Pro-Epanutin Concentrate for Infusion / Solution for Injection (Pfizer Limited)

1. Name Of The Medicinal Product

Pro-Epanutin 75 mg/ml, Concentrate for solution for infusion/Solution for injection

(Pro-Dilantin, PROAURANTIN, Cereneu)

2. Qualitative And Quantitative Composition

One ml of Pro-Epanutin contains 75 mg of fosphenytoin sodium (equivalent to 50 mg of phenytoin sodium) and referred to as 50 mg PE (see Section 4.2).

Each 10 ml vial contains 750 mg of fosphenytoin sodium (equivalent to 500 mg of phenytoin sodium) and referred to as 500 mg PE.

Each 2 ml vial contains 150 mg of fosphenytoin sodium (equivalent to 100 mg of phenytoin sodium) and referred to as 100 mg PE.

For a full list of excipients, see Section 6.1

3. Pharmaceutical Form

Concentrate for solution for infusion/Solution for injection.

Pro-Epanutin is a clear, colourless to pale yellow, sterile solution buffered with trometamol adjusted to pH 8.6 to 9.0 with hydrochloric acid.

4. Clinical Particulars

4.1 Therapeutic Indications

Pro-Epanutin is indicated:

• for the control of status epilepticus of the tonic-clonic (grand mal) type (see Section 4.2).

• for prevention and treatment of seizures occurring in connection with neurosurgery and/or head trauma.

• as substitute for oral phenytoin if oral administration is not possible and/or contra-indicated.

4.2 Posology And Method Of Administration

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 Special Warnings and Precautions for Use).

Phenytoin sodium equivalents (PE):

1.5 mg of fosphenytoin is equivalent to 1 mg PE (phenytoin sodium equivalent)

Administration:

Pro-Epanutin may be administered by IV infusion or by IM injection. The intramuscular route should be considered when there is not an urgent need to control seizures. Pro-Epanutin should not be administered by IM route in emergency situations such as status epilepticus.

Products with particulate matter or discoloration should not be used.

Intravenous infusion:

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 Special Warnings and Precautions for Use).

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	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

DOSAGE IN ADULTS

(For Dose reduction in the Elderly please see guidance towards the end of this section.)

Status Epilepticus

Intramuscular administration of Pro-Epanutin is contra-indicated 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: 100 to 150mg 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 15mg PE/kg, and recommendations for dilution (to 25mg 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 (50mg PE/ml)	Volume (ml) of diluent (5% glucose or 0.9% sodium chloride) for final concentration of 25 mg PE/ml	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 150mg PE / minute
No. of 10 ml vials to open	Volume (ml) to draw up
100	1500	3	30	30	10
95	1425	3	28.5	28.5	9.5
90	1350	3	27	27	9
85	1275	3	25.5	25.5	8.5
80	1200	3	24	24	8
75	1125	3	22.5	22.5	7.5
70	1050	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

Maintenance dose:

The recommended maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given by IV infusion or by IM injection. The total daily dose may be given in one or two divided doses.

Recommended IV infusion rate for maintenance dose: 50 to 100 mg PE/minute. See Table 2 for infusion times.

Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).

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 5mg PE/kg, recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml), and IV infusion times (at maximum rate of 100mg PE/minute) by body weight
Weight (Kg)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg 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	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

Treatment or Prophylaxis of Seizures

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 treatment or prophylaxis of seizures loading dose: 50 to 100 mg PE/minute (should not exceed 150 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 10mg PE/kga, and recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml) and IV infusion times (at maximum rate of 100mg PE/minute) by body weight
Weight (Kg)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg 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 1.5mg PE/ml
100	1000	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
*For IV infusion the final concentration should range between 1.5 and 25 mg PE/ml a Please refer to Table 1 for examples of calculations for loading doses of 15mg PE/kg

Maintenance dose:

The recommended maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given by IV infusion or by IM injection. The total daily dose may be given in one or two divided doses.

Recommended IV infusion rate for maintenance dose: 50 to 100 mg PE/minute. See Table 4 for infusion times.

Maintenance doses should be adjusted according to patient response and trough plasma phenytoin concentrations (see Therapeutic Drug Monitoring).

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 5mg PE/kg, recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml), and IV infusion times (at maximum infusion rate of 100mg PE/minute) by body weight
Weight (Kg)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg 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 1.5mg 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 to 25 mg PE/ml

Temporary substitution of oral phenytoin therapy with Pro-Epanutin.

The same dose and dosing frequency as for oral phenytoin therapy should be used and can be administered by IV infusion or by IM injection.

Recommended IV infusion rate for temporary substitution dosing: 50 to 100 mg PE/minute. See Table 5 for infusion times.

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).

Fosphenytoin has not been evaluated systemically for more than 5 days.

Table 5 displays dosing information for the temporary substitution of oral phenytoin in adults.

TABLE 5 TEMPORARY SUBSTITUTION OF ORAL PHENYTOIN THERAPY (ADULTS)
Examples of equivalent doses and recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml), and IV infusion times (at maximum rate of 100mg PE/minute)
Dose (mg phenytoin sodium)	Dose (mg PE)	Volume of Pro-Epanutin (50mg PE/ml)	Volume (ml) of diluent* ( 5% glucose or 0.9% sodium chloride)	Minimum Infusion Time (mins) to achieve the maximum recommended infusion rate of 100mg 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 1.5mg 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 to 25 mg PE/ml

DOSAGE IN CHILDREN

Pro-Epanutin may be administered to children (ages 5 and above) 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 administration in children is not recommended.

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 loading dose: 2 to 3 mg PE/kg/min (should not exceed 3mg PE/kg/minute or 150mg PE/minute). 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)