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PRO-EPANUTIN CONCENTRATE FOR INFUSION|SOLUTION FOR INJECTION

Active substance(s): FOSPHENYTOIN DISODIUM

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FPO 128 - 10 mil

14408300

Summary of Product Characteristics & Emergency Dosing Guidance

PRO-EPANUTINTM 75 mg/ml
Concentrate for Solution for
Infusion/Solution for Injection

United Kingdom/Ireland

For emergency dosing guidance, please tear off a back page of this booklet

00.indd 1

Pfizer Limited
Sandwich, England

5/24/16 8:

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
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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Pro-Epanutin 75 mg/ml, Concentrate for solution for infusion/Solution for injection

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).
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Table 1 displays dosing information for status epilepticus loading dose in adults.

Adults

Indication

Dosing Table

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

Children

Table 5

Status epilepticus

Loading dose

Table 6
Table 7

Status epilepticus

Maintenance dose

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 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.
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Please refer to Tables 1-10 for examples of dosing, dilution, and infusion time calculations
Population

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
Volume of
Pro-Epanutin
(50 mg PE/ml)

Volume (ml) of diluent
(5% glucose or 0.9%
sodium chloride)

Minimum Infusion
Time (mins)

Weight
(Kg)

Dose
(mg PE)

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

No. of
10 ml vials
to open

Volume
(ml) to
draw up

for final concentration of
25 mg PE/ml

to achieve the maximum
recommended infusion rate of
150 mg PE / minute

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.
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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)

100

500

Volume of
Pro-Epanutin
(50 mg PE/ml)
No. of
10 ml vials
to open
1

Volume (ml) of diluent*
( 5% glucose or
0.9% sodium chloride)

Minimum Infusion
Time (mins)

to achieve the maximum
for final
for final
Volume (ml)
concentration of concentration of recommended infusion rate of
to draw up
100 mg PE / minute
25 mg PE/ml
1.5 mg PE/ml
10

10

323

5
4.5

90

450

1

9

9

291

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

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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.

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 10 mg PE/kga, 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) by body weight

Weight
(Kg)

Dose
(mg PE)

100

1000

Volume of
Pro-Epanutin
(50 mg PE/ml)
No. of
10 ml vials
to open
2

Volume (ml) of diluent*
( 5% glucose or
0.9% sodium chloride)

Minimum Infusion
Time (mins)

to achieve the
for final
for final
maximum recommended
Volume (ml)
concentration of concentration of infusion rate of 100 mg
to draw up
25 mg PE/ml
1.5 mg PE/ml
PE / minute
20

647

90

900

2

18

18

582

80

800

2

20
16

16

517

10
8

70

700

2

14

14

453

7

9

60

600

2

12

12

388

6

50

500

1

10

10

323

5

a

* For IV infusion the final concentration should range between 1.5 and 25 mg PE/ml
Please refer to Table 1 for examples of calculations for loading doses of 15 mg PE/kg

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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)
No. of
10 ml vials
to open

Volume (ml) of diluent*
( 5% glucose or
0.9% sodium chloride)

Minimum Infusion Time
(mins)

to achieve the maximum
for final
for final
Volume (ml)
concentration of concentration of recommended infusion rate of
to draw up
100 mg PE / minute
25 mg PE/ml
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 to 25 mg PE/ml
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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.

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 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)
No. of
10 ml vials
to open

Volume (ml)
to draw up

Volume (ml) of diluent*
( 5% glucose or
0.9% sodium chloride)

Minimum Infusion Time
(mins)

to achieve the
for final
for final
maximum recommended
concentration concentration of
infusion rate of
of 25 mg PE/ml
1.5 mg PE/ml
100 mg PE / minute

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
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Table 6 displays dosing information for status epilepticus loading dose in children.
For emergency dosing guidance, please tear off a back page of this booklet

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
3 mg PE / kg / minute or 150 mg 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 STATUS EPILEPTICUS LOADING DOSE (CHILDREN)
Examples of IV loading doses of 15 mg PE/kg and recommendations for dilution (to 25 mg PE/ml) and
IV infusion times (at 3 mg PE/kg/minute) by body weight
Weight
(Kg)

Dose
(mg PE)

Volume of
Pro-Epanutin
(50 mg PE/ml)
No. of
Volume (ml)
10 ml vials to
to draw up
open

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 3 mg PE /kg/ minute

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

Maintenance dose:
The recommended maintenance dose of Pro-Epanutin of 4 to 5 mg PE/kg/day may be given by IV
infusion. The total daily dose may be given in one to four divided doses.
Recommended IV infusion rate for maintenance dose: 1 to 2 mg PE/kg/minute (should not exceed
100 mg PE/minute). See Table 7 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.
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TABLE 7 STATUS EPILEPTICUS MAINTENANCE DOSE (CHILDREN)
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)
No. of 10ml
vials to
open

Volume (ml) of diluent
( 5% glucose or
0.9% sodium chloride)

for final
for final
Volume (ml)
concentration of concentration of
to draw up
25 mg PE/ml
1.5 mg PE/ml

Minimum Infusion Time
(mins)
to achieve the maximum
recommended infusion rate
of 2 mg PE /kg/ minute

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

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.
Recommended IV infusion rate for treatment or prophylaxis of seizures loading dose:
1 to 2 mg PE/kg/minute (should not exceed 3 mg PE/kg/minute or 150 mg PE/minute). See Table 8
for infusion times.
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Table 8 displays dosing information for seizure treatment or prophylaxis loading dose in children.
For emergency dosing guidance, please tear off a back page of this booklet

Table 7 displays dosing information for status epilepticus maintenance dose in children.

TABLE 8 TREATMENT OR PROPHYLAXIS OF SEIZURES LOADING DOSE (CHILDREN)
Examples for IV loading doses of 10 mg PE/kga, 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) by body weight

Weight
(Kg)

Dose
(mg PE)

Volume of
Pro-Epanutin
(50 mg PE/ml)
No. of 10ml
vials to
open

Volume (ml) of diluent
( 5% glucose or
0.9% sodium chloride)

Minimum Infusion
Time (mins)

to achieve the
for final
for final
maximum recommended
Volume (ml)
concentration of concentration of
infusion
rate of
to draw up
25 mg PE/ml
1.5 mg PE/ml
2 mg PE /kg/ minute

35

350

1

7

7

226

32.5

325

1

6.5

6.5

210

5
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

175

1

3.5

3.5

113

5

17.5

a

*For IV infusion the final concentration should range between 1.5 to 25 mg PE/ml
Please refer to Table 6 for examples of calculations for loading doses of 15 mg 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. The total daily dose may be given in one to four divided doses.
Recommended IV infusion rate for maintenance dose: 1 to 2 mg PE/kg/minute (should not exceed
100 mg PE/minute). See Table 9 for infusion times.
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TABLE 9 TREATMENT OR PROPHYLAXIS OF SEIZURES MAINTENANCE DOSE (CHILDREN)
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)
No. of 10ml
vials to
open

Volume (ml) of diluent
( 5% glucose or
0.9% sodium chloride)

Minimum Infusion Time
(mins)

to achieve the maximum
for final
for final
Volume (ml)
concentration of concentration of recommended infusion rate of
to draw up
2 mg PE /kg/ minute
25 mg PE/ml
1.5 mg PE/ml

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

Temporary substitution of oral phenytoin therapy with Pro-Epanutin
The same dose and dosing frequency as for oral phenytoin therapy should be administered by IV
infusion.
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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 9 displays dosing information for seizure treatment or prophylaxis maintenance dose in children.

Recommended IV infusion rate for temporary substitution dosing: 1 to 2 mg PE/kg/minute
(should not exceed 100 mg PE/minute). See Table 10 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 10 displays dosing information for the temporary substitution of oral phenytoin in children.
Table 10 Temporary Substitution of Oral Phenytoin Therapy (Children)
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 Dose
sodium) (mg PE)
5 mg/kg
175

175

Volume of
Pro-Epanutin
(50 mg PE/ml)
No. of 10ml
vials to
open
1

Volume (ml) of diluent*
( 5% glucose or
0.9% sodium chloride)

for final
for final
Volume (ml)
concentration of concentration of
to draw up
25 mg PE/ml
1.5 mg PE/ml
3.5

3.5

Minimum Infusion
Time (mins)
to achieve the
maximum recommended
infusion rate of
2 mg PE /kg/ minute

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 to 25 mg PE/ml

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For emergency dosing guidance, please tear off a back page of this booklet

ELDERLY PATIENTS
A lower loading dose and/or infusion rate, and lower or less frequent maintenance dosing of ProEpanutin 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.
PATIENTS WITH RENAL OR HEPATIC DISEASE
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 but not the clearance of phenytoin may be
increased in these patients. Plasma unbound phenytoin concentrations may also be elevated. It may
therefore, be more appropriate to measure plasma unbound phenytoin concentrations rather than
plasma total phenytoin concentrations in these patients.
Therapeutic drug monitoring:
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 Special Warnings and Precautions for Use).
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.
4.3 Contraindications
Hypersensitivity to fosphenytoin sodium or the excipients of Pro-Epanutin, or to phenytoin or other
hydantoins.
Parenteral phenytoin affects ventricular automaticity. Pro-Epanutin is therefore, contra-indicated in
patients with sinus bradycardia, sino-atrial block, second and third degree A-V block and AdamsStokes syndrome.
Acute intermittent porphyria.
Coadministration of Pro-Epanutin is contra-indicated with delavirdine due to the potential for loss of
virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse
transcriptase inhibitors (see section 4.5).
4.4 Special Warnings and Precautions for Use
Doses of Pro-Epanutin are always expressed as their phenytoin sodium equivalents (PE =
phenytoin sodium equivalent). Therefore, when Pro-Epanutin is dosed as PE do not make any
adjustment in the recommended doses when substituting Pro-Epanutin for phenytoin sodium
or vice versa.
Note, however, that Pro-Epanutin has important differences in administration from parenteral
phenytoin sodium. Pro-Epanutin should not be administered intravenously at a rate greater
than 150 mg PE/min while the maximum intravenous infusion rate for phenytoin is 50 mg/min
(see Section 4.2).
Phenytoin is not effective in absence seizures. If tonic-clonic seizures are present simultaneously
with absence seizures, combined drug therapy is recommended.
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Withdrawal Precipitated Seizure/Status Epilepticus:
Abrupt withdrawal of antiepileptic drugs may increase seizure frequency and may lead to status
epilepticus.
Suicidal Ideation and Behaviour:
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has
also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not
known and the available data do not exclude the possibility of an increased risk for fosphenytoin.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical
advice should signs of suicidal ideation or behaviour emerge.
Cardiovascular Effect:
Pro-Epanutin should be used with caution in patients with hypotension and severe myocardial
insufficiency. Severe cardiovascular reactions including atrial and ventricular conduction depression and
ventricular fibrillation, and sometimes, fatalities have been reported following phenytoin and fosphenytoin
administration. Hypotension may also occur following IV administration of high doses and/or high
infusion rates of Pro-Epanutin and even within recommended doses and rates. A reduction in the rate of
administration or discontinuation of dosing may be necessary (see Section 4.2).
Severe complications have been reported in elderly, children (especially infants), or gravely ill patients
following administration of fosphenytoin. Therefore, careful cardiac monitoring is needed when
administering IV loading doses of fosphenytoin.
Patients with an acute cerebrovascular event may be at increased risk of hypotension and require
particularly close monitoring.
Local Toxicity (including Purple Glove Syndrome):
Edema, discoloration, and pain distal to the site of injection (described as “purple glove syndrome”) have
also been reported following peripheral intravenous fosphenytoin injection. This may or may not be
associated with extravasation. The syndrome may not develop for several days after injection. Although

resolution of symptoms may occur without treatment, skin necrosis and limb ischemia have occurred
that required surgical interventions and, in rare cases, amputation.
Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS):
Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS) has been reported in patients taking anticonvulsant drugs, including phenytoin and
fosphenytoin. Some of these events have been fatal or life threatening.
HSS/DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy,
in association with other organ system involvement, such as hepatitis, nephritis, hematological
abnormalities, myocarditis, myositis or pneumonitis. Initial symptoms may resemble an acute viral
infection. Other common manifestations include arthralgias, jaundice, hepatomegaly, leukocytosis,
and eosinophilia. The interval between first drug exposure and symptoms is usually 2-4 weeks of
treatment but has also been reported in individuals receiving anticonvulsants for 3 or more months. If
such signs and symptoms occur, the patient should be evaluated immediately. Fosphenytoin should
be discontinued if an alternative etiology for the signs and symptoms cannot be established.
Patients at higher risk for developing HSS/DRESS include black patients, patients who have
experienced this syndrome in the past (with phenytoin, fosphenytoin or other anticonvulsant
drugs), patients who have a family history of this syndrome and immuno‑suppressed patients. The
syndrome is more severe in previously sensitized individuals.
Serious Cutaneous Adverse Reactions:
Fosphenytoin can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson
Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin
reactions may occur without warning, patients should be alert for the occurrence of rash and other
symptoms of HSS/DRESS and should seek medical advice from their physician immediately when
observing any indicative signs or symptoms. The physician should advise the patient to discontinue
treatment if the rash appears. If the rash is of a milder type (measles-like or scarlatiniform), therapy may
be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy,
further fosphenytoin or phenytoin administration is contraindicated.
The risk of serious skin reactions and other hypersensitivity reactions to phenytoin may be higher in
black patients.
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Studies in patients of Chinese ancestry have found a strong association between the risk of developing
SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using
carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/
TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin.
Literature reports suggest that the combination of phenytoin, cranial irradiation and the gradual reduction
of corticosteroids may be associated with the development of erythema multiforme, and/or StevensJohnson syndrome, and/or toxic epidermal necrolysis.
Drug rash with eosinophilia and systemic symptoms (DRESS) reflects a serious hypersensitivity reaction
to drugs, characterized by skin rash, fever, lymph node enlargement, and internal organ involvement.
Cases of DRESS have been noted in patients taking phenytoin.
Hepatic Injury: The liver is the chief site of biotransformation of phenytoin.
Toxic hepatitis and liver damage have been reported with phenytoin and may, in rare cases, be fatal.
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported
with phenytoin. These incidents usually occur within the first 2 months of treatment and may be
associated with HSS/DRESS. Patients with impaired liver function, elderly patients, or those who are
gravely ill may show early signs of toxicity.
The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes.
In patients with acute hepatotoxicity, fosphenytoin should be immediately discontinued and not readministered.
The risk of hepatotoxicity and other hypersensitivity reactions to phenytoin may be higher in black
patients.
Haematopoietic System:
Haematopoietic complications, some fatal, have occasionally been reported in association with
administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia,
agranulocytosis, and pancytopenia with or without bone marrow suppression (see section 4.8).

Lymphadenopathy (local or generalised) including benign lymph node hyperplasia, pseudolymphoma,
lymphoma and Hodgkin’s Disease have been associated with administration of phenytoin, although
a cause and effect relationship has not been established. It is therefore, important to eliminate
other types of lymph node pathology before discontinuing therapy with Pro-Epanutin. Lymph node
involvement may occur with or without symptoms and signs resembling HSS/DRESS described above.
In all cases of lymphadenopathy, long term follow-up observations are indicated and every effort should
be made to achieve seizure control using alternative antiepileptic drugs.
Acute Toxicity:
Confusional states referred to as “delirium”, “psychosis” or “encephalopathy” or rarely irreversible
cerebellar dysfunction and/or cerebellar atrophy may occur if plasma phenytoin concentrations are
sustained above the optimal therapeutic range and/or long-term phenytoin use. Plasma phenytoin
concentrations should be determined at the first sign of acute toxicity (see Section 4.2). If plasma
phenytoin concentrations are excessive, the dose of Pro-Epanutin should be reduced. If symptoms
persist, administration of Pro-Epanutin should be discontinued.
Renal or Hepatic Disease:
Pro-Epanutin should be used with caution in patients with renal and/or hepatic disease, or in those
with hypoalbuminaemia. Alterations in dosing may be necessary in patients with impaired kidney
or liver function, elderly patients or those who are gravely ill (see Section 4.2). These patients
may show early signs of phenytoin toxicity or an increase in the severity of adverse events due to
alterations in Pro-Epanutin and phenytoin pharmacokinetics.
The phosphate load provided by Pro-Epanutin is 0.0037 mmol phosphate/mg fosphenytoin sodium.
Caution is advised when administering Pro-Epanutin in patients requiring phosphate restriction, such
as those with severe renal impairment.
Sensory Disturbances:
Overall these occur in 13% of the patients exposed to Pro-Epanutin. Transient itching, burning,
warmth or tingling in the groin during and shortly after intravenous infusion of Pro-Epanutin may
occur. The sensations are not consistent with the signs of an allergic reaction and may be avoided or
minimised by using a slower rate of IV infusion or by temporarily stopping the infusion.
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4.5 Interaction with Other Medicinal Products and Other Forms of Interaction
Drug interactions which may occur following the administration of Pro-Epanutin are those that are
expected to occur with drugs known to interact with phenytoin. Phenytoin metabolism is saturable and
other drugs that utilise the same metabolic pathways may alter plasma phenytoin concentrations. There
are many drugs which may increase or decrease plasma phenytoin concentrations. Equally phenytoin
may affect the metabolism of a number of other drugs because of its potent enzyme-inducing potential.
Determination of plasma phenytoin concentrations is especially helpful when possible drug interactions
are suspected (see Section 4.2).
No drugs are known to interfere with the conversion of fosphenytoin to phenytoin.
Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Drugs
highly bound to albumin could also increase the fosphenytoin unbound fraction with the potential to
increase the rate of conversion of fosphenytoin to phenytoin.
Phenytoin is mainly metabolized in the liver by the cytochrome P450 CYP2C9 and CYP2C19 enzymes.
Inhibition of phenytoin metabolism may produce significant increases in plasma phenytoin concentrations
and increase the risk of phenytoin toxicity. Phenytoin is also a potent inducer of hepatic drugmetabolising enzymes and may reduce the levels of drugs metabolized by these enzymes.
The following drug interactions are the most commonly occurring drug interactions with phenytoin:

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Drugs that may increase serum phenytoin concentrations listed by likely mechanism:
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Diabetes:
Phenytoin may raise blood glucose in diabetic patients.
Alcohol Use:
Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may
decrease plasma phenytoin concentrations.

Drug

Mechanism

Antineoplastic agents (fluorouracil)
Azole antifungals (ketoconazole, itraconazole, fluconazole, miconazole)
Capecitabine
Fluvastatin
Glibenclamide
Sulfaphenazole

CYP2C9 inhibition

Felbamate
Oxcarbazepine
Topiramate

CYP2C19 inhibition

Azapropazone
Fluvoxamine
Nifedipine
Sertraline
Ticlopidine
Tolbutamide
Voriconazole

CYP2C9/2C19 inhibition

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Mechanism

Acute alcohol intake
Amiodarone
Amphotericin B
Chloramphenicol
Diltiazem (high doses)
Disulfiram
Fluoxetine
H2-antagonists (cimetidine)
Halothane
Isoniazid
Methylphenidate
Oestrogens
Omeprazole
Phenothiazines
Phenylbutazone
Salicylates
Sodium valproate
Succinimides (ethosuximide)
Sulphonamides (sulfadiazine, sulfamethizole, sulfamethoxazole-trimethoprim)
Tacrolimus
Trazodone
Viloxazine

Unknown mechanism

Drugs that may decrease plasma phenytoin concentrations listed by likely mechanism:
Drug

Mechanism

Rifampicin

CYP2C/2C19 induction

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Drug

Drug

Mechanism

Antineoplastic agents (bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate)
Chronic alcohol abuse
Diazoxide
Folic acid
Fosamprenavir
Nelfinavir*
Theophylline
Vigabatrin
Ritonavir
St John’s Wort

Unknown

*Co-administration of nelfinavir tablets (1.250 mg twice a day) with phenytoin capsules (300 mg
once a day) did not change the plasma concentration of nelfinavir. However, co-administration
of nelfinavir reduced the AUC values of phenytoin (total) and free phenytoin by 29% and 28%,
respectively. Plasma concentrations of phenytoin should be monitored during concomitant treatment
with nelfinavir.
Drugs that may increase or decrease phenytoin concentrations listed by likely mechanism:
Drug

Mechanism

Antineoplastic agents
Carbamazepine
Chlordiazepoxide
Ciprofloxacin
Diazepam
Phenobarbital
Phenothiazines
Sodium valproate
Valproic acid
Certain antacids

Unknown

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Drug

Mechanism

Antineoplastic agents (e.g. Teniposide)
Atorvastatin
Carbamezepine
Ciclosporin
Efavirenz
Erythromycin
Fosamprenavir
Indinavir
Lopinavir/ritonavir
Methadone
Nelfinavir
Neuromuscular blocking agents (pancuronium, vecuronium)
Nicardipine
Nifedipine
Nisoldipine
Praziquantel
Ritonavir
Saquinavir
Simvastatin
Verapamil

CYP3A4 induction

Chlorpropamide
Fluvastatin

CYP2C9/2C19 induction

Theophylline

CYP1A2 induction

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Drugs whose serum levels and/or effects may be altered by phenytoin listed by likely mechanism:

Albendazole
Antibacterial agents (doxycycline, rifampicin, tetracycline)
Anticoagulants (warfarin)
Antifungal agents (azoles, posaconazole, voriconazole)
Cisatracurium
Corticosteroids
Cardiovascular agents (digoxin, nimodipine, quinidine)
Delavirdine
Furosemide
Glibenclamide
Hormones (oestrogens, oral contraceptives)
Lamotrigine
Mexiletine
Phenobarbital
Psychotropic agents (paroxetine, clozapine, quetiapine)
Rocuronium
Sodium valproate
Valproic acid
Vitamin D

Unknown

Although not a true pharmacokinetic interaction, tricyclic antidepressants and phenothiazines may
precipitate seizures in susceptible patients and Pro-Epanutin dosage may need to be adjusted.
Pharmacodynamic Interactions
Concomitant use of paroxetine or sertraline with phenytoin may lower the seizure threshold.
Phenytoin may increase serum glucose levels and therefore adjustment for insulin or oral antidiabetic
agents (glibenclamide, tolbutamide) may be necessary.
Drug/Laboratory Test Interactions:
Phenytoin may decrease serum concentrations of T4. It may also produce low results in
dexamethasone or metyrapone tests. This may be an artefact. Phenytoin may cause increased
blood glucose or serum concentrations of alkaline phosphatase and gamma glutamyl transpeptidase
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4.6 Fertility, pregnancy and lactation
Pregnancy
An increase in seizure frequency may occur during pregnancy because of altered phenytoin
pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the
management of pregnant women as a guide to appropriate adjustment of dosage (see Section 4.2).
However, postpartum restoration of the original dosage will probably be indicated.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the
patient should be informed of the potential harm to the fetus.
Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse
developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts
and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth
abnormalities (including microcephaly) and mental deficiency have been reported among children born
to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during
pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in
children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for
children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy
is about 10% or two-to-three-fold that in the general population. However, the relative contribution of
antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and
in most cases it has not been possible to attribute specific developmental abnormalities to particular
antiepileptic drugs.
It might be necessary to give vitamin K to the mother during the last gestational month. Neonates of
the mother receiving Pro-Epanutin should be monitored for haemorrhagic diathesis and if necessary
additional vitamin K should be administered.
Fetal toxicity, developmental toxicity and teratogenicity were observed in offspring of rats given
fosphenytoin during pregnancy, similar to those reported with phenytoin (see Section 5.3).
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(GGT). Phenytoin may affect blood calcium and blood sugar metabolism tests.
Phenytoin has the potential to lower serum folate levels.

Breast-feeding
It is not known whether Pro-Epanutin is excreted in human milk. Following administration of oral
phenytoin, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breastfeeding is not recommended for women receiving Pro-Epanutin.
Fertility
In animal studies, fosphenytoin had no effect on fertility in male rats but decreased fertility in female
rats (see Section 5.3).
4.7 Effects on Ability to Drive and Use Machines
Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery)
as treatment with fosphenytoin may cause central nervous system adverse effects such as dizziness
and drowsiness (see Section 4.8).
4.8 Undesirable Effects
The following adverse events have been reported in clinical trials in adults receiving Pro-Epanutin.
The list also includes adverse effects that have been reported spontaneously following both the
acute and chronic use of phenytoin.
The more important adverse clinical events caused by the IV use of fosphenytoin or phenytoin are
cardiovascular collapse and/or central nervous system depression. Hypotension can occur when
either drug is administered rapidly by the IV route.
The adverse clinical events most commonly observed with the use of fosphenytoin in clinical
trials were nystagmus, dizziness, pruritus, paraesthesia, headache, somnolence, and ataxia.
With two exceptions, these events are commonly associated with the administration of IV
phenytoin. Paraesthesia and pruritus, however, were seen much more often following fosphenytoin
administration and occurred more often with IV fosphenytoin administration than IM fosphenytoin
administration. These events were dose and rate related.
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In the table below all adverse reactions, which occurred at an incidence greater than placebo and in
more than one patient, are listed by class and frequency (very common (≥1/10), common (≥1/100, <1/10)
uncommon (≥1/1000, <1/100)) and Not known (cannot be estimated from available data). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Additional reactions reported from post-marketing experience are included as frequency ‘Not known’.
Blood and the lymphatic system disorders
Not known
leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone
marrow suppression, thrombocytopenia, aplastic anaemia, lymphadenopathy. Some of
these reports have been fatal.
Immune system disorders
Not known
anaphylactic/anaphylactoid reaction, hypersensitivity syndrome, periarteritis nodosa,
immunoglobulin abnormalities
Metabolism and nutrition disorders
Not known
hyperglycaemia, appetite disorder
Psychiatric disorders
Common
euphoric mood
Uncommon
nervousness, confusional state, abnormal thinking
Nervous system disorders
Very common nystagmus, dizziness
Common
paraesthesia, ataxia, somnolence, headache, tremor, abnormal coordination, dysgeusia,
stupor, dysarthria
Uncommon
hypoesthesia, reflexes increased, hyporeflexia
Not known
extrapyramidal disorder, dyskinesia including chorea, dystonia and asterixis similar
to those induced by phenothiazines or other neuroleptic drugs, drowsiness, motor
twitching, insomnia, tonic seizures. A predominantly sensory peripheral polyneuropathy
has been observed in patients receiving long-term phenytoin therapy. The incidence

and severity of adverse events related to the CNS and sensory disturbances were
greater at higher doses and rates.
Eye disorders
Common
blurred vision, visual impairment
Uncommon
diplopia
Ear and labyrinth disorders
Common
tinnitus, vertigo
Uncommon hypoacusis
Cardiac disorders
Not known
severe cardiotoxic reactions with atrial and ventricular conduction depression
(including bradycardia and all degrees of heart block), asystole ventricular fibrillation
and cardiovascular collapse (see Section 4.4).
Vascular disorders
Common
vasodilatation, hypotension
Respiratory, thoracic and mediastinal disorders
Not known
pneumonitis, alterations in respiratory function including respiratory arrest. Some of
these reactions have been fatal (see Section 4.2).
Gastrointestinal disorders
Common
nausea, dry mouth, vomiting
Uncommon
hypoaesthesia of the tongue
Not known
gingival hyperplasia, constipation
Hepatobiliary disorders
Not known
toxic hepatitis, hepatocellular damage
Skin and subcutaneous tissue disorders
Very Common pruritus
Common ecchymosis
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rash. Other more serious and rare forms have included bullous, exfoliative or purpuric
dermatitis, lupus erythematosus, Stevens-Johnson syndrome and toxic epidermal
necrolysis (see Section 4.4).
Not known
hirsutism, hypertrichosis, coarsening of the facial features, enlargement of the lips,
Peyronie’s disease, Dupuytren’s contracture, and drug reaction with eosinophilia and
systemic symptoms (DRESS) (see Section 4.4).
Musculoskeletal and connective tissue disorders
Uncommon
muscular weakness, muscle twitching, muscle spasms
Not known
systemic lupus erythematosus, polyarthritis, Purple Glove Syndrome (see Section 4.4).
Renal and urinary disorders
Not known
interstitial nephritis
General disorders and administration site conditions
Common
injection-site reaction, injection-site pain, asthenia, chills
Not known
feeling of warmth or tingling in the groin
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures
in patients on long-term therapy with phenytoin. The mechanism by which phenytoin affects bone
metabolism has not been identified.
No trends in laboratory changes were observed in Pro-Epanutin treated patients.
4.9 Overdose
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
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Uncommon

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.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
ATC-Code: N03AB
Pro-Epanutin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to
phenytoin.
The pharmacological and toxicological effects of fosphenytoin sodium include those of phenytoin.
The cellular mechanisms of phenytoin thought to be responsible for its anticonvulsant actions
include modulation of voltage-dependent sodium channels of neurones, inhibition of calcium flux
across neuronal membranes, modulation of voltage-dependent calcium channels of neurones and
enhancement of the sodium-potassium ATPase activity of neurones and glial cells. The modulation
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5.2. Pharmacokinetic Properties
Fosphenytoin is a pro-drug of phenytoin and it is rapidly converted into phenytoin mole for mole.
Fosphenytoin Pharmacokinetics
Absorption/Bioavailability:
When Pro-Epanutin is administered by IV infusion, maximum plasma fosphenytoin concentrations are
achieved at the end of the infusion. Fosphenytoin is completely bioavailable following IM administration
of Pro-Epanutin. Peak concentrations occur at approximately 30 minutes postdose. Plasma fosphenytoin
concentrations following IM administration are lower but more sustained than those following IV
administration due to the time required for absorption of fosphenytoin from the injection site.
Distribution:
Fosphenytoin is extensively bound (95% to 99%) to human plasma proteins, primarily albumin. Binding
to plasma proteins is saturable with the result that the fraction unbound increases as total fosphenytoin
concentrations increase. Fosphenytoin displaces phenytoin from protein binding sites. The volume of
distribution of fosphenytoin increases with fosphenytoin sodium dose and rate and ranges from 4.3 to
10.8 L.
Metabolism and Excretion:
The hydrolysis of fosphenytoin to phenytoin yields 2 metabolites, phosphate and formaldehyde.
Formaldehyde is subsequently converted to formate, which is in turn metabolised via a folate dependent
mechanism. Although phosphate and formaldehyde (formate) have potentially important biological
effects, these effects typically occur at concentrations considerably in excess of those obtained when
Pro-Epanutin is administered under conditions of use recommended in this labelling.
The conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes. The mechanism of
fosphenytoin conversion has not been determined but phosphatases probably play a major role. Each
mmol of fosphenytoin is metabolised to 1 mmol of phenytoin, phosphate and formate.
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of sodium channels may be a primary anticonvulsant mechanism because this property is shared with
several other anticonvulsants in addition to phenytoin.

Fosphenytoin is not excreted in urine.
Phenytoin Pharmacokinetics (after Pro-Epanutin administration):
The pharmacokinetics of phenytoin following IV administration of Pro-Epanutin, are complex and
when used in an emergency setting (e.g. status epilepticus), differences in rate of availability of
phenytoin could be critical. Studies have, therefore, empirically determined an infusion rate for
Pro-Epanutin that gives a rate and extent of phenytoin systemic availability similar to that of a 50
mg/min phenytoin sodium infusion. Because Pro-Epanutin is completely absorbed and converted
to phenytoin following IM administration, systemic phenytoin concentrations are generated that are
similar enough to oral phenytoin to allow essentially interchangeable use and to allow reliable IM
loading dose administration.
The following table displays pharmacokinetic parameters of fosphenytoin and phenytoin following IV
and IM Pro-Epanutin administration.
Mean Pharmacokinetic Parameter Values by Route of Pro-Epanutin Administration.
Free (Unbound)
Phenytoin

Dose
(mg PE)

Dose
(mg
PE/kg)

Infusion
Rate
(mg
PE/min)

Cmax
(µg/ml)

tmax
(hr)


(min)

Cmax
(µg/ml)

tmax
(hr)

Cmax
(µg/ml)

Intramuscular

855

12.4

--

18.5

0.61

41.2

14.3

3.23

2.02

4.16

Intravenous

1200

15.6

100

139

0.19

18.9

26.9

1.18

2.78

0.52

Intravenous

1200

15.6

150

156

0.13

20.5

28.2

0.98

3.18

0.58

Route

Fosphenytoin

Total Phenytoin

tmax
(hr)


Dose = Fosphenytoin dose (phenytoin sodium equivalents [mgPE] or phenytoin sodium
equivalents/kg [mg PE/kg]).
Infusion Rate = Fosphenytoin infusion rate (mg phenytoin sodium equivalents/min [mg PE/min]).

Cmax = Maximum plasma analyte concentration (µg/ml).

Tmax = Time of Cmax (hr).

t½ = Terminal elimination half-life (min).

Page 35

5/24/16 8:16 AM

Page 36

14408300.indd 36-37

For emergency dosing guidance, please tear off a back page of this booklet

Absorption/Bioavailability:
Fosphenytoin sodium is rapidly and completely converted to phenytoin following IV or IM Pro- Epanutin
administration. Therefore, the bioavailability of phenytoin following administration of Pro-Epanutin is the
same as that following parenteral administration of phenytoin.
Distribution:
Phenytoin is highly bound to plasma proteins, primarily albumin, although to a lesser extent than
fosphenytoin. In the absence of fosphenytoin, approximately 12% of total plasma phenytoin is unbound
over the clinically relevant concentration range. However, fosphenytoin displaces phenytoin from plasma
protein binding sites. This increases the fraction of phenytoin unbound (up to 30% unbound) during the
period required for conversion of fosphenytoin to phenytoin (approximately 0.5 to 1 hour postinfusion).
The volume of distribution for phenytoin ranges from 24.9 to 36.8 L.
Metabolism and Excretion:
Phenytoin derived from administration of Pro-Epanutin is extensively metabolised in the liver
and excreted in urine primarily as 5-(p-hydroxy-phenyl)-5-phenylhydantoin and its glucuronide;
little unchanged phenytoin (1%-5% of the Pro-Epanutin dose) is recovered in urine. Phenytoin
hepatic metabolism is saturable and, following administration of single IV Pro-Epanutin doses of
400 to 1200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose.
Mean total phenytoin half-life values (12.0 to 28.9 hr) following Pro-Epanutin administration at these
doses are similar to those after equal doses of parenteral phenytoin and tend to be longer at higher
plasma phenytoin concentrations.
Characteristics in Patients
Patients with Renal or Hepatic Disease:
Fosphenytoin conversion to phenytoin is more rapid in patients with renal or hepatic disease than with
other patients because of decreased plasma protein binding, secondary to hypoalbuminaemia, occurring
in these disease states. The extent of conversion to phenytoin is not affected. Phenytoin metabolism may
be reduced in patients with hepatic impairment resulting in increased plasma phenytoin concentrations
(see Section 4.2).

Elderly Patients:
Patient age had no significant impact on fosphenytoin pharmacokinetics. Phenytoin clearance tends
to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients
20-30 years of age) (see Section 4.2).
Gender:
Gender had no significant impact on fosphenytoin or phenytoin pharmacokinetics.
Children:
Limited studies in children (age 5 to 10) receiving Pro-Epanutin have shown similar concentrationtime profiles of fosphenytoin and phenytoin to those observed in adult patients receiving
comparable mg PE/ kg doses.
5.3. Preclinical Safety Data
The systemic toxicity of fosphenytoin is qualitatively and quantitatively similar to that of phenytoin at
comparable exposures.
Carcinogenicity studies with fosphenytoin are unavailable. Since fosphenytoin is a prodrug
of phenytoin, the carcinogenicity results with phenytoin can be extrapolated. Carcinogenicity
studies in mice have shown an increased incidence of hepatocellular tumours at phenytoin
plasma concentrations approximating the therapeutic range. Similar studies in rats have shown
an inconsistent increase in hepatocellular tumours. The clinical significance of these findings is
unknown.
Genetic toxicity studies showed that fosphenytoin was not mutagenic in bacteria or in mammalian
cells in vitro. It is clastogenic in vitro but not in vivo.
Fetal toxicity, developmental toxicity and teratogenicity occurred in offspring from rats given
fosphenytoin prior to and during mating, gestation, and lactation. No developmental effects were
observed in offspring of pregnant rabbits given fosphenytoin; malformations have been reported in
offspring of pregnant rabbits given phenytoin. Perinatal/postnatal effects in rats include decreased
growth of offspring and behavioural toxicity. Fosphenytoin had no effect on fertility in male rats. In
females, altered oestrous cycles, prolonged gestation, and delayed mating were observed.
Page 37

5/24/16 8:16 AM

6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
- Water for injection,
- Trometamol buffer,
- Hydrochloric acid (for pH adjustment)
6.2. Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
Section 6.6.
6.3. Shelf-Life
2 years
6.4. Special Precautions for Storage
Store in a refrigerator (2°C- 8°C).The undiluted product may be stored at room temperature (8°C to
25°C) for up to 24 hours.
6.5. Nature and Contents of Container
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.
Page 38

14408300.indd 38-39

For emergency dosing guidance, please tear off a back page of this booklet

Local irritation following IV or IM dosing or inadvertent perivenous administration was less severe with
fosphenytoin than with phenytoin and was generally comparable to that observed with vehicle injections.
The potential of fosphenytoin to induce intra-arterial irritation was not assessed.

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.
6.6. Instructions for Use, Handling and Disposal
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.
7. MARKETING AUTHORISATION HOLDER
United Kingdom:
Pfizer Limited,
Sandwich,
Kent,
CT13 9NJ
Ireland:
Pfizer Healthcare Ireland
9 Riverwalk,
National Digital Park,
Citywest Business Campus,
Dublin 24, Ireland
Pro-Epanutin is distributed in the UK by Blackstaff Pharmaceuticals Limited.

Page 39

5/24/16 8:16 AM

8. MARKETING AUTHORISATION NUMBER
PL 00057/0551
PA 822/19/1

Please refer to Summary of Product Characteristics for full prescribing details
Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
United Kingdom:
Date of first authorisation: 28th July 2004
Date of latest renewal: 11th September 2009
Ireland:
Date of first authorisation: 27th July 1998
Date of latest renewal: 27th July 2008

ADULT

10. DATE OF REVISION OF THE TEXT
UK: 01/2016
IE: 03/2016

Patient body
weight (kg)

Ref: UK PJ 21_0
14408300

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 40

14408300.indd 40-41

Page 41

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 42

14408300.indd 42-43

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 43

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 44

14408300.indd 44-45

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 45

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 46

14408300.indd 46-47

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 47

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 48

14408300.indd 48-49

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 49

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 50

14408300.indd 50-51

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 51

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 52

14408300.indd 52-53

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 53

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 54

14408300.indd 54-55

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 55

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 56

14408300.indd 56-57

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 57

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus

Please refer to Summary of Product Characteristics for full prescribing details

Please refer to Summary of Product Characteristics for full prescribing details.

Examples of loading doses, diluent volumes and infusion times for a range of patient
body weights for use as a guide in the emergency treatment of Status Epilepticus only

For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial

Patient body
weight (kg)

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 58

14408300.indd 58-59

TEAR HERE

Dose
(mg of PE)

Dose
(ml)

Minimum quantity
of diluent to
add (ml)

Minimum
infusion
time (mins)
10

100

3

1500

30

30

90

3

1350

27

27

9

80

3

1200

24

24

8

3

1050

21

21

70

7

60

2

900

18

18

6

50

2

750

15

15

5

45

2

675

13.5

13.5

4.5

525

10.5

10.5

35
CHILD

ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

ADULT

PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.

Number of vials
necessary for the
preparation of
infusion
(10ml/vials)

2

30

1

450

9

9

25

1

375

7.5

7.5

20

1

300

6

6

15

1

225

4.5

4.5

5

SEE OVERLEAF FOR LOADING DOSE ADMINISTRATION INSTRUCTIONS AND PRECAUTIONS
Page 59

5/24/16 8:16 AM

Recommendation for the IV use of Pro-Epanutin™ in Status Epilepticus
Please refer to Summary of Product Characteristics for full prescribing details.
For adults and children 5 years and over
PRO-EPANUTIN™ fosphenytoin sodium 500 mg PE per 10ml vial
PRO-EPANUTIN should always be prescribed and dispensed in Phenytoin Sodium
Equivalents (mg PE). It is important to strictly respect this method of administration.
ADMINISTRATION OF THE LOADING DOSE
1 Only use after failure to control status epilepticus with a benzodiazepine (eg. diazepam IV)
2 Administer 15 mg of PE/kg of Pro-Epanutin
• Dilute the dose in a solution of 5% glucose or in a solution of 0.9% sodium chloride to obtain
a concentration of Pro-Epanutin of between 1.5 and 25 mg of PE/ml.
• Infusion must not exceed more than 150 mg of PE/minute for adults and 3 mg of PE/kg/minute
for children.
3 Monitor ECG, blood pressure and respiratory function during and after the infusion (particularly
in the first 30 minutes following administration).
4 Elderly, patients with renal or hepatic disease: A lower loading dose and/or infusion rate, and
lower or less frequent maintenance dosing may be required. A 10-25% reduction in dose or rate
may be considered, and careful clinical monitoring is required.

PLEASE TURN OVER FOR GUIDANCE ON DOSING, DILUTION AND INFUSION
Page 60

00.indd 60

5/24/16 8:

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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