EPANUTIN READY MIXED Solution for injection or infusion Ref.[7332] Active ingredients: Phenytoin

Method of administration

For parenteral administration.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Parenteral Epanutin is suitable for use as long as it remains free of haziness and precipitate. Upon refrigeration or freezing a precipitate might form; this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. Only a clear solution should be used. A faint yellow colouration may develop, however, this has no effect on the potency of this solution.

There is a relatively small margin between full therapeutic effect and minimally toxic doses of this drug. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 mcg/mL and 20 mcg/mL (40-80 micromoles/l).

Because of the risk of local toxicity, intravenous phenytoin should be injected slowly directly into a large vein through a large-gauge needle or intravenous catheter.

Each injection or infusion of intravenous Epanutin should be preceded and followed by an injection of sterile saline through the same needle or catheter to avoid local venous irritation due to alkalinity of the solution (see section 4.4. Local Toxicity (including Purple Glove Syndrome)).

For infusion administration the parenteral phenytoin should be diluted in 50 ml-100 ml of normal saline, with the final concentration of phenytoin in the solution not exceeding 10 mg/ml. Administration should commence immediately after the mixture has been prepared and must be completed within one hour (the infusion mixture should not be refrigerated). An in-line filter (0.22 microns-0.50 microns) should be used.

The diluted form is suitable for use as long as it remains free of haziness and precipitate.

Parenteral Epanutin should neither be mixed with other drugs nor be added to dextrose or dextrose-containing solutions due to the potential for precipitation of phenytoin acid.

Continuous monitoring of the electrocardiogram and blood pressure is essential. Cardiac resuscitative equipment should be available. The patient should be observed for signs of respiratory depression. If administration of intravenous Epanutin does not terminate seizures, the use of other measures, including general anaesthesia, should be considered.

Epanutin Ready Mixed Parenteral contains phenytoin sodium whereas Epanutin Suspension and Epanutin Infatabs contain phenytoin. Although 100 mg of phenytoin sodium is equivalent to 92 mg of phenytoin on a molecular weight basis, these molecular equivalents are not necessarily biologically equivalent. Physicians should therefore exercise care in those situations where it is necessary to change the dosage form and serum level monitoring is advised.

Posology

Status Epilepticus

In a patient having continuous seizure activity, as compared to the more common rapidly recurring seizures, i.e. serial epilepsy, injection of intravenous diazepam or a short acting barbiturate is recommended because of their rapid onset of action, prior to administration of Epanutin.

Following the use of diazepam in patients having continuous seizures and in the initial management of serial epilepsy a loading dose of Epanutin 10 mg/kg-15 mg/kg should be injected slowly intravenously, at a rate not exceeding 50 mg per minute in adults (this will require approximately 20 minutes in a 70 kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6 to 8 hours.

Recent work in neonates has shown that absorption of phenytoin is unreliable after oral administration, but a loading dose of 15 mg/kg-20 mg/kg of Epanutin intravenously will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range (10 mcg/mL-20 mcg/mL).

The drug should be injected slowly intravenously at a rate of 1-3 mg/kg/min.

Determination of phenytoin serum levels is advised when using Epanutin in the management of status epilepticus and in the subsequent establishing of maintenance dosage. The clinically effective level is usually 10 mcg/mL–20 mcg/mL although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin.

Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours.

Use in Cardiac Arrhythmias

Dosage 3.5 mg per kg-5 mg per kg of bodyweight intravenously initially, repeated once if necessary. The solution should be injected slowly, intravenously and at a uniform rate which should not exceed 1 ml (50 mg) per minute.

Other clinical conditions

It is not possible to set forth a universally applicable dosage schedule.

The intravenous route (IV) of administration is preferred. Dosage and dosing interval will, of necessity, be determined by the needs of the individual patient. Factors such as previous antiepileptic therapy, seizure control, age and general medical condition must be considered. Notwithstanding the slow absorption of Epanutin, when given intramuscularly, its use in certain conditions may be appropriate.

When short-term intramuscular administration is necessary for a patient previously stabilised orally, compensating dosage adjustments are essential to maintain therapeutic serum levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose, for the same period of time the patient received Epanutin intramuscularly, to prevent excessive serum levels due to continued release from intramuscular tissue sites.

Neurosurgery

In a patient who has not previously received the drug, Parenteral Epanutin 100 mg-200 mg (2-4 ml) may be administered intramuscularly at approximately 4-hour intervals prophylactically during neurosurgery and continued during the post-operative period for 48-72 hrs. The dosage should then be reduced to a maintenance dose of 300 mg and adjusted according to serum level estimations.

If the patient requires more than a week of intramuscular Epanutin, alternative routes should be explored such as gastric intubation. For time periods less than one week, the patient switched from intramuscular administration should receive one half the original oral dose for the same period of time the patient received Epanutin intramuscularly.

Measurement of serum levels is of value as a guide to an appropriate adjustment of dosage.

Dosing in Special Populations

Patients with Renal or Hepatic Disease

See section 4.4.

Elderly (over 65 years)

Phenytoin clearance may be decreased in elderly patients and lower or less frequent dosing may be required (see section 5.2 – Special Populations – Age). As for adults, however, complications may occur more readily in older people.

Paediatric population

It has been shown that children tend to metabolise phenytoin more rapidly than adults. This should be borne in mind when determining dosage regimens; the use of serum level monitoring being particularly beneficial in such cases.

Neonates

Recent work in neonates has shown that absorption of phenytoin is unreliable after oral administration, but a loading dose of 15-20 mg/kg of Epanutin intravenously will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range (10 mcg/mL-20 mcg/mL).

The drug should be injected slowly intravenously at a rate of 1 mg/kg/min – 3 mg/kg/min.

The lethal dose in children is not known. The mean lethal dose in adults is estimated to be 2 g to 5 g. The initial symptoms are nystagmus, ataxia and dysarthria. Other signs are tremor, hyperflexia, lethargy, nausea and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.

Attempts to relate serum levels of the drug to toxic effects have shown wide interpatient variation. Nystagmus on lateral gaze usually appears at 20 mcg/mL, and ataxia at 30 mcg/mL, Dysarthria and lethargy appear when the serum concentration is >40 mcg/mL, but a concentration as high as 50 mcg/mL has been reported without evidence of toxicity.

As much as 25 times the therapeutic dose, which resulted in a serum concentration of 100 mcg/mL, was taken with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment

Treatment is non-specific since there is no known antidote.

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 presence of other Central Nervous System (CNS) depressants, including alcohol, should be borne in mind.

Shelf life

Unopened: 30 months.

Once opened, use immediately and discard any unused contents.

Do not store above 25°C. Keep the ampoule in the outer carton.

5 ml, colourless neutral glass, Type 1, Ph Eur, with a white colour break band. Each pack contains 10 ampoules.

For single use only.

Epanutin Ready Mixed Parenteral should be used immediately after opening. Discard any unused product once opened. See sections 4.2 and 6.2 for further information.

The product should not be used if a precipitate or haziness develops in the solution in the ampoule.

Any unused medicinal product or waste should be disposed of in accordance with local requirements.