Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom Pro-Epanutin is distributed in the UK by Blackstaff Pharmaceuticals Limited.
Pro-Epanutin is indicated in adults and children aged 5 years and older:
IMPORTANT NOTE: Throughout all Pro-Epanutin product labelling, the amount and concentration of fosphenytoin is always expressed in terms of phenytoin sodium equivalents (PE) to avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Pro-Epanutin should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). Note, however, that fosphenytoin has important differences in administration from parenteral phenytoin sodium (see section 4.4).
Phenytoin sodium equivalents (PE):
1.5 mg of fosphenytoin is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE) (see section 4.4).
Each 10 mL vial of Pro-Epanutin contains 500 mg PE.
Each 2 mL vial of Pro-Epanutin contains 100 mg PE.
Pro-Epanutin may be administered by intravenous (IV) infusion or by intramuscular (IM) injection. The IM route should be considered for adult patients when there is not an urgent need to control seizures. If rapid phenytoin loading is a primary goal, IV administration of Pro-Epanutin is preferred because the time to achieve therapeutic plasma phenytoin concentrations following IV administration is faster as compared to IM administration.
Pro-Epanutin should not be administered by IM route in emergency situations such as status epilepticus.
Intramuscular (IM) injection is not recommended for children.
Products with particulate matter or discoloration should not be used.
Pro-Epanutin is intended for short-term parenteral administration, and has not been evaluated for periods of more than 5 days.
For IV infusion, Pro-Epanutin should be diluted in 5% glucose or 0.9% sodium chloride solution. The concentration should range from 1.5 to 25 mg PE/mL.
Because of the risk of hypotension, the recommended rate of administration by IV infusion in routine clinical settings is 50-100 mg PE/minute. Even in an emergency, it should not exceed 150 mg PE/minute. The use of a device controlling the rate of infusion is recommended.
Please refer to tables 1 to 10 for examples of dosing, dilution and infusion time calculations.
Continuous monitoring of electrocardiogram, blood pressure and respiratory function for the duration of the infusion is essential. The patient should also be observed throughout the period where maximal plasma phenytoin concentrations occur. This is approximately 30 minutes after the end of the Pro-Epanutin infusions.
Cardiac resuscitative equipment should be available (see section 4.4).
Please refer to Tables 1-10 for examples of dosing, dilution, and infusion time calculations
| Population | Indication | Dosing Table | |
|---|---|---|---|
| Adults | Status epilepticus | Loading dose | Table 1 |
| Status epilepticus | Maintenance dose | Table 2 | |
| Seizure treatment or prophylaxis | Loading dose | Table 3 | |
| Seizure treatment or prophylaxis | Maintenance dose | Table 4 | |
| Temporary substitution for oral phenytoin | Table 5 | ||
| Children (aged 5 years and older) | Status epilepticus | Loading dose | Table 6 |
| Status epilepticus | Maintenance dose | Table 7 | |
| Seizure treatment or prophylaxis | Loading dose | Table 8 | |
| Seizure treatment or prophylaxis | Maintenance dose | Table 9 | |
| Temporary substitution for oral phenytoin | Table 10 | ||
(For Dose reduction in the Elderly or patients with Renal or Hepatic impairment, please see guidance towards the end of this section.)
Intramuscular (IM) administration of Pro-Epanutin is not recommended in the treatment of status epilepticus.
Loading dose: In order to obtain rapid seizure control in patients with continuous seizure activity, IV diazepam or lorazepam should be administered prior to administration of Pro-Epanutin.
The loading dose of Pro-Epanutin is 15 mg PE/kg administered as a single dose by IV infusion.
Recommended IV infusion rate (for loading dose in adults): 100 to 150 mg PE/min (should not exceed 150 mg PE/minute even for emergency use). See Table 1 for infusion times.
If administration of Pro-Epanutin does not terminate seizures, the use of alternative anticonvulsants should be considered.
Table 1 displays dosing information for status epilepticus loading dose in adults.
TABLE 1. STATUS EPILEPTICUS LOADING DOSE (ADULTS) :
| Examples of IV loading doses of 15 mg PE†/kg, and recommendations for dilution (to 25 mg PE/mL) and IV infusion times (at maximum rate of 150 mg PE/min) by body weight | |||||
|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent (5% glucose or 0.9% sodium chloride) for final concentration of 25 mg PE/mL | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 150 mg PE/minute | |
| No. of 10 mL vials to open | Volume (mL) to draw up | ||||
| 100 | 1,500 | 3 | 30 | 30 | 10 |
| 95 | 1,425 | 3 | 28.5 | 28.5 | 9.5 |
| 90 | 1,350 | 3 | 27 | 27 | 9 |
| 85 | 1,275 | 3 | 25.5 | 25.5 | 8.5 |
| 80 | 1,200 | 3 | 24 | 24 | 8 |
| 75 | 1,125 | 3 | 22.5 | 22.5 | 7.5 |
| 70 | 1,050 | 3 | 21 | 21 | 7 |
| 65 | 975 | 2 | 19.5 | 19.5 | 6.5 |
| 60 | 900 | 2 | 18 | 18 | 6 |
| 55 | 825 | 2 | 16.5 | 16.5 | 5.5 |
| 50 | 750 | 2 | 15 | 15 | 5 |
| 45 | 675 | 2 | 13.5 | 13.5 | 4.5 |
† PE – Phenytoin sodium equivalents
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
Maintenance dose: The recommended initial maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given as a single dose or in two divided doses, by IV infusion or by IM injection. The initial cumulative daily dose should not exceed 4 to 5 mg PE/kg/day. After administration of a loading dose, maintenance doses should typically be started at the next identified dosing interval. For example, if the intended dose frequency is every 12 hours then the first maintenance dose of Pro-Epanutin should be administered 12 hours after the loading dose.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).
Recommended IV infusion rate (for maintenance dose in adults): 50 to 100 mg PE/minute (should not exceed 100 mg PE/minute). See Table 2 for infusion times.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Table 2 displays dosing information for status epilepticus maintenance dose in adults.
TABLE 2. STATUS EPILEPTICUS MAINTENANCE DOSE (ADULTS):
| Examples for maximum IV maintenance doses of 5 mg PE†/kg, recommendations for dilution* (to 25 mg PE/mL or to 1.5 mg PE/mL), and IV infusion times (at maximum rate of 100 mg PE/minute) by body weight | ||||||
|---|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent* (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 100 mg PE/minute | ||
| No. of 10 mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 100 | 500 | 1 | 10 | 10 | 323 | 5 |
| 90 | 450 | 1 | 9 | 9 | 291 | 4.5 |
| 80 | 400 | 1 | 8 | 8 | 259 | 4 |
| 70 | 350 | 1 | 7 | 7 | 226 | 3.5 |
| 60 | 300 | 1 | 6 | 6 | 194 | 3 |
| 50 | 250 | 1 | 5 | 5 | 162 | 2.5 |
* For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
† PE – Phenytoin sodium equivalents
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
Loading dose: The loading dose of Pro-Epanutin is 10 to 15 mg PE/kg given as a single dose by IV infusion or by IM injection.
Recommended IV infusion rate (for loading dose in adults): 50 to 100 mg PE/minute (should not exceed 100 mg PE/minute). See Table 3 for infusion times.
Table 3 displays dosing information for seizure treatment or prophylaxis loading dose in adults.
TABLE 3. TREATMENT OR PROPHYLAXIS OF SEIZURES LOADING DOSE (ADULTS):
| Examples for IV loading doses of 10 mg PE†/kg, and recommendations for dilutiona (to 25 mg PE/mL or to 1.5 mg PE/mL) and IV infusion times (at maximum rate of 100 mg PE/minute) by body weight | ||||||
|---|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluenta (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 100 mg PE/minute | ||
| No. of 10mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 100 | 1,000 | 2 | 20 | 20 | 647 | 10 |
| 90 | 900 | 2 | 18 | 18 | 582 | 9 |
| 80 | 800 | 2 | 16 | 16 | 517 | 8 |
| 70 | 700 | 2 | 14 | 14 | 453 | 7 |
| 60 | 600 | 2 | 12 | 12 | 388 | 6 |
| 50 | 500 | 1 | 10 | 10 | 323 | 5 |
† PE – Phenytoin sodium equivalents
a For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
Maintenance dose: The recommended initial maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given as a single dose or in two divided doses, by IV infusion or by IM injection. The initial cumulative daily dose should not exceed 4 to 5 mg PE/kg/day. After administration of a loading dose, maintenance doses should typically be started at the next identified dosing interval. For example, if the intended dose frequency is every 12 hours then the first maintenance dose of Pro-Epanutin should be administered 12 hours after the loading dose.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).
Recommended IV infusion rate (for maintenance dose in adults): 50 to 100 mg PE/minute (should not exceed 100 mg PE/minute). See Table 4 for infusion times.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Table 4 displays dosing information for seizure treatment or prophylaxis maintenance dose in adults.
TABLE 4. TREATMENT OR PROPHYLAXIS OF SEIZURES MAINTENANCE DOSE (ADULTS):
| Examples for maximum IV maintenance doses of 5 mg PE†/kg, recommendations for dilution* (to 25 mg PE/mL or to 1.5 mg PE/mL), and IV infusion times (at maximum infusion rate of 100 mg PE/minute) by body weight | ||||||
|---|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent* (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 100 mg PE/minute | ||
| No. of 10 mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 100 | 500 | 1 | 10 | 10 | 323 | 5 |
| 90 | 450 | 1 | 9 | 9 | 291 | 4.5 |
| 80 | 400 | 1 | 8 | 8 | 259 | 4 |
| 70 | 350 | 1 | 7 | 7 | 226 | 3.5 |
| 60 | 300 | 1 | 6 | 6 | 194 | 3 |
| 50 | 250 | 1 | 5 | 5 | 162 | 2.5 |
* For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
† PE – Phenytoin sodium equivalents
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
The same total daily phenytoin sodium equivalents (PE) dose and dosing frequency as for oral phenytoin sodium therapy should be used and can be administered by IV infusion or by IM injection.
Therapeutic drug monitoring may be useful whenever switching between products and/or routes of administration. Doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).
Recommended IV infusion rate (for temporary substitution dose in adults): 50 to 100 mg PE/minute (should not exceed 100 mg PE/minute). See Table 5 for infusion times.
Table 5 displays dosing information for the temporary substitution of oral phenytoin sodium in adults.
TABLE 5. TEMPORARY SUBSTITUTION FOR ORAL PHENYTOIN SODIUM THERAPY (ADULTS):
| Examples of equivalent doses and recommendations for dilution* (to 25 mg PE†/mL or to 1.5 mg PE/mL), and IV infusion times (at maximum rate of 100 mg PE/minute) | ||||||
|---|---|---|---|---|---|---|
| Dose (mg phenytoin sodium) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent* (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 100 mg PE/minute | ||
| No. of 10 mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 500 | 500 | 1 | 10 | 10 | 323 | 5 |
| 450 | 450 | 1 | 9 | 9 | 291 | 4.5 |
| 400 | 400 | 1 | 8 | 8 | 259 | 4 |
| 350 | 350 | 1 | 7 | 7 | 226 | 3.5 |
| 300 | 300 | 1 | 6 | 6 | 194 | 3 |
| 250 | 250 | 1 | 5 | 5 | 162 | 2.5 |
* For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
† PE – Phenytoin sodium equivalents
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
The safety and efficacy of Pro-Epanutin in children under 5 years has not been established.
Pro-Epanutin may be administered to children (ages 5 years and older) by IV infusion only, at the same mg PE/kg dose used for adults. The doses of Pro-Epanutin for children have been predicted from the known pharmacokinetics of Pro-Epanutin in adults and children aged 5 to 10 years and of parenteral phenytoin in adults and children.
Intramuscular (IM) administration in children is not recommended.
For Dose reduction in patients with Renal or Hepatic impairment, please see guidance towards the end of this section.
Loading dose: In order to obtain rapid seizure control in patients with continuous seizure activity IV diazepam or lorazepam should be administered prior to administration of Pro-Epanutin.
The loading dose of Pro-Epanutin is 15 mg PE/kg administered as a single dose by IV infusion.
Recommended IV infusion rate (for loading dose in children): 2 to 3 mg PE/kg/min (should not exceed 3 mg PE/kg/minute or 150 mg PE/minute, whichever is slower). See Table 6 for infusion times.
If administration of Pro-Epanutin does not terminate seizures, the use of alternative anticonvulsants should be considered.
Table 6 displays dosing information for status epilepticus loading dose in children.
TABLE 6. STATUS EPILEPTICUS LOADING DOSE (CHILDREN AGED 5 YEARS AND OLDER):
| Examples of IV loading doses of 15 mg PE†/kg and recommendations for dilution (to 25 mg PE/mL) and IV infusion times (at maximum rate of 3 mg PE/kg/minute) by body weight | |||||
|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent (5% glucose or 0.9% sodium chloride) for final concentration of 25 mg PE/mL | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 3 mg PE/kg/minute | |
| No. of 10 mL vials to open | Volume (mL) to draw up | ||||
| 47.5 | 712.5 | 2 | 14.25 | 14.25 | 5 |
| 45 | 675 | 2 | 13.5 | 13.5 | 5 |
| 42.5 | 637.5 | 2 | 12.75 | 12.75 | 5 |
| 40 | 600 | 2 | 12 | 12 | 5 |
| 37.5 | 562.5 | 2 | 11.25 | 11.25 | 5 |
| 35 | 525 | 2 | 10.5 | 10.5 | 5 |
| 32.5 | 487.5 | 1 | 9.75 | 9.75 | 5 |
| 30 | 450 | 1 | 9 | 9 | 5 |
| 27.5 | 412.5 | 1 | 8.25 | 8.25 | 5 |
| 25 | 375 | 1 | 7.5 | 7.5 | 5 |
| 22.5 | 337.5 | 1 | 6.75 | 6.75 | 5 |
| 20 | 300 | 1 | 6 | 6 | 5 |
| 17.5 | 262.5 | 1 | 5.25 | 5.25 | 5 |
† PE – Phenytoin sodium equivalents
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
Maintenance dose: The recommended initial maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given as a single dose or in up to four divided doses, by IV infusion. The initial cumulative daily dose should not exceed 4 to 5 mg PE/kg/day. After administration of a loading dose, maintenance doses should typically be started at the next identified dosing interval. For example, if the intended dose frequency is every 12 hours then the first maintenance dose of Pro-Epanutin should be administered 12 hours after the loading dose.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).
Recommended IV infusion rate (for maintenance dose in children): 1 to 2 mg PE/kg/minute (should not exceed 2 mg PE/kg/minute or 100 mg PE/minute whichever is slower). See Table 7 for infusion times.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Table 7 displays dosing information for status epilepticus maintenance dose in children.
TABLE 7. STATUS EPILEPTICUS MAINTENANCE DOSE (CHILDREN AGED 5 YEARS AND OLDER):
| Examples for maximum IV maintenance doses of 5 mg PE†/kg, recommendations for dilution* (to 25 mg PE/mL or to 1.5 mg PE/mL) and IV infusion times (at maximum rate of 2 mg PE/kg/minute) by body weight | ||||||
|---|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 2 mg PE/kg/minute | ||
| No. of 10 mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 47.5 | 237.5 | 1 | 4.75 | 4.75 | 154 | 2.5 |
| 45 | 225 | 1 | 4.5 | 4.5 | 146 | 2.5 |
| 42.5 | 212.5 | 1 | 4.25 | 4.25 | 137 | 2.5 |
| 40 | 200 | 1 | 4 | 4 | 129 | 2.5 |
| 37.5 | 187.5 | 1 | 3.75 | 3.75 | 121 | 2.5 |
| 35 | 175 | 1 | 3.5 | 3.5 | 113 | 2.5 |
| 32.5 | 162.5 | 1 | 3.25 | 3.25 | 105 | 2.5 |
| 30 | 150 | 1 | 3 | 3 | 97 | 2.5 |
| 27.5 | 137.5 | 1 | 2.75 | 2.75 | 89 | 2.5 |
| 25 | 125 | 1 | 2.5 | 2.5 | 81 | 2.5 |
| 22.5 | 112.5 | 1 | 2.25 | 2.25 | 73 | 2.5 |
| 20 | 100 | 1 | 2 | 2 | 65 | 2.5 |
| 17.5 | 87.5 | 1 | 1.75 | 1.75 | 57 | 2.5 |
* For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
† PE – Phenytoin sodium equivalents
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
Loading dose: The loading dose of Pro-Epanutin is 10 to 15 mg PE/kg given as a single dose by IV infusion.
Recommended IV infusion rate (for loading dose in children): 1 to 2 mg PE/kg/minute (should not exceed 2 mg PE/kg/minute or 100 mg PE/minute, whichever is slower). See Table 8 for infusion times.
Table 8 displays dosing information for seizure treatment or prophylaxis loading dose in children.
TABLE 8. TREATMENT OR PROPHYLAXIS OF SEIZURES LOADING DOSE (CHILDREN AGED 5 YEARS AND OLDER):
| Examples for IV loading doses of 10 mg PE†/kg, and recommendations for dilutiona (to 25 mg PE/mL or to 1.5 mg PE/mL) and IV infusion times (at maximum rate of 2 mg PE/kg/minute) by body weight | ||||||
|---|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluenta (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 2 mg PE /kg/ minute | ||
| No. of 10 mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 47.5 | 475 | 1 | 9.5 | 9.5 | 307 | 5 |
| 45 | 450 | 1 | 9 | 9 | 291 | 5 |
| 42.5 | 425 | 1 | 8.5 | 8.5 | 275 | 5 |
| 40 | 400 | 1 | 8 | 8 | 259 | 5 |
| 37.5 | 375 | 1 | 7.5 | 7.5 | 243 | 5 |
| 35 | 350 | 1 | 7 | 7 | 226 | 5 |
| 32.5 | 325 | 1 | 6.5 | 6.5 | 210 | 5 |
| 30 | 300 | 1 | 6 | 6 | 194 | 5 |
| 27.5 | 275 | 1 | 5.5 | 5.5 | 178 | 5 |
| 25 | 250 | 1 | 5 | 5 | 161 | 5 |
| 22.5 | 225 | 1 | 4.5 | 4.5 | 145 | 5 |
| 20 | 200 | 1 | 4 | 4 | 129 | 5 |
| 17.5 | 175 | 1 | 3.5 | 3.5 | 113 | 5 |
† PE – Phenytoin sodium equivalents
a For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
Maintenance dose: The recommended initial maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given as a single dose or in up to four divided doses, by IV infusion. The initial cumulative daily dose should not exceed 4 to 5 mg PE/kg/day. After administration of a loading dose, maintenance doses should typically be started at the next identified dosing interval. For example, if the intended dose frequency is every 12 hours then the first maintenance dose of Pro-Epanutin should be administered 12 hours after the loading dose.
Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).
Recommended IV infusion rate (for maintenance dose in children): 1 to 2 mg PE/kg/minute (should not exceed 2 mg PE/kg/minute or 100 mg PE/minute, whichever is slower). See Table 9 for infusion times.
Transfer to maintenance therapy with oral phenytoin should be made when appropriate.
Table 9 displays dosing information for seizure treatment or prophylaxis maintenance dose in children.
TABLE 9. TREATMENT OR PROPHYLAXIS OF SEIZURES MAINTENANCE DOSE (CHILDREN AGED 5 YEARS AND OLDER):
| Examples for maximum IV maintenance doses of 5 mg PE†/kg, recommendations for dilution* (to 25 mg PE/mL or to 1.5 mg PE/kg), and IV infusion times (at a maximum rate of 2 mg PE/kg/minute) by body weight | ||||||
|---|---|---|---|---|---|---|
| Weight (Kg) | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 2 mg PE/kg/minute | ||
| No. of 10 mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 47.5 | 237.5 | 1 | 4.75 | 4.75 | 154 | 2.5 |
| 45 | 225 | 1 | 4.50 | 4.50 | 146 | 2.5 |
| 42.5 | 212.5 | 1 | 4.25 | 4.25 | 137 | 2.5 |
| 40 | 200 | 1 | 4 | 4 | 129 | 2.5 |
| 37.5 | 187.5 | 1 | 3.75 | 3.75 | 121 | 2.5 |
| 35 | 175 | 1 | 3.5 | 3.5 | 113 | 2.5 |
| 32.5 | 162.5 | 1 | 3.25 | 3.25 | 105 | 2.5 |
| 30 | 150 | 1 | 3 | 3 | 97 | 2.5 |
| 27.5 | 137.5 | 1 | 2.75 | 2.75 | 89 | 2.5 |
| 25 | 125 | 1 | 2.5 | 2.5 | 81 | 2.5 |
| 22.5 | 112.5 | 1 | 2.25 | 2.25 | 73 | 2.5 |
| 20 | 100 | 1 | 2 | 2 | 65 | 2.5 |
| 17.5 | 87.5 | 1 | 1.75 | 1.75 | 57 | 2.5 |
* For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
† PE – Phenytoin sodium equivalents
Note: Appropriate dose, dosing volume, number of vials of Pro-Epanutin, volume of diluent, and minimum infusion time should always be calculated for the patient’s exact body weight when not included in the examples.
The same total daily phenytoin sodium equivalents (PE) dose and dosing frequency as for oral phenytoin sodium therapy should be administered by IV infusion.
Therapeutic drug monitoring may be useful whenever switching between products and/or routes of administration Doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).
Recommended IV infusion rate (for temporary substitution dose in children): 1 to 2 mg PE/kg/minute (should not exceed 2 mg PE/kg/minute or 100 mg PE/minute, whichever is slower). See Table 10 for infusion times.
Table 10 displays dosing information for the temporary substitution of oral phenytoin sodium in children.
TABLE 10. TEMPORARY SUBSTITUTION FOR ORAL PHENYTOIN SODIUM THERAPY (CHILDREN AGED 5 YEARS AND OLDER):
| Examples of equivalent doses and recommendations for dilution* (to 25 mg PE†/mL or to 1.5 mg PE/mL), and IV infusion times (at maximum rate of 2 mg PE/kg/minute) | ||||||
|---|---|---|---|---|---|---|
| Dose (mg phenytoin sodium) 5 mg/kg | Dose (mg PE) | Volume of Pro-Epanutin (50 mg PE/mL) | Volume (mL) of diluent* (5% glucose or 0.9% sodium chloride) | Minimum Infusion Time (minutes) to achieve the maximum recommended infusion rate of 2 mg PE/kg/minute | ||
| No. of 10 mL vials to open | Volume (mL) to draw up | for final concentration of 25 mg PE/mL | for final concentration of 1.5 mg PE/mL | |||
| 175 | 175 | 1 | 3.5 | 3.5 | 113 | 2.5 |
| 150 | 150 | 1 | 3 | 3 | 97 | 2.5 |
| 125 | 125 | 1 | 2.5 | 2.5 | 81 | 2.5 |
| 100 | 100 | 1 | 2 | 2 | 65 | 2.5 |
| 75 | 75 | 1 | 1.5 | 1.5 | 49 | 2.5 |
| 50 | 50 | 1 | 1 | 1 | 32 | 2.5 |
* For IV infusion the final concentration should range between 1.5 and 25 mg PE/mL
† PE – Phenytoin sodium equivalents
A lower loading dose and/or infusion rate, and lower or less frequent maintenance dosing of Pro-Epanutin may be required. Phenytoin metabolism is slightly decreased in elderly patients. A 10% to 25% reduction in dose or rate may be considered and careful clinical monitoring is required.
Except in the treatment of status epilepticus, a lower loading dose and/or infusion rate, and lower or less frequent maintenance dosing may be required in patients with renal and/or hepatic disease or in those with hypoalbuminaemia. A 10% to 25% reduction in dose or rate may be considered and careful clinical monitoring is required.
The rate of conversion of IV Pro-Epanutin to phenytoin may be increased in these patients. While the clearance rate of total phenytoin is not affected, the plasma unbound phenytoin concentrations may be elevated. Unbound concentration of phenytoin may be elevated in patients with hyperbilirubinaemia (see section 4.4). It is therefore more appropriate to measure plasma unbound phenytoin concentrations rather than plasma total phenytoin concentrations in these patients (see section 5.2).
Prior to complete conversion, immunoanalytical techniques may significantly overestimate plasma phenytoin concentrations due to cross-reactivity with fosphenytoin. Chromatographic assay methods (e.g. HPLC) accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. It is advised that blood samples to assess phenytoin concentration should not be obtained for at least 2 hours after IV Pro-Epanutin infusion or 4 hours after IM Pro-Epanutin injection.
Optimal seizure control without clinical signs of toxicity occurs most often with plasma total phenytoin concentrations of between 10 and 20 mg/l (40 and 80 micromoles/l) or plasma unbound phenytoin concentrations of between 1 and 2 mg/l (4 and 8 micromoles/l).
Plasma phenytoin concentrations sustained above the optimal range may produce signs of acute toxicity (see section 4.4).
Phenytoin capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as Pro-Epanutin, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase when IM or IV Pro-Epanutin is substituted for oral phenytoin sodium therapy. However, it is not necessary to adjust the initial doses when substituting oral phenytoin with Pro-Epanutin or vice versa.
Therapeutic drug monitoring may be useful whenever switching between products and/or routes of administration.
Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcaemia, metabolic acidosis and death have been reported in cases of overdosage with Pro-Epanutin.
Initial symptoms of Pro-Epanutin toxicity are those associated with acute phenytoin toxicity. These are nystagmus, ataxia and dysarthria. Irreversible cerebellar dysfunction and atrophy have been reported with phenytoin. Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma and hypotension. There is a risk of potentially fatal respiratory or circulatory depression. There are marked variations among individuals with respect to plasma phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 20 mg/l, ataxia at 30 mg/l and dysarthria and lethargy appear when the plasma concentration is over 40 mg/l. However, phenytoin concentrations as high as 50 mg/l have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in plasma phenytoin concentrations over 100 mg/l, with complete recovery.
Treatment is non-specific since there is no known antidote to Pro-Epanutin or phenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children. In acute overdosage the possibility of the use of other CNS depressants, including alcohol, should be borne in mind.
Formate and phosphate are metabolites of fosphenytoin 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 hypocalcaemia with paraesthesia, muscle spasms and seizures. Ionised free calcium levels can be measured and, if low, used to guide treatment.
2 years.
Store in a refrigerator (2°C to 8°C).The undiluted product may be stored at room temperature (8°C to 25°C) for up to 24 hours.
5 and 10 mL untreated Type I clear glass vials (containing 2 and 10 mL solution, respectively) with a Fluorotec coated stopper, and an aluminium seal with flip-off cap.
Boxes of 5 vials with 2 mL solution.
Boxes of 10 vials with 2 mL solution.
Boxes of 25 vials with 2 mL solution.
Boxes containing 10 boxes of 5 vials (=50 vials) with 2 mL solution.
Boxes of 5 vials with 10 mL solution.
Boxes of 10 vials with 10 mL solution.
Boxes containing 5 boxes of 5 vials (=25 vials) with 10 mL solution.
Not all pack sizes may be marketed.
Pro-Epanutin must be diluted to a concentration ranging from 1.5 to 25 mg PE/mL prior to infusion, with 5% glucose or 0.9% saline solution for injection (see section 4.2). After dilution Pro-Epanutin is suitable only for immediate use.
For single use only. After opening, unused product should be discarded.
Vials that develop particulate matter should not be used.
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