Cerebyx Drug Information

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.

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. 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. Adult and Pediatric Status Epilepticus Dosing: Table 1.

Status Epilepticus Loading 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.

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). 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.

Adult and Pediatric Non-emergent Loading and Maintenance Dosing: Table 2. Non-emergent Loading Because of the risks of cardiac and local toxicity associated with intravenous CEREBYX, oral phenytoin should be used whenever possible.

• Laboratory Tests and Monitoring Levels Laboratory Tests: CEREBYX (or phenytoin) doses are usually selected to attain therapeutic serum 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 intramuscular (IM) injection. Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx ® /TDxFLx™ (fluorescence polarization) and Emit ® 2000 (enzyme multiplied), may significantly overestimate serum phenytoin concentrations because of cross-reactivity with fosphenytoin. The error is dependent on serum 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.
• Monitoring Levels: Trough levels provide information about clinically effective serum level range and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total phenytoin concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant.

Parenteral 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 phenytoin sodium equivalents (PE) dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin, derived from administration of CEREBYX, is 100% bioavailable by both the IM and IV routes.

For this reason, serum phenytoin concentrations may increase modestly when IM or IV CEREBYX is substituted for oral phenytoin sodium therapy. 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 Patients with Renal or Hepatic Impairment or Hypoalbuminemia 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 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.

Dosing in Geriatrics

The clearance of phenytoin (the active metabolite of CEREBYX) is decreased slightly in elderly patients and lower or less frequent dosing may be required.

Dosing during Pregnancy

Decreased serum concentrations of phenytoin (the active metabolite of CEREBYX) may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the CEREBYX dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated.

Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

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. 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 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. 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) 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. Incidence in Controlled Trials - IM Administration to Adult Patients with Epilepsy: Table 5 lists adverse reactions 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 phenytoin or continuing oral phenytoin.

Both treatments were administered for 5 days. TABLE 5. Adverse Reaction Incidence Following Substitution of IM CEREBYX for Oral Phenytoin in Adult Patients with Epilepsy (Events in at Least 2% of CEREBYX-Treated Patients) s During Clinical Trials in Adult and Pediatric Patients CEREBYX 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. Laboratory Test Abnormality: Phenytoin (the active metabolite of CEREBYX) 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.

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 Hematologic: Pure red cell aplasia Laboratory Test Abnormality: Phenytoin or CEREBYX 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

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

Drugs Affected by Phenytoin or CEREBYX Table 7 includes commonly occurring drug interactions affected by phenytoin (the active metabolite of CEREBYX). 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 Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance.

Hyperammonemia with Concomitant Use of Valproate

Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia. Patients treated concomitantly with these two drugs should be monitored for signs and symptoms of hyperammonemia.

Drug/Laboratory Test Interactions Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations following CEREBYX administration.

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. 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.

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 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. 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 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. 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.

• CEREBYX is contraindicated in patients with:
• A history of hypersensitivity to CEREBYX or its inactive ingredients, or to phenytoin or other hydantoins. 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.
• 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
• Sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome
• Coadministration with delavirdine

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.