2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions to Avoid Dosing Errors
Use caution when administering CEREBYX because of the risk of dosing errors [see Warnings and Precautions (5.1)].
Phenytoin Sodium Equivalents (PE)
The dose, concentration, and infusion rate of CEREBYX 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. CEREBYX 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 CEREBYX 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 CEREBYX since each of the vials actually contains a total of 100 mg PE (2 mL vial) or 500 mg PE (10 mL vial). Ensure the appropriate volume of CEREBYX is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some CEREBYX medication errors from occurring.
Prior to intravenous (IV) infusion, dilute CEREBYX 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 CEREBYX in any solution should be 25 mg PE/mL. When CEREBYX is given as an IV infusion, CEREBYX 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 CEREBYX 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 CEREBYX infusions.
- Because the full antiepileptic effect of phenytoin, whether given as CEREBYX 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 CEREBYX or phenytoin [see Dosage and Administration (2.4)].
- If administration of CEREBYX does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
|Adult||15 mg PE/kg to 20 mg PE/kg||100 mg PE/min to 150 mg PE/min, do not exceed a maximum rate of 150 mg PE/min|
|Pediatric (Birth to less than 17 years of age)||15 mg PE/kg to 20 mg PE/kg||2 mg PE/kg/min, or 150 mg PE/min, whichever is slower|
Even though loading doses of CEREBYX have been given by the IM route for other indications when IV access is impossible, IM CEREBYX 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.
Intramuscular administration of CEREBYX should ordinarily not be used in pediatric patients. When IV access has been impossible, loading doses of CEREBYX 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 CEREBYX 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 CEREBYX 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||10 mg PE/kg to 20 mg PE/kg||Not to exceed a maximum rate of 150 mg PE/min|
|Pediatric (Birth to less than 17 years of age)||10 mg PE/kg to 15 mg PE/kg||1 mg PE/kg/min to 2 mg PE/kg/min, or 150 mg PE/min, whichever is slower|
|Adult||Initial Maintenance Dosage: 4 mg PE/kg/day to 6 mg PE/kg/day in divided doses||Not to exceed a maximum rate of 150 mg PE/min|
|Pediatric (Birth to less than 17 years of age)||Initial Maintenance Dosage: 2 mg PE/kg to 4 mg PE/kg (dose given 12 hours after the loading dose)||1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower|
|Maintenance Dosage after Initial Maintenance Dosage: 4 mg PE/kg/day to 8 mg PE/kg/day in divided doses (continued every 12 hours after initial maintenance dose)||1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower|
Because of the risks of cardiac and local toxicity associated with intravenous CEREBYX, oral phenytoin should be used whenever possible. Intramuscular administration of CEREBYX should ordinarily not be used in pediatric patients.
2.5 Laboratory Tests and Monitoring Levels
CEREBYX (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 CEREBYX 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® 2000 (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 CEREBYX 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.
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, CEREBYX can be substituted for oral phenytoin at the same total daily phenytoin sodium equivalents (PE) dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin, derived from administration of CEREBYX, is 100% bioavailable by both the IM and IV routes. For this reason, serum phenytoin concentrations may increase modestly when IM or IV CEREBYX is substituted for oral phenytoin sodium therapy. The rate of administration for IV CEREBYX 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 CEREBYX was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing. Intramuscular administration of CEREBYX 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 CEREBYX) 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 CEREBYX 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 CEREBYX) 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 CEREBYX) 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 CEREBYX 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.