Fosphenytoin

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. CEREBYX can also be substituted, as short-term use, for oral phenytoin.

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.

• The dose, concentration, and infusion rate of CEREBYX should always be expressed as phenytoin sodium equivalents (PE). • For Status Epilepticus: o Adult loading dose is 15 to 20 mg PE/kg at a rate of 100 to 150 mg PE/min 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). • 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 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). • Intramuscular Administration: o CEREBYX should ordinarily not be given intramuscularly

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.

Boxed warning (cardiovascular risk associated with rapid 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 because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous CEREBYX. • 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. • Withdrawal Precipitated Seizure: May precipitate status epilepticus. Dose reductions or discontinuation should be done gradually. • Serious Dermatologic Reactions: Discontinue at the first sign of a rash, unless clearly not drug-related.

The following serious adverse reactions are described elsewhere in the labeling: • Cardiovascular Risk Associated with Rapid Infusion • Withdrawal Precipitated Seizure, Status Epilepticus • Serious Dermatologic Reactions • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity • Hypersensitivity • Angioedema • Hepatic Injury • Hematopoietic Complications • Sensory Disturbances • Local Toxicity (Including Purple Glove Syndrome) • Exacerbation of Porphyria • Teratogenicity and Other Harm to the Newborn • Hyperglycemia Most common adverse reactions (incidence ≥10%) are: • Adults: pruritus, nystagmus, dizziness, somnolence, and ataxia • Pediatrics: vomiting, nystagmus, and ataxia

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.

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.