SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

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

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 in adults and children aged 5 years and older:

•    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 (aged 5 years and older)	Status epilepticus	Loading dose	Table 6
	Status epilepticus	Maintenance dose	Table 7
	Seizure treatment or prophylaxis	Loading dose	Table 8
	Seizure treatment or prophylaxis	Maintenance dose	Table 9
	Temporary substitution for oral phenytoin		Table 10

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 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
Weigh t (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).

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 TREATMENT OR PROPHYLAXIS OF SEIZURES LOADING DOSE (ADULTS)
Examples for IV loading doses of 10mg I PE/ml or to 1.5mg PE/ml) and IV infusi<				*E/kga, and recommendations for dilution* (to 25mg m 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 concentratio n 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).

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 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 concentrati on 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 (AGED 5 YEARS AND OLDER)

Pro-Epanutin may be administered to children (ages 5 years and older) by IV infusion only, at the same mg PE/kg dose used for adults. The doses of Pro-Epanutin for children have been predicted from the known pharmacokinetics of Pro-Epanutin in adults and children aged 5 to 10 years and of parenteral phenytoin in adults and children.

Intramuscular 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.

RecommendedIV 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 STATUS EPILEPTICUS LOADING DOSE (CHILDREN AGED 5 YEARS AND OLDER)
Examples of IV l PE/ml		oading doses of 15mg PE/kg and recommendation and IV infusion times (at 3mg PE/kg/minute) by			s for dilution (to 25mg 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 recommendedinfusion rate of 3mg PE /kg/ minute
		No. of 10ml vials to open	Volume (ml) to draw up
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.

TABLE 7 STATUS EPILEPTICUS MAINTENANCE DOSE

_(CHILDREN AGED 5 YEARS AND OLDER)_

Examples for maximum IV maintenance doses of 5mg PE/kg, recommendations for dilution* (t 25mg PE/ml or to 1.5mg PE/ml) and IV infusion times (at maximum rate of 2mg PE/kg/minute)

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 Infusi Time (mins) to achieve the maximum recommendec infusion rate o 2mg PE /kg/ 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
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.

TABLE 8 TREATMENT OR PROPHYLAXIS OF SEIZURES LOADING DOSE (CHILDREN AGED 5 YEARS AND OLDER)
Examples for IV loading doses of 10mg I PE/ml or to 1.5mg PE/ml) and IV infusio				*E/kga, and recommendations for dilution* (to 25mg n times (at maximum rate of 2mg PE/kg/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 2mg PE /kg/ minute
		No. of 10ml vials to open	Volume (ml) to draw up	for final concentration of 25mg PE/ml	for final concentration of 1.5mg PE/ml
35	350	1	7	7	226	5
32.5	325	1	6.5	6.5	210	5
30	300	1	6	6	194	5
27.5	275	1	5.5	5.5	178	5
25	250	1	5	5	161	5
22.5	225	1	4.5	4.5	145	5
20	200	1	4	4	129	5
17.5	175	1	3.5	3.5	113	5
*For IV infusion the final concentration should range between 1.5 to 25 mg PE/ml a 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.

phenytoin concentrations (see Therapeutic Drug Monitoring).

Transfer to maintenance therapy with oral phenytoin should be made when appropriate.

TABLE 9 TREATMENT OR PROPHYLAXIS OF SEIZURES MAINTENANCE DOSE (CHILDREN AGED 5 YEARS AND OLDER)
Examples for maximum IV maintenance doses of 5mg PE/kg, recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/kg), and IV infusion times (at a maximum rate of 2mg PE/kg/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 2mg PE /kg/ 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
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.

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 Temporary Substitution of Oral Phenytoin Therapy _(Children AGED 5 YEARS AND OLDER)_

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 2mg PE/kg/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 Infusio Time (mins)
5mg/kg		No. of 10ml vials to open	Volume (ml) to draw up	for final concentrati on of 25 mg PE/ml	for final concentration of 1.5mg PE/ml	to achieve the maximum recommended infusion rate of 2mg PE /kg/ minute
175	175	1	3.5	3.5	113	2.5
150	150	1	3	3	97	2.5
125	125	1	2.5	2.5	81	2.5
100	100	1	2	2	65	2.5
75	75	1	1.5	1.5	49	2.5
50	50	1	1	1	32	2.5

*For IV infusion the final concentration should range between 1.5 to 25 mg PE/ml

ELDERLY PATIENTS

A lower loading dose and/or infusion rate, and lower or less frequent maintenance dosing of Pro-Epanutin may be required. Phenytoin metabolism is slightly decreased in elderly patients. A 10% to 25% reduction in dose or rate may be considered and careful clinical monitoring is required.

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 Adams-Stokes 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.

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 antiepileptic 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.

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 Stevens-Johnson 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 re-administered.

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.

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.

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 drug-metabolising 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:

Drugs that may increase serum phenytoin concentrations listed by likely mechanism:

Drug	Mechanism
Antineoplastic agents (fluorouracil)	CYP2C9 inhibition

Azole antifungals (ketoconazole, itraconazole, fluconazole, miconazole) Capecitabine Fluvastatin Glibenclamide Sulfaphenazole
Felbamate	CYP2C19 inhibition
Oxcarbazepine
Topiramate
Azapropazone	CYP2C9/2C19
Fluvoxamine	inhibition
Nifedipine
Sertraline
Ticlopidine
Tolbutamide
Voriconazole
Acute alcohol intake	Unknown mechanism
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

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

Drug	Mechanism
Rifampicin	CYP2C/2C19 induction
Antineoplastic agents (bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate) Chronic alcohol abuse Diazoxide Folic acid Fosamprenavir Nelfinavir* Theophylline	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	Unknown
Carbamazepine
Chlordiazepoxide
Ciprofloxacin
Diazepam
Phenobarbital
Phenothiazines
Sodium valproate
Valproic acid
Certain antacids

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

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

Albendazole	Unknown
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

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 (GGT). Phenytoin may affect blood calcium and blood sugar metabolism tests.

Phenytoin has the potential to lower serum folate levels.

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).

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, breast-feeding 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 Undesirable Effects).

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.

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

Uncommon 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 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 of sodium channels may be a primary anticonvulsant mechanism because this property is shared with several other anticonvulsants in addition to phenytoin.

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.

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.

Route	Dose (mg PE)	Dose (mg PE/k g)	Infusion Rate (mg PE/min)	Fosphenytoin			Total Phenytoin		Free (Unbound) Phenytoin
				Cmax (pg/ml)	tmax (hr)	t/ (min)	Cmax (pg/ml)	Tmax (hr)	Cmax (pg/ml)	tmax (hr)
Intramuscular	855	12.4	--	18.5	0.61	41.2	4.3	3.23	2.02	4.16
Intravenous	1200	15.6	100	139	0.19	18.9	6.9	1.18	2.78	0.52
Intravenous	200	15.6	150	156	0.13	20.5	28.2	0.98	3.18	0.58

Fosphenytoin dose (phenytoin sodium equivalents [mgPE] or phenytoin sodium equivalents/kg [mg PE/kg]).

Fosphenytoin infusion rate (mg phenytoin sodium equivalents/min [mg PE/min]). Maximum plasma analyte concentration (pg/ml).

Time of Cmax (hr).

Terminal elimination half-life (min).

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. Posology and Method of Administration).

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. Posology and Method of Administration).

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 concentration-time 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.

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 intraarterial irritation was not assessed.

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.

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.

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    Special precautions for 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

Pfizer Limited

Sandwich

Kent

CT13 9NJ United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00057/0551

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28^th July 2004 Date of latest renewal: 11^th September 2009

10 DATE OF REVISION OF THE TEXT

01/08/2016