Fosphenytoin (Cerebryx)

A prodrug intended for parenteral administration, with its active metabolite being phenytoin.

Each fosphenytoin Sodium Injection, vial contains 75 mg/mL fosphenytoin sodium and is equivalent to 50 mg/mL phenytoin sodium after admininstration, and therefore the amount and concentration of fosphenytoin is expressed in terms of phenytoin sodium equivalents (PE).

Following parenteral administration it is converted to the anticonvulsant phenytoin, and for every mmol of fosphenytoin administered, one mmol of phenytoin is produced. Trade name Cerebyx

Routes are administration intravenous, and intramuscular.

Bioavailability is 100% by parenteral administration.

Protein binding at 95 to 99%.

Metabolism is hepatic, with renal excretion.

Half-life is 15 minutes as it is converted to phenytoin.

A water-soluble phenytoin prodrug that is administered intravenously to deliver phenytoin more safely than intravenous phenytoin.

Most commonly used in the acute treatment convulsive status epilepticus.

Approved for the short term treatment of epilepsy, of 5 days or fewer.

Used when means of phenytoin administration are not possible or are ill-advised, such as endotracheal intubation, status epilepticus or some other type of repeated seizures; vomiting, and/or the patient is unalert or not awake or both.

Maybe effective in mania, refractory pain to opiates,

One millimole of phenytoin is produced for every millimole of fosphenytoin administered.

Fosphenytoin hydrolysis yields phosphate and formaldehyde.

Side effects include: hypotension, cardiac arrhythmias, CNS adverse events such as nystagmus, dizziness, sedation, ataxia and stupor, and local dermatological reactions.

Purple glove syndrome occurs with fosphenytoin but possibly at lower frequency than with intravenous phenytoin.

Can cause hyperphosphatemia in end-stage renal failure patients.

The pharmacological and toxicological effects are those of phenytoin, and its anticonvulsant effects are attributable to phenytoin.

Cellular mechanisms of phenytoin for anticonvulsant effect 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 enhancement of the sodium-potassium ATPase activity of neurons and glial cells.

When administered by IV infusion, maximum plasma concentrations are achieved at the end of the infusion. and it has a half-life of approximately 15 minutes.

Peak concentrations of the drug occur at 30 minutes after intramuscular injection.

Extensively bound (95% to 99%) to human plasma proteins, primarily albumin.

Conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes.

Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin.

Intramuscular administration manifests systemic phenytoin concentrations that are similar enough to oral phenytoin sodium to allow essentially interchangeable use.

15 to 20 mg PE/kg of fosphenytoin infused at 100 to 150 mg PE/min yields plasma free phenytoin concentrations over time that approximate those achieved when an equivalent dose of phenytoin sodium administered at 50 mg/min.

Completely converted to phenytoin following IV administration, with a half-life of approximately 15 minutes.

Completely converted to phenytoin following IM administration and plasma total phenytoin concentrations peak in approximately 3 hours.

Highly bound to plasma proteins, primarily albumin, although to a greater extent than phenytoin.

Patient age had no significant impact on pharmacokinetics.

Equimolar doses of IM Fosphenytoin may be substituted for oral phenytoin sodium with no dosage adjustments needed when initiating IM or returning to oral therapy.

Indicated for short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate or deemed less advantageous.

The safety and effectiveness has not been systematically evaluated for more than 5 days.

Can be used for the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery and can also be substituted, short-term, for oral phenytoin.

Contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity.

Should not be adminstered at a rate greater than 150 mg PE/min.

The dose of IV Fosphenytoin is 15 to 20 mg PE/kg for status epilepticus is administered at a maximum rate of 150 mg PE/min, and should take between 5 and 7 minutes.

Parenteral phenytoin sodium injection cannot be accomplished in less than 15 to 20 minutes in status epilepticus because of the cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min.

Hypotension may occur after IV administration at high doses and high rates of administration so that cardiac monitoring is needed when administering IV loading doses.

Should be used with caution in patients with hypotension and severe myocardial insufficiency.

Burning, itching, and/or paresthesia are associated with the maximum rate of administration (150 mg PE/min), with the groin the most frequent site of discomfort, and the occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion.

No permanent sequelae have been reported for these positive sensory phenomena.

The phosphate load provided by Fosphenytoin should be considered when treating patients who require phosphate restriction, such as those with severe renal insufficiency.

Not indicated for the treatment of absence seizures.

Following Fosphenytoin Injection it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete and this occurs within approximately 2 hours after the end of IV infusion and 4 hours after IM injection.

No drugs are known to interfere with the conversion to phenytoin.

Safety in pediatric patients has not been established.

The more important adverse clinical events caused by the IV use are cardiovascular collapse and/or central nervous system depression.

Rate of administration should not exceed 150 mg PE/min.

Most common adverse effects include: nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia.

Most alert patients administered doses of ≥15 mg PE/kg at 150 mg/hr experience itching, burning, or tingling.

Approximately 2% of patients discontinue treatment because of an adverse event, such as pruritus, hypotension, and bradycardia.

No known antidote for overdosage, so appropriate supportive measures employed for respiratory and cardiovascular systems in the presence of an overdose.

Hemodialysis can be considered in accidental overdosage and exchange transfusion has been used in the treatment of severe intoxication in children. I

Formate and phosphate are metabolites and may contribute to signs of toxicity following overdosage.

Signs of formate toxicity are similar to those of methanol toxicity with anion-gap metabolic acidosis.

Phosphate, delivered rapidly, could cause hypocalcemia with paresthesia, muscle spasms, and seizures.

The drug should be diluted in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL.

The loading dose of Fosphenytoin Sodium Injection, USP is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.

Monitoring of the EKG, 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 Fosphenytoin Sodium Injection.

The initial daily maintenance dose is 4 – 6 mg PE/kg/day.

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