Sesquient Injection Dosage

Important Administration Instructions to Avoid Dosing Errors

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

Phenytoin Sodium Equivalents (PE)

The dose, concentration, and infusion rate of SESQUIENT 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. SESQUIENT 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 SESQUIENT 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 tenfold overdoses of SESQUIENT since each of the vials actually contains a total of 100 mg PE (2 mL ) or 500 mg PE (10 mL). Ensure the appropriate volume of SESQUIENT is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some SESQUIENT medication errors from occurring.

Preparation

Prior to intravenous infusion, dilute SESQUIENT in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 mg PE/mL to 25 mg PE/mL. The maximum concentration of SESQUIENT in any solution should be 25 mg PE/mL. When SESQUIENT is given as an intravenous infusion, SESQUIENT needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min in adults or 0.4 mg PE/kg/min in pediatric patients 2 years to less than 17 years of age.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Drug product with particulate matter or discoloration should not be used.

The diluted SESQUIENT solution is stable for 4 hours at room temperature.

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

Status Epilepticus in Adults

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Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for SESQUIENT should be no greater than 150 mg PE/min in adults [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 SESQUIENT infusions.

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Because the full antiepileptic effect of phenytoin, whether given as SESQUIENT or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an intravenous benzodiazepine, will usually be necessary for the control of status epilepticus.

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The loading dose should be followed by maintenance doses of either SESQUIENT or phenytoin [see Dosage and Administration (2.4)].

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If administration of SESQUIENT does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

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See Table 1 for status epilepticus dosing in adult patients.

Table 1. Status Epilepticus Loading Dosages in Adult Patients

Non-emergent Loading and Maintenance Dosing in Adult and Pediatric Patients

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Rate of Administration

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Adult Patients (17 years of age and older): Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for SESQUIENT should not exceed 150 mg PE/min in adults.

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Pediatric Patients (2 years to less than 17 years of age): Because of the betadex sulfobutyl ether sodium ingredient in SESQUIENT, the rate of administration for SESQUIENT should not exceed 0.4 mg PE/kg/min in pediatric patients. The rate of administration of intravenous SESQUIENT in pediatric patients differs from that of other intravenous fosphenytoin products.

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Monitoring: 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 SESQUIENT infusions).

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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 (5.17)].

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See Table 2 and Table 3 for adult and pediatric non-emergent loading and maintenance dosing, respectively.

Table 2. Non-emergent Loading Dosages

Table 3. Maintenance Dosages

Laboratory Tests and Monitoring Levels

Laboratory Tests

SESQUIENT (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 SESQUIENT 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 intravenous infusion. 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 SESQUIENT 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)].

Parenteral Substitution for Oral Phenytoin Therapy

Because of the risks of cardiac and local toxicity associated with intravenous SESQUIENT, oral phenytoin should be used whenever possible. When treatment with oral phenytoin is not possible, SESQUIENT 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 SESQUIENT, is 100% bioavailable by the intravenous route. For this reason, serum phenytoin concentrations may increase modestly when SESQUIENT is substituted for oral phenytoin sodium therapy. The rate of administration for SESQUIENT should be no greater than 150 mg PE/min in adults and 0.4 mg PE/kg/min in pediatric patients.

Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia

Because the fraction of unbound phenytoin (the active metabolite of SESQUIENT) 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 intravenous SESQUIENT 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)].

Closely monitor serum creatinine levels and estimated glomerular filtration rate (eGFR) in patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) receiving intravenous SESQUIENT. If serum creatinine level increases occur, consider changing to oral phenytoin [see Use in Specific Populations (8.6)].

Dosing in Geriatrics

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

Dosing during Pregnancy

Decreased serum concentrations of phenytoin (the active metabolite of SESQUIENT) 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 SESQUIENT 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.