Fosphenytoin: Package Insert and Label Information

FOSPHENYTOIN — fosphenytoin sodium injection, solution
Fresenius Kabi USA, LLC

WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES

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. 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)] .

1 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions to Avoid Dosing Errors

Use caution when administering fosphenytoin sodium injection because of the risk of dosing errors [see Warnings and Precautions (5.1)].

Phenytoin Sodium Equivalents (PE)

The dose, concentration, and infusion rate of fosphenytoin sodium injection 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. Fosphenytoin sodium injection 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).

Concentration of 50 mg PE/mL

Do not confuse the concentration of fosphenytoin sodium injection with the total amount of drug in the vial.

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 ten fold overdoses of fosphenytoin sodium injection since each of the vials actually contains a total of 100 mg PE (5 mL vial) or 500 mg PE (10 mL vial). Ensure the appropriate volume of fosphenytoin sodium is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some fosphenytoin sodium injection medication errors from occurring.

2.2 Preparation

Prior to intravenous (IV) infusion, dilute fosphenytoin sodium injection in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL. The maximum concentration of fosphenytoin sodium in any solution should be 25 mg PE/mL. When fosphenytoin sodium injection is given as an intravenous infusion, fosphenytoin sodium needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

For single-dose only. After opening, any unused product should be discarded.

2.3 Status Epilepticus

  • Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection 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 [see Warnings and Precautions (5.2)]. 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 fosphenytoin sodium infusions.
  • Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin sodium injection 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 fosphenytoin sodium injection or phenytoin [see Dosage and Administration (2.4)].
  • If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

Adult Dosing:

The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.

Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin sodium injection should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.

Pediatric Dosing From Birth to < 17 Years of Age:

The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg at a rate of 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower).

Intramuscular administration of fosphenytoin sodium injection should ordinarily not be used in pediatric patients. When IV access has been impossible, loading doses of fosphenytoin sodium injection have been given by the IM route.

2.4 Non-emergent Loading and Maintenance Dosing

  • Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults. For loading doses in pediatric patients, the rate should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower). For maintenance doses in pediatric patients, the rate should not exceed 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower). 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 fosphenytoin sodium infusions).
  • After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin [see Dosage and Administration (2.5) and Warnings and Precautions (5.18)].

Adult Dosing:

Because of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.

Loading Dose

The non-emergent loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM.

Maintenance Dose

Following either the loading dose for Status Epilepticus or a Non-emergent situation, the initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses at a rate no greater than 150 mg PE/min. After administration of a loading dose, maintenance doses should be started at the next identified dosing interval.

Pediatric Dosing From Birth to < 17 Years of Age:

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

Loading Dose

The non-emergent loading dose of fosphenytoin sodium injection 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).

Maintenance Dose

Following either the loading dose for Status Epilepticus or a Non-Emergent situation, the initial maintenance dose of fosphenytoin sodium injection is 2 to 4 mg PE/kg which should be given 12 hours after the loading dose and then continued every 12 hours (4 to 8 mg PE/kg/day in divided doses) at a rate of 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower).

2.5 Laboratory Tests and Monitoring Levels

Laboratory Tests:

Fosphenytoin sodium injection (or phenytoin) 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). Following fosphenytoin sodium injection administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after intramuscular (IM) injection. Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx® /TDxFLx™ (fluorescence polarization) and Emit® 2,000 (enzyme multiplied), may significantly overestimate serum phenytoin concentrations because of cross-reactivity with fosphenytoin. The error is dependent on serum phenytoin and fosphenytoin concentration (influenced by fosphenytoin sodium injection dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved.

Monitoring Levels:

Trough levels provide information about clinically effective serum level range and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. Therapeutic effect without clinical signs of toxicity occurs more often with serum total phenytoin concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.7)].

2.6 Parenteral Substitution for Oral Phenytoin Therapy

When treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily phenytoin sodium equivalents (PE) dose. Phenytoin sodium capsules are approximately 90% bioavailable by the oral route. Phenytoin, derived from administration of fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes. For this reason, serum phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection 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. In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing. Intramuscular administration of fosphenytoin sodium injection should ordinarily not be used in pediatric patients.

2.7 Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia

Because the fraction of unbound phenytoin (the active metabolite of fosphenytoin sodium injection) is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients. After IV fosphenytoin sodium administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events [see Warnings and Precautions (5.13)].

2.8 Dosing in Geriatrics

The clearance of phenytoin (the active metabolite of fosphenytoin sodium injection) is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)].

2.9 Dosing during Pregnancy

Decreased serum concentrations of phenytoin (the active metabolite of fosphenytoin sodium injection) may occur during pregnancy because of altered phenytoin pharmacokinetics [see Clinical Pharmacology (12.3)]. Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the fosphenytoin sodium injection dosage should be adjusted as necessary. Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)]. Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

3 DOSAGE FORMS AND STRENGTHS

Fosphenytoin Sodium Injection, USP is a clear, colorless to pale yellow solution available as 50 mg phenytoin sodium equivalents (PE) per mL in:

  • 10 mL single-dose injection vials, each containing 500 mg phenytoin sodium equivalents in 10 mL vials.
  • 2 mL single-dose injection vials, each containing 100 mg phenytoin sodium equivalents in 5 mL vials.

4 CONTRAINDICATIONS

Fosphenytoin sodium injection 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 injection on ventricular automaticity.
  • A history of prior acute hepatotoxicity attributable to fosphenytoin sodium injection 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.

5 WARNINGS AND PRECAUTIONS

5.1 Dosing Errors

Phenytoin Sodium Equivalents (PE)

Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial.

Doses of fosphenytoin sodium injection are always expressed in terms of milligrams of phenytoin sodium equivalents (mg PE). 1 mg PE is equivalent to 1 mg phenytoin sodium.

Do not, therefore, make any adjustment in the recommended doses when substituting fosphenytoin sodium injection for phenytoin sodium or vice versa. For example, if a patient is receiving 1,000 mg PE of fosphenytoin sodium that is equivalent to 1,000 mg of phenytoin sodium.

Concentration of 50 mg PE/mL

Medication errors associated with fosphenytoin sodium injection have resulted in patients receiving the wrong dose of fosphenytoin sodium. Fosphenytoin sodium injection is marketed in 5 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Errors 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 ten-fold overdoses of fosphenytoin sodium since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of fosphenytoin sodium injection should always be expressed in milligrams of phenytoin equivalents (mg PE) [see Dosage and Administration (2.1)]. Additionally, when ordering and storing fosphenytoin sodium injection, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg PE/ 10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of fosphenytoin sodium is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some fosphenytoin sodium medication errors from occurring.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.