Fosphenytoin Sodium — Active Pharmaceutical Ingredient

Fosphenytoin Sodium is an active pharmaceutical ingredient found in 3 FDA-approved drug products. Forms: INJECTABLE, SOLUTION. Routes: INJECTION, INTRAVENOUS.

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Fosphenytoin Sodium (3 brand names, 2 dosage forms, 2 routes)

Available dosage forms: INJECTABLE, SOLUTION.

Routes of administration: INJECTION, INTRAVENOUS.

Brand Names

  • CEREBYX
  • FOSPHENYTOIN SODIUM
  • SESQUIENT

Boxed Warning

The rate of intravenous fosphenytoin sodium injection 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 fosphenytoin sodium injection. 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 [see Dosage and Administration (2.3, 2.4) and Warnings and Precautions (5.2)].

Indications and Usage

Fosphenytoin sodium injection is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium injection can also be substituted, short-term, for oral phenytoin. Fosphenytoin sodium injection should be used only when oral phenytoin administration is not possible [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)].

Contraindications

Fosphenytoin sodium is contraindicated in patients with: •A history of hypersensitivity to fosphenytoin sodium injection or its inactive ingredients, or to phenytoin or other hydantoins [see Warnings and Precautions (5.6)]. 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 fosphenytoin sodium on ventricular automaticity. •A history of prior acute hepatotoxicity attributable to fosphenytoin sodium or phenytoin [see Warnings and Precautions (5.8)]. •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.

Adverse Reactions

The following serious adverse reactions are described elsewhere in the labeling: •Cardiovascular Risk Associated with Rapid Infusion [see Warnings and Precautions (5.2)] •Withdrawal Precipitated Seizure, Status Epilepticus [see Warnings and Precautions (5.3)] •Serious Dermatologic Reactions [see Warnings and Precautions (5.4)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [seeWarnings and Precautions (5.5)] •Hypersensitivity [see Warnings and Precautions (5.6)] •Angioedema [see Warnings and Precautions (5.7)] •Hepatic Injury [see Warnings and Precautions (5.8)] •Hematopoietic Complications [see Warnings and Precautions (5.9)] •Sensory Disturbances [seeWarnings and Precautions (5.10)] •Local Toxicity (Including Purple Glove Syndrome) [see Warnings and Precautions (5.11)] •Exacerbation of Porphyria [see Warnings and Precautions (5.14)] •Teratogenicity and Other Harm to the Newborn [see Warnings and Precautions (5.15)] •Hyperglycemia [see Warnings and Precautions (5.16)]

Drug Interactions

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 fosphenytoin sodium with other drugs that significantly bind to serum albumin. The most significant drug interactions following administration of fosphenytoin sodium 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. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected. Phenytoin or fosphenytoin sodium is a potent inducer of hepatic drug-metabolizing enzymes.

Mechanism of Action

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.

Overdosage

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin sodium.Because fosphenytoin sodium 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 fosphenytoin sodium 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 fosphenytoin sodium or phenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed, and appr

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