Drug: Cerebyx

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. 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. CEREBYX is supplied in vials as a ready-mixed solution in Water for Injection, USP, and Tromethamine, USP (TRIS), 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]-2,4imidazolidinedione disodium salt. The molecular structure of fosphenytoin is: The molecular weight of fosphenytoin is 406.24. IMPORTANT NOTE: Throughout all CEREBYX® product labeling, the amount and concentration of fosphenytoin are always expressed in terms 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 Care should be taken to ensure that CEREBYX is always prescribed and dispensed in phenytoin sodium equivalent (PE) (see DOSAGE AND ADMINISTRATION).

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The more important adverse clinical events caused by the IV use of CEREBYX or phenytoin are cardiovascular collapse and/or central nervous system 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. The adverse clinical events most commonly observed with the use of CEREBYX in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following CEREBYX administration and occurred more often with IV CEREBYX administration than with IM CEREBYX administration. These events 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 events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see PRECAUTIONS, Sensory Disturbances). Approximately 2% of the 859 individuals 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 Events Following IV CEREBYX: The incidence of adverse events 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. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. Incidence in Controlled Clinical Trials -IV Administration To Patients With Epilepsy or Neurosurgical Patients: Table 2 lists treatment-emergent adverse events 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 2: Treatment-Emergent Adverse Event Incidence Following IV Administration at the Maximum Dose and Rate to Patients With Epilepsy or Neurosurgical Patients (Events in at Least 2% of CEREBYX -Treated Patients)
BODY SYSTEM Adverse Event IV CEREBYX N=90 IV Phenytoin N=22 BODY AS A WHOLE   Pelvic Pain 4.4 0.0   Asthenia 2.2 0.0   Back Pain 2.2 0.0   Headache 2.2 4.5 CARDIOVASCULAR   Hypotension 7.7 9.1   Vasodilatation 5.6 4.5   Tachycardia 2.2 0.0 DIGESTIVE   Nausea 8.9 13.6   Tongue Disorder 4.4 0.0   Dry Mouth 4.4 4.5   Vomiting 2.2 9.1 NERVOUS   Nystagmus 44.4 59.1   Dizziness 31.1 27.3   Somnolence 20.0 27.3   Ataxia 11.1 18.2   Stupor 7.7 4.5   Incoordination 4.4 4.5   Paresthesia 4.4 0.0   Extrapyramidal Syndrome 4.4 0.0   Tremor 3.3 9.1   Agitation 3.3 0.0   Hypesthesia 2.2 9.1   Dysarthria 2.2 0.0   Vertigo 2.2 0.0   Brain Edema 2.2 4.5 SKIN AND APPENDAGES   Pruritus 48.9 4.5 SPECIAL SENSES   Tinnitus 8.9 9.1   Diplopia 3.3 0.0   Taste Perversion 3.3 0.0   Amblyopia 2.2 9.1   Deafness 2.2 0.0 Incidence in Controlled Trials -IM Administration to Patients With Epilepsy: Table 3 lists treatment-emergent adverse events that occurred in at least 2% of CEREBYX-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either IM CEREBYX substituted for oral Dilantin or continuing oral Dilantin. Both treatments were administered for 5 days. TABLE 3: Treatment-Emergent Adverse Event Incidence Following Substitution of IM CEREBYX for Oral Dilantin in Patients With Epilepsy (Events in at Least 2% of CEREBYX -Treated Patients)
BODY SYSTEM Adverse Event IM CEREBYX
N=179 Oral Dilantin
N=61 BODY AS A WHOLE   Headache 8.9 4.9   Asthenia 3.9 3.3   Accidental Injury 3.4 6.6 DIGESTIVE   Nausea 4.5 0.0   Vomiting 2.8 0.0 HEMATOLOGIC AND LYMPHATIC   Ecchymosis 7.3 4.9 NERVOUS   Nystagmus 15.1 8.2   Tremor 9.5 13.1   Ataxia 8.4 8.2   Incoordination 7.8 4.9   Somnolence 6.7 9.8   Dizziness 5.0 3.3   Paresthesia 3.9 3.3   Reflexes Decreased 2.8 4.9 SKIN AND APPENDAGES   Pruritus 2.8 0.0 Adverse Events During All Clinical Trials CEREBYX has been administered to 859 individuals during all clinical trials. All 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. 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, hypesthesia; Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, brain edema, 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: Frequent: taste perversion; Infrequent: deafness, 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. Post-Marketing Experience The following adverse reactions have been identified during postapproval use of 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. There have been post-marketing reports of anaphylactoid reaction and anaphylaxis. Other Phenytoin-Associated Adverse Events Dyskinesia. Read the Cerebyx (fosphenytoin sodium injection) Side Effects Center for a complete guide to possible side effectsLearn More »

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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). 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 (mg PE). Do not confuse the concentration of CEREBYX with the total amount of drug in the vial. Caution must be used when administering CEREBYX due to the risk of dosing errors (see WARNINGS). 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. Both vials contain a concentration of 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 of the vials 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). 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 dose for administration. Attention to these details may prevent some CEREBYX medication errors from occurring. Prior to IV infusion, dilute CEREBYX in 5% dextrose or 0.9% saline solution for 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 intravenous 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. Status Epilepticus
  • The loading dose of CEREBYX is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.
  • Because of the risk of hypotension, CEREBYX should be administered no faster than 150 mg PE/min. 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.
If administration of CEREBYX does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered. 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. Nonemergent Loading And Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous CEREBYX, oral phenytoin should be used whenever possible. The loading dose of CEREBYX is 10 – 20 mg PE/kg given IV or IM. The rate of administration for IV CEREBYX should be no greater than 150 mg PE/min. 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 20 minutes after the end of CEREBYX infusion). The initial daily maintenance dose of CEREBYX is 4 – 6 mg PE/kg/day in divided doses. IM Or IV Substitution For Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, CEREBYX can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as CEREBYX, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV CEREBYX is substituted for oral phenytoin sodium therapy. The rate of administration for IV CEREBYX should be no greater than 150 mg PE/min. In controlled trials, IM CEREBYX was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more Frequent dosing. Dosing In Special Populations Patients with Renal or Hepatic Disease Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY: Special Populations). Unbound phenytoin concentrations may be more useful in these patient populations. After IV CEREBYX 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 (see PRECAUTIONS). Elderly Patients Age does not have a significant impact on the pharmacokinetics of fosphenytoin following CEREBYX administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less Frequent dosing may be required. Pediatric The safety and efficacy of CEREBYX in pediatric patients have not been established.

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No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. Conversion could be affected by alterations in the level of phosphatase activity, but given the abundance and wide distribution of phosphatases in the body it is unlikely that drugs would affect this activity enough to affect conversion of fosphenytoin to phenytoin. 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 pharmacokinetics and protein binding of fosphenytoin, phenytoin, and diazepam were not altered when diazepam and CEREBYX were concurrently administered in single submaximal doses. 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 metabolized by hepatic cytochrome P450 enzymes CYP2C9 and 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. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. Drugs That Affect Phenytoin Concentrations
  • Drugs that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
  • Drugs that may decrease plasma phenytoin concentrations include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John's Wort, theophylline, and vigabatrin.
  • Drugs that may either increase or decrease plasma phenytoin concentrations include: phenobarbital, valproic acid, and sodium valproate. Similarly, the effects of phenytoin on phenobarbital, valproic acid and sodium plasma valproate concentrations are unpredictable.
  • 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.
Drugs Affected By Phenytoin
  • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS).
  • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D.
  • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
  • Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), antiepileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin and verapamil.
  • 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.
  • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
  • 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.
Monitoring of plasma phenytoin concentrations may be helpful when possible drug interactions are suspected (see Laboratory Tests). Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce artifactually low results in dexamethasone or metyrapone tests. Phenytoin may also cause increased serum concentrations of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following CEREBYX administration (see Laboratory Tests). Read the Cerebyx Drug Interactions Center for a complete guide to possible interactions Learn More »

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CEREBYX is indicated for the control 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. CEREBYX must not be given orally.

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CEREBYX is contraindicated in patients who have demonstrated hypersensitivity to CEREBYX or its ingredients, or to phenytoin or other hydantoins. Because of the effect of parenteral phenytoin on ventricular automaticity, CEREBYX is contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome. Coadministration of CEREBYX is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.Last reviewed on RxList: 6/30/2014
This monograph has been modified to include the generic and brand name in many instances.

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Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m²basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity. Because CEREBYX is a prodrug of phenytoin, the following information 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. Depression of respiratory and circulatory systems leads to death. There are marked variations among individuals with respect to plasma 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 plasma 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 plasma phenytoin concentrations over 100 μg/mL, with complete recovery. 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 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. Formate and phosphate are metabolites of fosphenytoin 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.

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CEREBYX Injection is supplied as follows: 10 mL per vial — Each 10 mL vial contains 500 mg phenytoin sodium equivalents (PE): NDC 0069-6001-10. Package of 1.
NDC 0069-6001-21. Packages of 10. 2 mL per vial — Each 2 mL vial contains 100 mg of phenytoin sodium equivalents (PE): NDC 0069-6001-02. Package of 1.
NDC 0069-6001-25. Packages of 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). 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. 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. This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com. Distributed by Pfizer Labs, Division of Pfizer Inc., New York, NY 10017. Revised April 2014Last reviewed on RxList: 6/30/2014
This monograph has been modified to include the generic and brand name in many instances.

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General: (CEREBYX specific) Sensory Disturbances Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered IV CEREBYX 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 CEREBYX 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 CEREBYX 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. Local toxicity (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 CEREBYX injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection. Phosphate Load The phosphate load provided by CEREBYX (0.0037 mmol phosphate/mg PE CEREBYX) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment. IV Loading in Renal and/or Hepatic Disease or in Those with Hypoalbuminemia 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 (see CLINICAL PHARMACOLOGY: Special Populations, and DOSAGE AND ADMINISTRATION: Dosing in Special Populations). General (phenytoin associated) CEREBYX is not indicated for the treatment of absence seizures. A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. Phenytoin has been Infrequently associated with the exacerbation of porphyria. Caution should be exercised when CEREBYX is used in patients with this disease. Hyperglycemia, resulting from phenytoin's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose concentrations in diabetic patients. Plasma concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely, irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, determination of plasma phenytoin concentrations is recommended (see PRECAUTIONS: Laboratory Tests). CEREBYX dose reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, administration of CEREBYX should be discontinued. The liver is the primary site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity. Phenytoin and other hydantoins are not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin has the potential to lower serum folate levels. Laboratory Tests Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL, (unbound phenytoin concentrations of 1 to 2 mcg/mL). Following CEREBYX administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after IM injection. Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx®/TDxFLx™ (fluorescence polarization) and Emit® 2000 (enzyme multiplied), may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by CEREBYX dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved. Carcinogenesis, Mutagenesis, Impairment Of Fertility The carcinogenic potential of fosphenytoin has not been studied. Assessment of the carcinogenic potential of phenytoin in mice and rats is ongoing. Structural chromosome aberration frequency in cultured V79 Chinese hamster lung cells was increased by exposure to fosphenytoin in the presence of metabolic activation. No evidence of mutagenicity was observed in bacteria (Ames test) or Chinese hamster lung cells in vitro, and no evidence for clastogenic activity was observed in an in vivo mouse bone marrow micronucleus test. No effects on fertility were noted in rats of either sex given fosphenytoin. Maternal toxicity and altered estrous cycles, delayed mating, prolonged gestation length, and developmental toxicity were observed following administration of fosphenytoin during mating, gestation, and lactation at doses of 50 mg PE/kg or higher (approximately 40% of the maximum human loading dose or higher on a mg/m²basis). Pregnancy -Category D (see WARNINGS) Use in Nursing Mothers It is not known whether fosphenytoin is excreted in human milk. Following administration of Dilantin, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breast-feeding is not recommended for women receiving CEREBYX. Pediatric Use The safety and efficacy of CEREBYX in pediatric patients has not been established. Geriatric Use No systematic studies in geriatric patients have been conducted. Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). Last reviewed on RxList: 6/30/2014
This monograph has been modified to include the generic and brand name in many instances.

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