EPILIM Powder and solvent for solution for injection / infusion Ref.[7407] Active ingredients: Valproic acid

Epilim Intravenous may be given by direct slow intravenous injection or by infusion using a separate intravenous line in normal saline, dextrose 5%, or dextrose saline.

Dosage

Daily dosage requirements vary according to age and body weight.

To reconstitute, inject the solvent provided (4 ml) into the vial, allow to dissolve and extract the appropriate dose. Due to displacement of solvent by sodium valproate the concentration of reconstituted sodium valproate is 95 mg/ml.

Each vial of Epilim Intravenous is for single dose injection only. It should be reconstituted immediately prior to use and infusion solutions containing it used within 24 hours. Any unused portion should be discarded (see section 6.6).

Epilim Intravenous should not be administered via the same IV line as other IV additives. The intravenous solution is suitable for infusion by PVC, polyethylene or glass containers.

Patients already satisfactorily treated with Epilim may be continued at their current dosage using continuous or repeated infusion. Other patients may be given a slow intravenous injection over 3–5 minutes, usually 400–800 mg depending on body weight (up to 10 mg/kg) followed by continuous or repeated infusion up to a maximum of 2500 mg/day.

Epilim Intravenous should be replaced by oral Epilim therapy as soon as practicable.

Use with children

Daily requirement for children is usually in the range 20–30 mg/kg/day and method of administration is as above. Where adequate control is not achieved within this range the dose may be increased up to 40 mg/kg/day but only in patients in whom plasma valproic acid levels can be monitored. Above 40 mg/kg/day clinical chemistry and haematological parameters should be monitored.

Use in the elderly

Although the pharmacokinetics of Epilim are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.

In patients with renal insufficiency

It may be necessary to decrease the dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2).

In patients with hepatic insufficiency

Salicylates should not be used concomitantly with Epilim since they employ the same metabolic pathway (see sections 4.4 and 4.8).

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 and 4.4).

Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome). In addition in conjunction with Epilim, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1).

Female children and women of childbearing potential

Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see sections 4.3, 4.4 and 4.6).

Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (see sections 4.3 and 4.4). The benefits and risks should be carefully reconsidered at regular treatment reviews (see section 4.4).

Valproate should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see section 4.6).

Combined Therapy

When starting Epilim in patients already on other anti-convulsants, these should be tapered slowly; initiation of Epilim therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5–10 mg/kg/day when used in combination with anti-convulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Epilim. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

NB: In children requiring doses higher than 40 mg/kg/day clinical chemistry and haematological parameters should be monitored.

Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2).

Cases of accidental and deliberate Epilim overdose have been reported. At plasma concentrations of up to 5–6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.

Signs of acute massive overdose, i.e. plasma concentration 10–20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension and circulatory collapse/shock. A favourable outcome is usual, however some deaths have occurred following massive overdose.

Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2 Pharmacokinetic Properties). Cases of intracranial hypertension related to cerebral oedema have been reported.

The presence of sodium content in the Epilim formulations may lead to hypernatraemia when taken in overdose.

Hospital management of overdose should be symptomatic, including cardio-respiratory monitoring. Gastric lavage may be useful up to 10–12 hours following ingestion.

Haemodialysis and haemoperfusion have been used successfully.

Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally.

In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.

36 months as unopened vial of freeze-dried powder. 60 months as unopened ampoule of Water for Injection. 24 hours after reconstitution and dilution for use as infusion solution (see sections 6.4 and 6.6).

Epilim freeze-dried powder: No specific storage conditions.

Solvent: No specific storage conditions.

Reconstituted infusion solutions: at 2–8°C if stored before use, discarding any remaining solution after 24 hours.

Colourless, Type I glass vial flat base for lyophilisation. Closed by a slotted, chlorobutyl rubber stopper, secured by an aluminium collar and a plastic flip-off cap. The vial is supplied packed in a cardboard carton along with one colourless Type I glass, bottle-shaped ampoule containing 4 ml of solvent (Water for Injection).

For intravenous use, the reconstituted solution should be used immediately and any unused portion discarded.

If the reconstituted solution is further diluted for use as an infusion solution, the dilute solution may be stored for up to 24 hours if kept at 2–8°C before use, discarding any remaining after 24 hours.