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.

Use caution when administering CEREBYX because of the risk of dosing errors.

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).

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 tenfold 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 Ensure the appropriate volume of CEREBYX is withdrawn from the vial when preparing the dose for administration.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.

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.

Careful cardiac monitoring is needed during and after administering intravenous CEREBYX.

Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed.

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.

Because of the risks of cardiac and local toxicity associated with intravenous CEREBYX, oral phenytoin should be used whenever possible. Intramuscular administration of CEREBYX should ordinarily not be used in pediatric patients.

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

In view of isolated reports associating phenytoin (the active metabolite of CEREBYX) with exacerbation of porphyria, caution should be exercised in using CEREBYX in patients suffering from this disease.

CEREBYX is contraindicated in patients with:

• A history of hypersensitivity to CEREBYX or its inactive ingredients, or to phenytoin or other hydantoins 
• Sinus bradycardia, sinoatrial 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
• Co-administration 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

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). 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.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding CEREBYX as an alternative for carbamazepine patients positive for HLA-B*1502.

In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding CEREBYX as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin and CEREBYX.

Angioedema has been reported in patients treated with phenytoin and CEREBYX in the postmarketing setting. CEREBYX should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. CEREBYX should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin (the active metabolite of CEREBYX).

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin (the active metabolite of CEREBYX). These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports that have suggested a relationship between phenytoin and the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease.

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).

Edema, discoloration, and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous CEREBYX injection.

Hyperglycemia, resulting from the inhibitory effect of phenytoin (the active metabolite of CEREBYX) on insulin release, has been reported. Phenytoin may also raise the serum glucose concentrations in diabetic patients.

Serum levels of phenytoin (the active metabolite of CEREBYX) sustained above the therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy.

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.

The following drugs may increase phenytoin serum levels: ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate, fluconazole, ketoconazole, itraconazole, miconazole, voriconazole, capecitabine, fluorouracil, fluoxetine, fluvoxamine, sertraline, H2 antagonists (cimetidine), omeprazole, sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim, acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, and warfarin. 

The following drugs may decrease phenytoin serum levels: bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate, fosamprenavir, nelfinavir, ritonavir, carbamazepine, vigabatrin, chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort and theophylline.

The following drugs are decreased by phenytoin: carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, atorvastatin, fluvastatin, simvastatin, efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir, nifedipine, nimodipine, nisoldipine, verapamil, albendazole, chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel and quetiapine.

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.

The efficacy of the following drugs are impaired by phenytoin: fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole, irinotecan, paclitaxel, teniposide, delavirdine, neuromuscular blocking agents, warfarin, corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D.

Decreased serum concentrations of phenytoin (the active metabolite of CEREBYX) may occur during pregnancy because of altered phenytoin pharmacokinetics.

CEREBYX may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin (the active metabolite of CEREBYX) may increase the risks for congenital malformations and other adverse developmental outcomes. 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.

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.

GoToSource

• Seizure prevention in childhood coma. GoToSource

• Benign convulsions and mild gastroenteritis. GoToSource

• Subarachnoid hemorrhage. GoToSource

• Acute mania. GoToSource

• Acute trigeminal neuralgia crisis. GoToSource

• Partial seizures. GoToSource

⚠️  Patients with HLA-B*1502 or CYP2C9 gene variation are at risk for severe cutaneous adverse reactions.

Perineal pruritus (itching of perianal skin). GoToSource

Cardiac arrest, syncope (loss of consciousness), palpitation (rapid or irregular heartbeat), sinus bradycardia (slow heart rate), atrial flutter (abnormal heart rhythm), bundle branch block, QT-interval prolongation (heart rhythm condition), ventricular extrasystoles and congestive heart failure. GoToSource

Liver injury. GoToSource

Hyperphosphatemia (elevated phosphate level in the blood). GoToSource

Stevens-johnson syndrome and toxic epidermal necrolysis (severe drug reactions). GoToSource

Anticonvulsant hypersensitivity syndrome. GoToSource

Dizziness, nystagmus (rapid involuntary eye movements) and ataxia (lack of muscle control or coordination). GoToSource

Hypotension (low blood pressure) and purple glove syndrome (skin discoloration, swelling and pain at site of injection. GoToSource

Lawsuits filed for stevens-johnson syndrome.