Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Aventis Pharma Limited, One Onslow StreetGuildford, Surrey, GU1 4YS, UK or trading as: Sanofi-aventis or Sanofi, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Treatment of generalised, partial or other epilepsy.
Epilim Chronosphere is a pharmaceutical form for oral administration, particularly suitable for children (when they are able to swallow soft food) and adults with swallowing difficulties.
Epilim Chronosphere is a controlled release formulation of Epilim, which reduces peak concentration and ensures more even plasma concentration throughout the day. Epilim Chronosphere may be given once or twice daily.
In patients where adequate control has been achieved, Epilim Chronosphere formulations are interchangeable with other conventional or prolonged release formulations of Epilim on an equivalent daily dosage basis.
Daily dosage should be established according to age and body weight and should be given to the nearest whole 50 mg sachet. Partial sachets should not be used. However, the wide individual sensitivity to valproate should also be considered.
Usual requirements are as follows:
Dosage should start at 600 mg daily increasing by 200 mg at three-day intervals until control is achieved. This is generally within the dosage range 1000–2000 mg per day, i.e. 20–30 mg/kg/day body weight (to the nearest whole 50 mg sachet). Where adequate control is not achieved within this range the dose may be further increased to 2500 mg per day.
Initial dosage should be 400 mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20–30 mg/kg body weight per day (to the nearest whole 50 mg sachet. Where adequate control is not achieved within this range the dose may be increased to 35 mg/kg body weight per day. Above 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.
20 mg/kg of body weight per day (to the nearest whole 50 mg sachet); in severe cases this may be increased but only in patients in whom plasma valproic acid levels can be monitored. Above 40 mg/kg/day, clinical chemistry and haemotological parameters should be monitored.
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.
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).
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 failures 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).
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. The daily dose should be divided into at least two single doses (see section 4.6).
When starting Epilim Chronosphere 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 Chronosphere. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.
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).
Epilim Chronosphere modified release granules should be sprinkled on a small amount of soft food or in drinks, which should be cold or at room temperature, for example yoghurt, mousse, jam, ice-cream, milk shake, orange juice or something similar.
If the granules are taken in a drink, after the drink has been finished the glass should be rinsed with a small amount of water and this water should be taken as well, as some granules may stick to the glass.
The mixture of food or drink and granules should be swallowed immediately; the granules should not be crushed or chewed.
A mixture of the granules with liquid or soft food should not be stored for future use.
Epilim Chronosphere modified release granules should not be sprinkled on warm or hot foods and drinks, for example soup, coffee, tea, or something similar.
If preferred the granules can be poured directly into the mouth and washed down with a cold drink.
Epilim Chronosphere modified release granules should not be given in babies' bottles as they can block the nipple.
In view of the sustained release process and the nature of the excipients in the formula, the inert matrix of the granules is not absorbed by the digestive tract; it is eliminated in the stools after the active substances have been released.
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, 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 overdose, haemodialysis and haemoperfusion have been used successfully.
24 months.
Do not store above 25°C. Store in the original packaging. Do not refrigerate or freeze.
Epilim Chronosphere MR 50 mg modified release granules are filled into sachets of a paper/aluminium/ionomer resin complex.
Epilim Chronosphere sachets are available in cartons of 30 and 50 sachets.
See 4.2. Posology and Method of Administration.
This medicinal product must not be administered with hot meals or drinks.
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