Maintenance Dosing: o Adult loading dose is 10 to 20 mg PE/kg given IV or IM; initial maintenance dose is 4 to 6 mg PE/kg/day in divided doses ( 2.4 ) o Pediatric loading dose is 10 to 15 mg PE/kg at a rate of 1 to 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower); initial maintenance dose is 2 to 4 mg PE/kg every 12 hours at a rate of 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower) ( 2.4 )
• Intramuscular Administration: o CEREBYX should ordinarily not be given intramuscularly ( 2.3 , 2.4 ) 2.1 Important Administration Instructions to Avoid Dosing Errors Use caution when administering CEREBYX because of the risk of dosing errors [see Warnings and Precautions (5.1) ]. Phenytoin Sodium Equivalents (PE) The dose, concentration, and infusion rate of CEREBYX should always be expressed as phenytoin sodium equivalents (PE). There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. CEREBYX should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE). Concentration of 50 mg PE/mL Do not confuse the concentration of CEREBYX with the total amount of drug in the vial. Errors, including fatal overdoses, 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 CEREBYX since each of the vials actually contains a total of 100 mg PE (2 mL vial) or 500 mg PE (10 mL vial). Ensure the appropriate volume of CEREBYX is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some CEREBYX medication errors from occurring. 2.2 Preparation Prior to intravenous (IV) infusion, dilute CEREBYX in 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a concentration ranging from 1.5 to 25 mg PE/mL. The maximum concentration of CEREBYX in any solution should be 25 mg PE/mL. When CEREBYX is given as an IV infusion, CEREBYX needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. For single-dose only. After opening, any unused product should be discarded. 2.3 Status Epilepticus
• Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV CEREBYX should be no greater than 150 mg PE/min in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Warnings and Precautions (5.2) ] . Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential, and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of CEREBYX infusions.
• Because the full antiepileptic effect of phenytoin, whether given as CEREBYX or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus.
• The loading dose should be followed by maintenance doses of either CEREBYX or phenytoin [see Dosage and Administration (2.4) ] .
• If administration of CEREBYX does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered. Adult and Pediatric Status Epilepticus Dosing: Table 1. Status Epilepticus Loading Dosages Population Dosage Infusion rate Adult 15 mg PE/kg to 20 mg PE/kg 100 mg PE/min to 150 mg PE/min, do not exceed a maximum rate of 150 mg PE/min Pediatric (Birth to less than 17 years of age) 15 mg PE/kg to 20 mg PE/kg 2 mg PE/kg/min, or 150 mg PE/min, whichever is slower Even though loading doses of CEREBYX have been given by the IM route for other indications when IV access is impossible, IM CEREBYX should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration. Intramuscular administration of CEREBYX should ordinarily not be used in pediatric patients. When IV access has been impossible, loading doses of CEREBYX have been given by the IM route. 2.4 Non-emergent Loading and Maintenance Dosing
• Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV CEREBYX should be no greater than 150 mg PE/min in adults. For loading doses in pediatric patients, the rate should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower). For maintenance doses in pediatric patients, the rate should not exceed 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower). Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential, and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 10 to 20 minutes after the end of CEREBYX infusions).
• After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin [see Dosage and Administration (2.5) and Warnings and Precautions (5.17) ]. Adult and Pediatric Non-emergent Loading and Maintenance Dosing: Table 2.
Dosage forms and strengths
Injection is a clear, colorless to pale yellow solution available as 50 mg phenytoin sodium equivalents (PE) per mL in:
• 10 mL single-dose injection vials, each containing 500 mg PE/10 mL (50 mg PE/mL)
• 2 mL single-dose injection vials, each containing 100 mg PE/2 mL (50 mg PE/mL) Injection: 50 mg phenytoin sodium equivalents (PE)/mL available as:
• 10 mL single-dose injection vials, each containing 500 mg PE/10 mL (50 mg PE/mL) ( 3 )
• 2 mL single-dose injection vials, each containing 100 mg PE/2 mL (50 mg PE/mL) ( 3 )
Contraindications
4 CONTRAINDICATIONS CEREBYX is contraindicated in patients with:
• A history of hypersensitivity to CEREBYX or its inactive ingredients, or to phenytoin or other hydantoins [see Warnings and Precautions (5.6) ] . Reactions have included angioedema.
• Sinus bradycardia, sino-atrial block, second and third degree A-V block, or Adams-Stokes syndrome because of the effect of parenteral phenytoin or CEREBYX on ventricular automaticity.
• A history of prior acute hepatotoxicity attributable to CEREBYX or phenytoin [see Warnings and Precautions (5.8) ] .
• 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 CEREBYX, its ingredients, phenytoin, 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 CEREBYX or phenytoin ( 4 , 5.8 )
• Coadministration with delavirdine ( 4 )
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, CEREBYX 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 CEREBYX 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 CEREBYX for phenytoin sodium or vice versa. For example, if a patient is receiving 1000 mg PE of CEREBYX, that is equivalent to 1000 mg of phenytoin sodium. Concentration of 50 mg PE/mL Medication errors associated with CEREBYX have resulted in patients receiving the wrong dose of fosphenytoin. CEREBYX 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 CEREBYX 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 CEREBYX should always be expressed in milligrams of phenytoin equivalents (mg PE) [see Dosage and Administration (2.1) ] . Additionally, when ordering and storing CEREBYX, 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 CEREBYX is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some CEREBYX medication errors from occurring. 5.2 Cardiovascular Risk Associated with Rapid Infusion Rapid intravenous administration of CEREBYX 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 CEREBYX 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 CEREBYX should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV CEREBYX, 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 CEREBYX. 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 CEREBYX can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin (the active metabolite of CEREBYX)-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. CEREBYX should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related.
Side effects
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 Pfizer, Inc. at 1-800-438-1985 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 CEREBYX 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 CEREBYX, it should not exceed 150 mg PE/min [see Warnings and Precautions (5.2) ] . The adverse reactions most commonly observed with the use of CEREBYX 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 CEREBYX administration and occurred more often with IV CEREBYX administration than with IM CEREBYX 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 CEREBYX 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 CEREBYX 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 CEREBYX: 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 CEREBYX 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 CEREBYX at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and CEREBYX 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 CEREBYX-Treated Patients) BODY SYSTEM IV CEREBYX IV Phenytoin The study was not designed to assess comparative safety. 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 49 5 SPECIAL SENSES Tinnitus 9 9 Diplopia 3 0 Taste Perversion 3 0 Amblyopia 2 9 Deafness 2 0 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 CEREBYX.
Drug interactions
Fosphenytoin is extensively bound to human plasma proteins. Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin. Although, it is unknown whether this could result in clinically significant effects, caution is advised when administering CEREBYX with other drugs that significantly bind to serum albumin. The most significant drug interactions following administration of CEREBYX are expected to occur with drugs that interact with phenytoin. Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme 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 or CEREBYX 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 or CEREBYX Table 6 includes commonly occurring drug interactions that affect phenytoin (the active metabolite of CEREBYX) 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 6. 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, The induction potency of St. John's wort may vary widely based on preparation. theophylline Drugs that may either increase or decrease phenytoin serum levels Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid 7.2 Drugs Affected by Phenytoin or CEREBYX Table 7 includes commonly occurring drug interactions affected by phenytoin (the active metabolite of CEREBYX). 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 7: 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 Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable. Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide Antiplatelets Ticagrelor 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 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.
Use in specific populations
• Pregnancy: Phenytoin (the active metabolite of CEREBYX) prenatal exposure may increase risks for congenital malformations and other adverse developmental outcomes ( 5.15 , 8.1 )
• Renal and/or Hepatic Impairment or Hypoalbuminemia: Monitor unbound phenytoin concentrations in these patients ( 8.6 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as CEREBYX, during pregnancy. Physicians are advised to recommend that pregnant patients taking CEREBYX 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 (the active metabolite of CEREBYX) 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 (2.5 , 2.9) ] . 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 hydantoin 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. 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 It is not known whether fosphenytoin is secreted in human milk. Following administration of phenytoin (the active metabolite of CEREBYX), phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CEREBYX and any potential adverse effects on the breastfed infant from CEREBYX or from the underlying maternal condition. 8.4 Pediatric Use CEREBYX is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery in all pediatric age groups [see Indications and Usage (1) and Dosage and Administration (2.3 , 2.4) ]. Because rapid intravenous administration of CEREBYX increases the risk of adverse cardiovascular reactions, the rate of administration should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Dosage and Administration (2.3 , 2.4) and Warnings and Precautions (5.2) ]. 8.5 Geriatric Use No systematic studies in geriatric patients have been conducted. Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3) ] . Lower or less frequent dosing may be required [see Clinical Pharmacology (12.3) and Dosage and Administration (2.8) ] . 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 (the active metabolite of CEREBYX) 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.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as CEREBYX, during pregnancy. Physicians are advised to recommend that pregnant patients taking CEREBYX 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 (the active metabolite of CEREBYX) 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 (2.5 , 2.9) ] . 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 hydantoin 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. 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.
Pediatric use
8.4 Pediatric Use CEREBYX is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery in all pediatric age groups [see Indications and Usage (1) and Dosage and Administration (2.3 , 2.4) ]. Because rapid intravenous administration of CEREBYX increases the risk of adverse cardiovascular reactions, the rate of administration should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Dosage and Administration (2.3 , 2.4) and Warnings and Precautions (5.2) ].
Geriatric use
8.5 Geriatric Use No systematic studies in geriatric patients have been conducted. Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3) ] . Lower or less frequent dosing may be required [see Clinical Pharmacology (12.3) and Dosage and Administration (2.8) ] .
Overdosage
Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with CEREBYX. Because CEREBYX is a prodrug of phenytoin, the following information about phenytoin overdosage may be helpful. Initial symptoms of acute phenytoin toxicity are nystagmus, ataxia, and dysarthria. Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma, and hypotension. Death is caused by respiratory and circulatory depression. The lethal dose of phenytoin in adults is estimated to be 2 to 5 grams. The lethal dose in pediatrics is not known. There are marked variations among individuals with respect to serum phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 20 µg/mL, ataxia at 30 µg/mL, and dysarthria and lethargy appear when the serum concentration is over 40 µg/mL. However, phenytoin concentrations as high as 50 µg/mL have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in serum phenytoin concentrations over 100 µg/mL, with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported after overdosage. Formate and phosphate are metabolites of CEREBYX and therefore may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with severe anion-gap metabolic acidosis. Large amounts of phosphate, delivered rapidly, could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. Ionized free calcium levels can be measured and, if low, used to guide treatment. Treatment: Treatment is nonspecific since there is no known antidote to CEREBYX or phenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin (the active metabolite of CEREBYX) is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
Description
11 DESCRIPTION CEREBYX ® (fosphenytoin sodium injection) is a prodrug intended for parenteral administration; its active metabolite is phenytoin. 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE). The amount and concentration of fosphenytoin is always expressed in terms of mg PE . The pharmacological class of the fosphenytoin sodium is hydantoin derivative, and the therapeutic class is anticonvulsant. CEREBYX is marketed in 2 mL vials containing a total of 100 mg PE/2 mL (50 mg PE/mL) and 10 mL vials containing a total of 500 mg PE/10 mL (50 mg PE/mL), for intravenous or intramuscular administration. The concentration of each vial is 50 mg PE/mL. CEREBYX is supplied in vials as a sterile solution in Water for Injection, USP, and Tromethamine, USP (TRIS) (12.11 mg/mL), buffer adjusted to pH 8.6 to 9.0 with either Hydrochloric Acid, NF, or Sodium Hydroxide, NF. CEREBYX is a clear, colorless to pale yellow, sterile solution. The chemical name of fosphenytoin is 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4-imidazolidinedione disodium salt. The molecular structure of fosphenytoin is: The molecular weight of fosphenytoin is 406.24. Chemical Structure
Mechanism of action
12.1 Mechanism of Action Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. 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.
How supplied
16.1 How Supplied CEREBYX Injection is a clear, colorless to pale yellow solution supplied as follows: mg phenytoin sodium equivalents (PE) per vial Volume per vial (mL) Package Configuration NDC 500 mg PE/10 mL vial 10 mL per vial Package contains 10 vials of NDC 0069-6001-10 NDC 0069-6001-21 100 mg PE/2 mL vial 2 mL per vial Package contains 25 vials of NDC 0069-6001-02 NDC 0069-6001-25 Both sizes of vials contain Tromethamine, USP (TRIS), Hydrochloric Acid, NF, or Sodium Hydroxide, NF, and Water for Injection, USP. CEREBYX should always be prescribed in phenytoin sodium equivalents (PE) [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ] . 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin's weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa. 16.2 Storage and Handling Store under refrigeration at 2°C to 8°C (36°F to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used. Injection vials are single-dose only. After opening, any unused product should be discarded.
Storage
16.2 Storage and Handling Store under refrigeration at 2°C to 8°C (36°F to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used. Injection vials are single-dose only. After opening, any unused product should be discarded.
Patient information
Cardiovascular Risk Associated with Rapid Infusion Inform patients that rapid intravenous administration of CEREBYX 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. Patients should report cardiac signs or symptoms to their healthcare provider [see Warnings and Precautions (5.2) ] . Withdrawal of Antiepileptic Drugs Advise patients not to discontinue use of CEREBYX without consulting with their healthcare provider. CEREBYX should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.3) ] . Serious Dermatologic Reactions Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.4) ] . Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions 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 (5.4 , 5.5 , 5.6 , 5.8 , 5.9) ] . Angioedema Advise patients to discontinue CEREBYX and seek immediate medical care if they develop signs or symptoms of angioedema such as facial, perioral, or upper airway swelling [ see Warnings and Precautions (5.7) ] . Hyperglycemia Advise patients that CEREBYX may cause an increase in blood glucose levels [see Warnings and Precautions (5.16) ] . 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 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. Use in Pregnancy Inform pregnant women and women of childbearing potential that use of CEREBYX 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 CEREBYX, 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) ] .
Label text from the FDA structured product label by Pfizer Laboratories Div Pfizer Inc (revised Aug 28, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Fosphenytoin Sodium in 3 products
Cerebyx NDC products (3)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0069-5471 | Fosphenytoin Sodium 50 mg/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | NDA |
| 0069-5474 | Fosphenytoin Sodium 50 mg/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | NDA |
| 0069-6001 | Fosphenytoin Sodium 50 mg/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | NDA |
Frequently asked questions
What is Cerebyx used for?
1 INDICATIONS AND USAGE CEREBYX is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. CEREBYX can also be substituted, short-term, for oral phenytoin. CEREBYX should be used only when oral phenytoin administration is not possible [see Dosage and Administration (2.4) and Warnings and Precautions (5.2) ]…
What are the side effects of Cerebyx?
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… See the full label for the complete list.
Who makes Cerebyx?
Cerebyx is listed by 1 labeler in the FDA NDC directory, including Pfizer Laboratories Div Pfizer Inc.