Fosphenytoin dose, injection, side effects and brand name

Description of Fosphenytoin 

Fosphenytoin is a water-soluble, parenteral prodrug of phenytoin, a hydantoin anticonvulsant Intravenous (IV) fosphenytoin is used for status epilepticus. IV or intramuscular (IM) fosphenytoin may be substituted short-term for oral phenytoin in situations where oral phenytoin is not appropriate or advantageous. Unlike phenytoin, fosphenytoin is soluble in standard intravenous solutions and is rapidly absorbed via the IM route. Fosphenytoin has fewer local adverse reactions and does not contain propylene glycol; thus, IV doses can be given at a faster rate. Since fosphenytoin is converted to phenytoin in vivo, systemic adverse reactions are generally similar between the 2 products. While fosphenytoin represents an improvement over phenytoin in terms of infusion-related reactions, fosphenytoin causes transient, infusion-related paresthesias and pruritus not seen with phenytoin. Fosphenytoin is more expensive than corresponding doses of generic phenytoin but is an attractive alternative in pediatric patients, where IV access is often limited and tenuous. Most fosphenytoin formulations require storage under refrigeration; however, Sesquient is a room temperature stable formulation of fosphenytoin available for intravenous use, allowing for point-of-care storage. Unlike other formulations, Sesquient contains the soluble carrier betadex sulfobutyl ether sodium, which limits its use in the pediatric population to non-urgent indications because of the slower infusion rate in patients 2 years and older. Additionally, this formulation is indicated for IV use only.

Mechanism of Action of Fosphenytoin

Fosphenytoin is a phosphate ester prodrug of the anticonvulsant phenytoin. Thus, phenytoin is responsible for all of the pharmacological effects of fosphenytoin. Phenytoin exerts its anticonvulsant effect mainly by limiting the spread of seizure activity and reducing seizure propagation unlike phenobarbital and carbamazepine, which elevate the seizure threshold. Because phenytoin does not elevate the seizure threshold, it is less effective against drug-induced or electroconvulsive-induced seizures.

The cellular mechanisms thought to be responsible for phenytoin’s anticonvulsant activities include modulation of voltage-dependent sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and the enhancement of Na+/K+ ATPase activity of neurons and glial cells. The limitation of repetitive firing in neurons caused by slowing the rate of recovery in inactivated sodium channels is thought to be phenytoin’s primary mechanism. Phenytoin exerts its anticonvulsant effects with less sedation than does phenobarbital. In toxic concentrations, phenytoin is excitatory and can induce seizures. Phenytoin is also a weak antiarrhythmic. Antiarrhythmic actions are also mediated through effects on sodium channels, in this case, in Purkinje fibers.

Pharmacokinetics of Fosphenytoin

Fosphenytoin is administered via the intravenous or intramuscular routes only. While 150 mg of fosphenytoin yields 100 mg of phenytoin, fosphenytoin is dosed in phenytoin sodium equivalents (PE). Thus, 100 mg of phenytoin is equivalent to a 100 mg PE dose of fosphenytoin. After parenteral administration, fosphenytoin is quickly hydrolyzed to phenytoin (the active form), yielding 2 metabolites, phosphate and formaldehyde. While phosphate and formaldehyde have biologic effects, the amount produced appears to be too small to exert clinically significant biological effects. Formaldehyde is eventually converted to formate, which is, in turn, metabolized via a folate-dependent pathway. Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate. The half-life of conversion of fosphenytoin to phenytoin is approximately 8 minutes.

Fosphenytoin is extensively bound (95% to 99%), primarily to albumin; binding is saturable (i.e., the percentage of bound drug decreases as total drug concentration increases). Phenytoin is also extensively bound to albumin, but less than fosphenytoin. Fosphenytoin effectively displaces phenytoin from protein binding sites, temporarily increasing the free fraction from 12% up to 30%, until fosphenytoin is converted to phenytoin (about 0.5 to 1 hour post-infusion). Phenytoin is extensively metabolized in the liver and excreted in the urine. Hepatic metabolism of phenytoin is saturable, leading to AUC values that increase disproportionately with increasing dose. The Vd increases with injection dose and rate and ranges from 4.3 to 10.8 liters in adults.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19, P-gp Fosphenytoin (converted to phenytoin) is an inducer of the hepatic cytochrome P450 microsomal isoenzymes CYP3A4, CYP2D6, CYP1A2, CYP2C9, and CYP2C19. Limited data suggest phenytoin is also a mild inducer of P-glycoprotein (P-gp). Phenytoin is metabolized primarily by CYP2C9 (major) and CYP2C19 (minor); thus, several drugs may inhibit or induce phenytoin’s metabolism. CYP2C9 activity is decreased in individuals with CYP2C9 2 and 3 alleles. Patients who are intermediate (e.g., 1/3, 2/2) or poor (e.g., 2/3, 3/3) metabolizers of CYP2C9 have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles (e.g., 5, 6, 8, 11) may also result in decreased clearance of phenytoin.

Route-Specific Pharmacokinetics

Intravenous Route
The pharmacokinetics of intravenously-administered fosphenytoin are complex. Studies have determined a fosphenytoin dose and infusion rate that yields phenytoin plasma concentrations similar to those of conventional phenytoin at a rate of 50 mg/minute. For example, fosphenytoin 15 to 20 mg/kg PE infused at 100 to 150 mg PE/minute yields free phenytoin concentrations the same as 15 to 20 mg/kg phenytoin at 50 mg/minute in adults. Fosphenytoin is completely converted to phenytoin after IV administration. Peak plasma concentrations are achieved by the end of infusion. Conversion to phenytoin is complete within 2 hours after the end of the infusion.

Intramuscular Route
Fosphenytoin is completely bioavailable after IM administration. Peak fosphenytoin concentrations are achieved approximately 30 minutes after administration; peak phenytoin concentrations are observed after 3 hours. Due to time required for absorption from the IM site, plasma fosphenytoin concentrations are lower but more sustained when compared to IV administration. The pharmacokinetics of phenytoin after the IM administration of fosphenytoin are similar to those of orally administered phenytoin; these 2 products are considered interchangeable. Conversion to phenytoin is complete within 4 hours after administration.

Special Populations
Hepatic Impairment
Patients with hepatic disease may have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance, potentially increasing the frequency and severity of adverse events.

Renal Impairment
Patients with renal disease may have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance, potentially increasing the frequency and severity of adverse events.

Pediatrics
Infants, Children, and Adolescents
Infants and young children up to 24 months old may have enhanced hepatic clearance, leading to larger maintenance dose requirements of fosphenytoin. Limited data in children and adolescents 5 to 18 years of age demonstrate comparable pharmacokinetic profiles when compared to adult patients. The half-life of conversion of fosphenytoin to phenytoin is approximately 8 minutes in pediatric patients, with no significant difference between neonates, infants, children, and adolescents. Although more variable in pediatric patients, this value is comparable to that of adults.

Neonates
Fosphenytoin is highly protein-bound; in general, neonates have a more variable and lower level of protein binding compared to older populations. Hyperbilirubinemia, which is often present in critically ill neonates, may further decrease protein binding. The half-life of conversion of fosphenytoin to phenytoin is approximately 8 minutes, with no significant difference between neonates, infants, children, adolescents, and adults.

• Fosphenytoin Sodium

• Cerebyx
• Sesquient

• Anticonvulsant
• Hydantoin (class)

• Seizure, During neurosurgery; Treatment and Prophylaxis: Adult
• Seizure, During neurosurgery; Treatment and Prophylaxis: Pediatric: yes (All ages, Cerebyx(R); 17 years or older, Sesquient(TM))
• Seizure, For short-term administration when oral phenytoin is not possible: Adult
• Seizure, For short-term administration when oral phenytoin is not possible: Pediatric: yes (All ages, Cerebyx(R); 2 years or older, Sesquient(TM))
• Status epilepticus: Adult
• Status epilepticus: Pediatric: yes (All ages, Cerebyx(R); 17 years or older, Sesquient(TM))

• Dermatologic: Pruritus (Adult: IV, 49%; IM, 3%; pediatric: IV, 6% )
• Neurologic: Ataxia (8% to 11% ), Dizziness (IM, 5%; IV, 31.1% ), Headache (IV, 2.2%; IM, 8.9% ), Paresthesia (IM, 3.9%; IV, 4.4% ), Somnolence (6% to 20% )
• Ophthalmic: Nystagmus (Adult: IM, 15%; IV, 44%; pediatric: IV, 18% )

• Cardiovascular: Bradyarrhythmia (0.1% to 1% ), Cardiac arrest (0.1% to 1% ), Heart block, Hypotension (5% to 8% ), Prolonged QT interval, Sudden cardiac death
• Dermatologic: Generalized exanthematous pustulosis, acute, Purple glove syndrome, Stevens-Johnson syndrome, Toxic epidermal necrolysis
• Hematologic: Leukopenia (0.1% to 1% ), Macrocytosis, Megaloblastic anemia, Pure red cell aplasia, Thrombocytopenia (0.1% to 1% )
• Immunologic: Anaphylaxis, Angioedema, Drug reaction with eosinophilia and systemic symptoms
• Neurologic: Sensory disorder

• NIOSH Group 2 Non-antineoplastics
• NIOSH: In the preparation and administration of injections, use double gloves and a protective gown. Prepare in a biological safety cabinet or a compounding aseptic containment isolator; eye/face and respiratory protection may be needed. Prepare compounds in a closed system drug transfer device. During administration, if there is a potential that the substance could splash or if the patient may resist, use eye/face protection. Administer certain dosage forms via a closed system drug transfer device .
• Intravenous: Must be diluted when given as an IV infusion
• Intravenous: Single use only; discard any unused product .
• Intravenous: Dilute with D5W or NS to a concentration of 1.5 to a MAX of 25 mg phenytoin sodium equivalents (PE)/mL
• Intravenous: (Sesquient(TM)) Once diluted, the solution is stable for 4 hours at room temperature
• Intravenous: (Cerebyx(R), adult) Status epilepticus loading dose: Administer at a rate of 100 to 150 mg phenytoin sodium equivalents (PE)/min; do not exceed 150 mg PE/min
• Intravenous: (Cerebyx(R), adult) Nonemergent loading and maintenance doses: Administer at a maximum rate of 150 mg PE/min
• Intravenous: (Cerebyx(R), pediatric) Status epilepticus loading dose: Administer at rate of 2 mg PE/kg/min or 150 mg PE/min, whichever is slower
• Intravenous: (Cerebyx(R), pediatric) Nonemergent loading dose: Administer at rate of 1 to 2 mg phenytoin sodium equivalents (PE)/kg/min or 150 mg PE/min, whichever is slower
• Intravenous: (Cerebyx(R), pediatric) Maintenance dose: Administer at rate of 1 to 2 mg phenytoin sodium equivalents (PE)/kg/min or 100 mg PE/min, whichever is slower
• Intravenous: (Sesquient(TM), adult) Administer at a maximum rate of 150 mg PE/min
• Intravenous: (Sesquient(TM), pediatric) Administer at a maximum rate of 0.4 mg PE/kg/min
• Intramuscular: (Cerebyx(R)) Single daily dose utilizing either 1 or 2 injection sites has been used

• Cerebyx: Injection Solution: 50 mg PE/1 ML
• Cerebyx Novaplus: Injection Solution: 50 mg PE/1 ML

• Injection Solution: 50 mg PE/1 ML

• Important Note: Dose, concentration, and infusion rate of fosphenytoin sodium should always be expressed as phenytoin sodium equivalents (PE) and should always be prescribed and dispensed in PE units .
• Important Note: Do not confuse the vial concentration (50 mg phenytoin sodium equivalents (PE) per mL) with the total amount of drug in vial (actually contains a total of 100 mg PE [2 mL] or 500 mg PE [10 mL]) as errors, including fatal overdoses (2- or 10-fold overdoses) have been reported
• Important Note: Orphan drug designation: For the acute treatment of patients with status epilepticus of the grand mal type
• General Dosage Information: Therapeutic drug monitoring: 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) .
• General Dosage Information: Withdrawal: Gradual dosage reduction, discontinuation, and substitution of alternative antiepileptic medication is recommended over abrupt discontinuation. If an allergic or hypersensitivity reaction necessitates rapid substitution of alternative therapy, chose an antiepileptic drug not belonging to the hydantoin chemical class .
• Seizure, During neurosurgery; Treatment and Prophylaxis: (Cerebyx(R)) Nonemergent loading dose, 10 to 20 mg phenytoin sodium equivalents (PE)/kg IV or IM; maintenance, 4 to 6 mg PE/kg/day in divided doses beginning at the next identified dosing interval after loading dose, and individualize subsequent dosage with careful monitoring; MAX infusion rate, 150 mg PE/min
• Seizure, During neurosurgery; Treatment and Prophylaxis: (Sesquient(TM)) Nonemergent loading dose, 10 to 20 mg phenytoin sodium equivalents (PE)/kg IV; maintenance, 4 to 6 mg PE/kg/day in divided doses beginning at the next identified dosing interval after loading dose, and individualize subsequent dosage with careful monitoring; MAX infusion rate, 150 mg PE/min
• Seizure, For short-term administration when oral phenytoin is not possible: (Cerebyx(R)) Substitution for oral therapy, give same total daily phenytoin sodium equivalents (PE) dose IV or IM as oral phenytoin sodium; MAX rate 150 PE/min IV
• Seizure, For short-term administration when oral phenytoin is not possible: (Cerebyx(R)) Nonemergent loading dose, 10 to 20 mg phenytoin sodium equivalents (PE)/kg IV or IM; maintenance, 4 to 6 mg PE/kg/day in divided doses beginning at the next identified dosing interval after loading dose, and individualize subsequent dosage with careful monitoring; MAX infusion rate, 150 mg PE/min
• Seizure, For short-term administration when oral phenytoin is not possible: (Sesquient(TM)) Substitution for oral therapy, give same total daily phenytoin sodium equivalents (PE) dose IV as oral phenytoin sodium; MAX rate 150 PE/min IV
• Seizure, For short-term administration when oral phenytoin is not possible: (Sesquient(TM)) Nonemergent loading dose, 10 to 20 mg phenytoin sodium equivalents (PE)/kg IV; maintenance, 4 to 6 mg PE/kg/day in divided doses beginning at the next identified dosing interval after loading dose, and individualize subsequent dosage with careful monitoring; MAX infusion rate, 150 mg PE/min
• Status epilepticus: Loading dose, 15 to 20 mg phenytoin sodium equivalents (PE)/kg IV at a rate of 100 to 150 mg PE/min; MAX rate 150 mg PE/min. Concomitant IV benzodiazepine will usually be necessary; follow with maintenance doses of fosphenytoin or phenytoin (FDA dosage) .
• Status epilepticus: Loading dose, 20 mg PE/kg IV as a single dose when seizure has continued for 20 minutes after initial benzodiazepine; MAX 1500 mg PE/dose (guideline dosage)

• Important Note: Dose, concentration, and infusion rate of fosphenytoin sodium should always be expressed as phenytoin sodium equivalents (PE) and should always be prescribed and dispensed in PE units .
• Important Note: Do not confuse the vial concentration (50 mg phenytoin sodium equivalents (PE) per mL) with the total amount of drug in vial (actually contains a total of 100 mg PE [2 mL] or 500 mg PE [10 mL]) as errors, including fatal overdoses (2- or 10-fold overdoses) have been reported
• Important Note: Orphan drug designation: For the acute treatment of patients with status epilepticus of the grand mal type
• General Dosage Information: Cerebyx(R) IM administration should ordinarily not be used in pediatric patients .
• General Dosage Information: Therapeutic drug monitoring: 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) .
• General Dosage Information: Withdrawal: Gradual dosage reduction, discontinuation, and substitution of alternative antiepileptic medication is recommended over abrupt discontinuation. If an allergic or hypersensitivity reaction necessitates rapid substitution of alternative therapy, chose an antiepileptic drug not belonging to the hydantoin chemical class .
• Seizure, During neurosurgery; Treatment and Prophylaxis: (Cerebyx(R) less than 17 years) Nonemergent loading dose, 10 to 15 mg phenytoin sodium equivalents (PE)/kg IV at a rate of 1 to 2 mg PE/kg/min or 150 mg PE/min, whichever is slower. Followed by 2 to 4 mg PE/kg given 12 hours after loading dose, and then 4 to 8 mg PE/kg/day in divided doses given every 12 hours, at a rate of 1 to 2 mg PE/kg/min or 100 mg PE/min, whichever is slower. Individualize subsequent dosage with careful monitoring .
• Seizure, During neurosurgery; Treatment and Prophylaxis: (17 years or older) Nonemergent loading dose, 10 to 20 mg phenytoin sodium equivalents (PE)/kg IV; maintenance, 4 to 6 mg PE/kg/day in divided doses beginning at the next identified dosing interval after loading dose, and individualize subsequent dosage with careful monitoring; MAX infusion rate, 150 mg PE/min
• Seizure, For short-term administration when oral phenytoin is not possible: (Cerebyx(R) less than 17 years) Substitution for oral therapy, give same total daily phenytoin sodium equivalents (PE) dose IV as oral phenytoin sodium, at a rate of 2 mg PE/kg/min or 150 mg PE/min, whichever is slower .
• Seizure, For short-term administration when oral phenytoin is not possible: (Cerebyx(R) less than 17 years) Nonemergent loading dose, 10 to 15 mg phenytoin sodium equivalents (PE)/kg IV at a rate of 1 to 2 mg PE/kg/min or 150 mg PE/min, whichever is slower. Follow with an initial maintenance dose, 2 to 4 mg PE/kg given 12 hours after loading dose; and then 4 mg to 8 mg PE/kg/day in divided doses continued every 12 hours; MAX rate, 1 to 2 PE/kg/min, or 100 mg PE/min, whichever is slower
• Seizure, For short-term administration when oral phenytoin is not possible: (Sesquient(TM) 2 to less than 17 years ) Substitution for oral therapy, give same total daily phenytoin sodium equivalents (PE) dose IV as oral phenytoin sodium; MAX rate 0.4 PE/kg/min .
• Seizure, For short-term administration when oral phenytoin is not possible: (Sesquient(TM) 2 to less than 17 years) Nonemergent loading dose, 10 to 15 mg PE/kg IV; MAX rate, 0.4 mg PE/kg/min. Follow with an initial maintenance dose, 2 to 4 PE/kg 12 hours after the loading dose; and then 4 mg to 8 mg PE/kg/day in divided doses continued every 12 hours; MAX rate, 0.4 mg PE/kg/min
• Seizure, For short-term administration when oral phenytoin is not possible: (Cerebyx(R) 17 years or older) Substitution for oral therapy, give same total daily phenytoin sodium equivalents (PE) dose IV or IM as oral phenytoin sodium; MAX rate 150 PE/min IV
• Seizure, For short-term administration when oral phenytoin is not possible: (Sesquient(TM), 17 years or older) Substitution for oral therapy, give same total daily phenytoin sodium equivalents (PE) dose IV as oral phenytoin sodium; MAX rate 150 PE/min IV
• Seizure, For short-term administration when oral phenytoin is not possible: (17 years or older) Nonemergent loading dose, 10 to 20 mg phenytoin sodium equivalents (PE)/kg IV; maintenance, 4 to 6 mg PE/kg/day in divided doses beginning at the next identified dosing interval after loading dose, and individualize subsequent dosage with careful monitoring; MAX infusion rate, 150 mg PE/min
• Status epilepticus: (Cerebyx(R) less than 17 years) Loading dose, 15 to 20 mg phenytoin sodium equivalents (PE)/kg IV at a rate of 2 mg PE/kg/min or 150 mg PE/min whichever is slower. Concomitant IV benzodiazepine will usually be necessary; follow with maintenance doses of fosphenytoin or phenytoin (FDA dosage) .
• Status epilepticus: (Cerebyx(R) less than 17 years) Should generally not be given IM in pediatric patients, if IV access is impossible loading doses have been given IM (FDA dosage)
• Status epilepticus: (Older than neonate) Loading dose, 20 mg phenytoin sodium equivalents (PE)/kg IV as a single dose when seizure has continued for 20 minutes after initial benzodiazepine; MAX 1500 mg PE/dose (guideline dosage)
• Status epilepticus: (Cerebyx(R) or Sesquient(TM) 17 years or older) Loading dose, 15 to 20 mg phenytoin sodium equivalents (PE)/kg IV at a rate of 100 to 150 mg PE/min; MAX rate 150 mg PE/min. Concomitant IV benzodiazepine will usually be necessary; follow with maintenance doses of fosphenytoin or phenytoin (FDA dosage) .