Hydantoins (anticonvulsants / anti-epileptics) - ATC code: N03AB

Fosphenytoin Sodium

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. 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.

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.

Pro-Epanutin is indicated:

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

• 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.

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.

Phenytoin sodium equivalents (PE):

1.5mg of fosphenytoin is equivalent to 1mg 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 25mg PE/ml.

Because of the risk of hypotension, the recommended rate of administration by IV infusion in routine clinical settings is 50-100mg PE/minute. Even in an emergency, it should not exceed 150mg 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.

DOSAGE IN ADULTS

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 15mg PE/kg administered as a single dose by IV infusion

Recommended IV infusion rate: 100 to 150mg PE/min. ( should not exceed 150mg PE/minute even for emergency use)..

Examples of infusion times are presented in Table 1.

Intramuscular administration of Pro-Epanutin is contra-indicated in the treatment of status epilepticus. If administration of Pro-Epanutin does not terminate seizures, the use of alternative anticonvulsants should be considered.

Table 1:

Status Epilepticus: 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 150mg PE/min by body weight)

Maintenance dose:

The recommended maintenance dose of Pro-Epanutin of 4 to 5mg 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 100mg PE/minute.

Examples of infusion times are provided in Table 2.

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:

Status Epilepticus: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

Treatment or Prophylaxis of Seizures

Loading dose:

The loading dose of Pro-Epanutin is 10 to 15mg PE/kg given as a single dose by IV infusion or by IM injection.

Recommended IV infusion rate for treatment or prophylaxis of seizures:

50 to 100mg PE/minute (should not exceed 150mg PE/minute).

Examples of infusion times are presented in Table 3.

Table 3:

Treatment or Prophylaxis of seizures: Examples for IV loading doses of 10mg PE/kg^a, and recommendations for dilution* (to 25mg PE/ml or to 1.5mg PE/ml) and IV infusion times (at maximum rate of 100mg PE/minute) by body weight

Maintenance dose:

The recommended maintenance dose of Pro-Epanutin of 4 to 5mg 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 100mg PE/minute.

Examples of infusion times are presented in Table 4.

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:

Treatment or Prophylaxis of seizures : 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

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 100mg PE/minute.

Examples of infusion times are presented in Table 5.

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: 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)

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.

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 15mg PE/kg administered as a single dose by IV infusion

Recommended IV infusion rate:2 to 3mg PE/kg/min. (should not exceed 3mg PE/kg/minute or 150mg PE/minute).

The recommended infusion rate is presented in Table 6.

If administration of Pro-Epanutin does not terminate seizures, the use of alternative anticonvulsants should be considered.

Table 6:

Status Epilepticus: Examples of IV loading doses of 15mg PE/kg and recommendations for dilution (to 25mg PE/ml) and IV infusion times (at 3mg PE/kg/minute) by body weight

Maintenance dose:

The recommended maintenance dose of Pro-Epanutin of 4 to 5mg 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 dosing:1 to 2mg PE/kg/minute (should not exceed 100mg PE/minute).

The recommended infusion time is presented in Table 7.

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: 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 2mg PE/kg/minute) by body weight

Pro-Epanutin may be administered to children (ages 5 and above) by  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. As for adults, the recommended rate of IV infusion in routine clinical settings is 50 to 100 mg PE / minute (1 to 2 mg PE / kg / minute). In an emergency for the treatment of status epilepticus, the rate of IV infusion is 100 to 150 mg PE / minute (2 to 3 mg PE / kg / minute) and should not exceed 3 mg PE/kg/minute (150 mg PE/minute). 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.

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.

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.

Phenytoin is not effective in absence seizures. If tonic-clonic seizures are present simultaneously with absence seizures, combined drug therapy is recommended.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.

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.

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 signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, 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.

Published literature has suggested that there may be an increased risk of hypersensitivity reactions, including skin rash, SJS and TEN 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.

Anticonvulsant Hypersensitivity Syndrome and Hepatoxicity:

Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome, which is potentially fatal and has been associated with anticonvulsant administration, including phenytoin. Fever, skin eruptions, lymphadenopathy, and other multiorgan pathologies may occur within the first 2-4 weeks of treatment but has also been reported in individuals receiving anticonvulsants for 3 or more months. The mechanism is not known. Hepatotoxicity is often associated with this hypersensitivity syndrome. Acute hepatotoxicities, including acute hepatic failure, jaundice, hepatomegaly and elevated serum transaminase levels have also been reported. Recovery from acute hepatotoxicity may be prompt, however fatal outcomes have also occurred.

Pro-Epanutin should be discontinued immediately following signs of acute hepatotoxicity and not readministered. Leucocytosis, eosinophilia and arthralgias may also occur.

Although still rare, there may be an increased incidence of hypersensitivity reactions in black patients, patients who have a family history of or who have experienced this syndrome in the past and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals. If a patient is diagnosed with AHS, discontinue the fosphenytoin or phenytoin and provide appropriate supportive measures.

Lymphadenopathy:

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 serum sickness, e.g. fever, rash and liver involvement, as part of the hypersensitivity syndrome 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 may occur if plasma phenytoin concentrations are sustained above the optimal therapeutic range. Plasma phenytoin concentrations should be determined at the first sign of acute toxicity. 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. 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.

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.

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. Phenytoin clearance, thus plasma levels, might be affected by inhibitors (e.g. sulfaphenazole, fluconazole, voriconazole, fluvoxamine, omeprazole, ticlopidine) and inducers (e.g. rifampicin, St John's Wort, carbamazepine) of these 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.

The following drug interactions are the most commonly occurring drug interactions with phenytoin:

Drugs that may increase plasma phenytoin concentrations listed by likely mechanism (where known):

Drugs that may decrease plasma phenytoin concentrations listed by likely mechanism (where known):

*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 (where known):

Similarly, the effects of phenytoin on plasma phenobarbital, sodium valproate and valproic acid concentrations are unpredictable.

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

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.

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'.

No trends in laboratory changes were observed in Pro-Epanutin treated patients.

Pfizer Limited

(POM)

14 February 2012