1.0 TRADE NAME OF THE MEDICINAL PRODUCT 

Episenta 150 mg prolonged-release capsule, Episenta 300 mg prolonged-release capsule, Episenta 500 mg prolonged-release granules and Episenta 1000 mg prolonged-release granules.

2.0 QUALITATIVE AND QUANTITATIVE COMPOSITION  

Each prolonged-release capsule contains Sodium Valproate 150 mg or 300mg.
Each sachet of prolonged-release granules contains Sodium Valproate 500mg or 1000 mg

For excipients see 6.1

3.0 PHARMACEUTICAL FORM 

Sachets or prolonged-release capsule, hard (blue and transparent) containing white or almost white, round, film-coated, prolonged-release granules.

4.0 CLINICAL PARTICULARS 

4.1 Therapeutic indications 
Sodium valproate is used in the treatment of all forms of epilepsy.

4.2 Posology and method of administration 
Dosage requirements vary according to age and body weight and should be adjusted individually to achieve adequate seizure control. The daily dosage should be given in 1 - 2 single doses.

Monotherapy: usual requirements are as follows:

Adults: Dosage should start at 600mg daily increasing by 150-300mg at three day intervals until control is achieved. This is generally within the dosage range of 1000mg to 2000mg per day i.e. 20-30mg/kg body weight daily. Where adequate control is not achieved within this range the dose may befurther increased to a maximum of 2500mg per day.

Children over 20kg: Initial dosage should be 300mg/day increasing until control is achieved. This is usually within the range 20-30mg/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.

Children under 20kg: 20mg/kg of body weight per day; in severe cases this may be increased up to 40mg/kg/day.

Use in the elderly: Care should be taken when adjusting dosage in the elderly since the pharmacokinetics of sodium valproate are modified. 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. Dosage should be determined by seizure control.

In patients with renal insufficiency: It may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.

Combined Therapy: In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with liver enzyme inducing drugs such as phenytoin, phenobarbitone and carbamazepine.

When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

Method of administration
For oral administration.

The capsules should be swallowed whole without chewing, with plenty of liquid, such as a full glass of water. For patients with swallowing difficulties, the contents of the capsule may be used in the same way as sachets.

The contents of the sachet may be sprinkled or stirred into soft food or drinks and swallowed immediately without chewing or crushing the prolonged-release granules. The food or drink should be cold or at room temperature. A mixture of the granules with liquid or soft food should not be stored for future use. If the contents of the sachet are taken in a drink, as some granules may stick to the glass after the drink has been finished, the glass should be rinsed with a small amount of water and this water swallowed as well. The prolonged-release granules should not be given in babies’ bottles as they can block the teat.

When changing from sodium valproate enteric coated tablets to Episenta it is recommended to keep the same daily dose.

4.3   Contraindications
Liver disease. Hypersensitivity to valproate.

4.4 Special warnings and special precautions for use
Clinical symptoms are a more sensitive indicator in the early stages of hepatic failure than laboratory investigations. The onset of an acute illness, especially within the first six months, which may include symptoms of vomiting, lethargy or weakness, drowsiness, anorexia, jaundice or loss of seizure control is an indication for immediate withdrawal of the drug.

Patients should be instructed to report any such signs to the clinician should they occur.

Routine measurement of liver function should be undertaken in those at risk before and during the first six months of therapy including children under three years, especially those with mental retardation, organic brain damage or metabolic disorder.
The drug should be discontinued if signs of liver damage occur or if serum amylase levels are elevated.

Valproic acid inhibits the second stage of platelet aggregation.

If spontaneous bruising or bleeding occurs medication should be withdrawn. It is recommended that patients receiving sodium valproate be monitored for platelet function and clotting time before major surgery.

Withdrawal of sodium valproate or transition to another antiepileptic should be made gradually to avoid precipitation of an increase in seizure frequency.

Sodium valproate may give false positives for ketone bodies in the urine testing of diabetics.

4.5  Interaction with other medicinal products and other forms of interaction
Concomitant use of hepatic enzyme inducers (e.g. barbiturates, carbamazepine, phenytoin) may enhance metabolism of valproic acid, while cimetidine has been reported to decrease clearance. Valproic acid has been reported to have variable effects on blood levels of other hepatically metabolised or highly protein bound agents. Caution is recommended when administering with other drugs affecting clotting (e.g. warfarin, aspirin). Other hepatotoxic drugs should be avoided. Antidepressants and antipsychotics may lower the threshold for convulsions and higher doses of sodium valproate may be needed.

4.6 Pregnancy and lactation
There is an increased incidence of congenital abnormalities in offspring born to mothers with epilepsy, both untreated and treated.

The benefits of anti-epileptic therapy in pregnancy should be evaluated against the possible risks. There have been reports of foetal abnormalities including neural tube defects in women receiving valproate during the first trimester. This incidence has been estimated to be in the region of 1%. Women should be informed of the possible risk and carefully screened by alpha foetoprotein measurement and ultra sound, and if indicated, amniocentesis.

The concentration of valproate in breast milk is very low, between 1% and 10% of total maternal plasma levels, and at this level appears not to have harmful effects on the nursing child.

4.7  Effects on ability to drive and use machines
Sodium valproate in appropriate doses may not impair driving skills but driving should be restricted to patients whose seizures are adequately controlled. Administration of the drug may occasionally induce drowsiness.

4.8  Undesirable effects
Most frequently, gastrointestinal disturbances, particularly on initiation of therapy. Less commonly, increased appetite and weight gain, tremor, drowsiness, ataxia, confusion, headache, reversible prolongation of bleeding time, thrombocytopenia, leucopenia and bone marrow depression have been reported. Occasionally rashes, transient alopecia with regrowth of curly hair. Transient elevation of liver enzyme levels is common and dose related. Liver dysplasia and hepatic failure (rarely fatal) occurs occasionally, usually in the first few months, necessitating withdrawal.

Hyperammonaemia without liver failure, hyperglycinaemia and pancreatitis have been reported.

Congenital malformations have been reported in women receiving anti-epileptic agents including sodium valproate during pregnancy.

4.9  Overdose
Treatment includes induced vomiting, gastric lavage, assisted ventilation and forced diuresis.

5.0   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
ATC no.: N03AG01

The mode of action of valproic acid in epilepsy is not fully understood but may involve an elevation of gamma-amino butyric acid levels in the brain.

In certain in-vitro studies, it was reported that sodium valproate could stimulate HIV replication, but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed, the effect of sodium valproate on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.

5.2  Pharmacokinetic properties
With per oral administration 90-100% of the dose is rapidly absorbed. Maximal plasma concentration is achieved with Episenta within 6,5 ± 3,3 hours. The half-life is 12-16 h in most patients but can in exceptional cases be considerably lower. Impaired renal function prolongs the half-life. In infants under 2 months the half-life can be prolonged up to 60 hours but in older children it is the same as in adults.

Steady-state concentration is normally achieved after treatment in 3-5 days. A satisfactory effect is most often achieved at 50 - 100 μg/ml, but the patient's overall situation must be considered.

The relation between dose and effect, and between plasma concentration and effect, has not been fully clarified. The CSF concentration is up to 10% of the plasma concentration. About 90% of sodium valproate is bound to plasma protein, which may entail a risk for clinically significant interactions with other antiepileptics, primarily phenytoin. Sodium valproate is metabolized to a great extent and is excreted in the urine as conjugated metabolites. Sodium valproate crosses the placental barrier and concentrations in fetal plasma are comparable to those in the mother.

Valproic acid passes into breast milk but is not likely to influence the child when therapeutic doses are used.

5.3   Preclinical safety data
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.0 PHARMACEUTICAL  PARTICULARS

6.1 List of excipients 

Prolonged-release granule: calcium stearate, silicon dioxide (methylated), ammonia methacrylate copolymer type B, sodium lauryl sulphate, polysorbate 80.

Granule coating: ethylcellulose, dibutylsebacate, oleic acid,
Capsule shell: gelatine, indigo carmine (E132), sodium lauryl sulphate.

6.2 Incompatibilities 

None known

6.3 Shelf life  

36 Months

6.4 Special precautions for storage 

Do not store above 30 °C. Store in the original container. Keep the container tightly closed. 

6.5 Nature and contents of container 

Polypropylene container with polyethylene stopper containing 50, 100 or 200 prolonged-release capsules or 50, 100 or 200 Clay coated kraftpaper/Aluminium/PE sachets.

6.6. Instructions for use/handling 

None

7.0 MARKETING AUTHORISATION HOLDER 

Beacon Pharmaceuticals Ltd. 85, High Street, Tunbridge Wells, Kent TN1 1YG

8.0 MARKETING AUTHORISATION NUMBER 

Episenta 150 mg prolonged-release capsule PL 18157/0021
Episenta 300 mg prolonged-release capsule PL 18157/0022

Episenta 500 mg prolonged-release granules PL 18157/0023
Episenta 1000 mg prolonged-release granules PL 18157/0024

9.0 DATE OF FIRST AUTHORISATION

29th November 2006

10.0 DATE OF (PARTIAL) REVISION OF TEXT