Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: G.L. Pharma GmbH, Schlossplatz 1, A-8502 Lannach, Austria
Treatment of primary generalised epileptic seizures, secondary generalised epileptic seizures, and partial epileptic seizures.
Treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to Epival CR for acute mania.
Epival CR prolonged-release tablets are a prolonged-release formulation of sodium valproate which reduces peak concentration and ensures more even plasma concentrations throughout the day.
Daily dosage requirements vary according to age and body weight. 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).
Valproate must be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see sections 4.4 and 4.6) and the benefit and risk should be carefully reconsidered at regular treatment reviews.
Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (sections 4.3 and 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).
Usual requirements are as follows:
Adults:
Dosage should start at 600 mg (5-10 mg/kg body weight) daily, followed by gradual increases of 5-10 mg/kg at 3-7 day intervals until control is achieved. This is generally within the dosage range 1000 mg to 2000 mg per day, i.e. 20-30 mg/kg body weight. Where adequate control is not achieved within this range, the dose may be further increased up to 2500 mg per day.
Paediatic population:
For children the starting dose for sodium valproate is 10-20 mg/kg and the maintenance dose between 20 and 30 mg/kg; doses higher than 40 mg/kg daily may be required in individual cases. (See dosage table for orientation.)
Children over 20 kg: The recommended starting dose for Epival CR prolonged-release tablets is 300 mg/day with increases at 3-7 day intervals until control is achieved; this is usually within the range 20-30 mg/kg body weight per day. Where adequate control is not achieved within this range, the dose may be increased to 35 mg/kg body weight per day. In children requiring doses higher than 40mg/kg/day, clinical chemistry and haematological parameters should be monitored.
Children under 20 kg: An alternative formulation of valproate should be used in this group of patients, due to the need for dose titration.
Elderly patients:
The pharmacokinetics of valproate may be altered in the elderly. Dosage should be determined by seizure control. (see 5.2).
The following daily doses for sodium valproate are recommended (table for orientation purposes):
| Age | Body weight (kg) | Average dose (mg/day) |
|---|---|---|
| 3 – 6 months | ≈ 5.5 – 7.5 | 150 |
| 6 – 12 months | ≈ 7.5 – 10 | 150 – 300 |
| 1 – 3 years | ≈ 10 – 15 | 300 – 450 |
| 3 – 6 years | ≈ 15 – 20 | 450 – 600 |
| 7 – 11 years | ≈ 20 – 40 | 600 – 1200 |
| 12 – 17 years | ≈ 40 – 60 | 1000 – 1500 |
| Adults and elderly | ≥ 60 | 1200 – 2100 |
Patients with renal insufficiency and/or hepatic dysfunction:
It may be necessary in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. valproate is dialysable (see section 4.9). Dosing should be modified according to clinical monitoring of the patient (see section 4.4). Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading. (See 5.2. Pharmacokinetic properties.)
When starting Epival CR prolonged-release tablets in patients already on other anticonvulsants, these should be tapered slowly; initiation of therapy with Epival CR prolonged-release tablets 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 to 10 mg/kg/day when used in combination with anticonvulsants 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 Epival CR prolonged-release tablets. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.
The daily dosage should be established and controlled individually by the treating physician.
The initial recommended daily dose is 750 mg. In addition, in clinical trials a starting dose of 20 mg valproate/kg body weight has also shown an acceptable safety profile. Prolonged-release formulations can be given once or twice daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient.
The mean daily dose usually ranges between 1000 and 2000 mg valproate. Patients receiving daily doses higher than 45mg/kg/day body weight should be carefully monitored.
Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.
The efficacy of Epival CR prolonged-release tablets in children below 18 years of age in the treatment of manic episodes of bipolar disorder has not been established. With respect to safety information in children see section 4.8.
Epival CR prolonged-release tablets are for oral use.
Epival CR prolonged-release tablets should be given once or twice daily. The tablets should be swallowed whole with fluid and not crushed or chewed. If at the start or during treatment gastrointestinal irritation occurs, Epival CR prolonged-release tablets should be taken with or after food (see section 4.8).
Cases of accidental and deliberate valproate overdosage have been reported. At plasma concentrations of up to 5 to 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.
In massive overdose, i.e. with plasma concentrations 10 to 20 times maximum therapeutic levels, there may be serious CNS depression and respiration may be impaired.
Symptoms and signs of massive overdose usually include coma, muscular weakness, hyporeflexia/areflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension and circulatory collapse/shock. However, the symptoms may be variable and seizures have been reported in the presence of very high plasma levels (see section 5.2). Cerebral oedema and intracranial hypertension have been reported. Single cases of massive overdose with a fatal outcome have been published. The presence of sodium content in the valproate formulations may lead to hypernatraemia when taken in overdose.
No specific antidote is known.
Management of overdose should be symptomatic, including activities to eliminate the active substance and support of vital functions: Gastric lavage (up to 10 to 12 hours following ingestion) with aspiration protection and monitoring within the scope of intensive care, if necessary.
Haemodialysis and forced diuresis have been used successfully, however, only the free portion of valproic acid (approx. 10%) is eliminated. Peritoneal dialysis shows little effect. Insufficient experience is available regarding the effect of charcoal haemoperfusion, total plasma replacement and plasma transfusion. Therefore intensive internistic treatment without any particular method of detoxification, especially in children, but with drug level monitoring, is recommended.
In a few cases naloxone has been successfully used for improving the patient’s state of consciousness.
5 years.
Keep the container tightly closed.
a) Amber glass tablet container (hydrolytic resistance type III, Ph.Eur.) with HDPE tamper-resistant white screw-cap, and HDPE white tear-band lid further packed into a cardboard carton.
Or alternatively
b) HDPE cylindrical tablet container with LDPE tamper-resistant snap-on cap with LDPE tear-band lid and LDPE sealing ring further packed into a cardboard carton
Pack sizes: 30, 50, 100 tablets.
No special requirements.
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