DEPAKINE CHRONO Prolonged-release tablet Ref.[51019] Active ingredients: Valproic acid

Depakine Chrono 500 mg is for oral administration.

Daily dosage administration varies according to age and body weight.

Depakine Chrono is a slow release formulation of Depakine which reduces the peak concentration and ensures more even plasma concentrations throughout the day.

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.

Depakine Chrono may be given once or twice daily. The tablets should be swallowed whole and not crushed or chewed.

In patients where adequate control has been achieved Depakine Chrono formulations are interchangeable with other conventional or slow release formulations on an equivalent daily dosage basis.

Manic episodes in Bipolar Disorder

In Adults

The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750mg. In addition, in clinical trials a staring dose of 20mg 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 desire 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 that 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.

In children and adolescents

The efficacy of Depakine Chrono 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.

Female children and women of childbearing potential

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.

Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Program (see section 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).

Dosage in Epilepsy

Usual requirements are as follows

Adults:

Dosage should start at 600mg daily increasing by 200mg at three-day intervals until control is achieved. This is generally within the dosage range 1000mg to 2000mg per day, i.e. 20-30mg/kg/day body weight. Where adequate control is not achieved within this range the dose may be further increased to 2500mg per day.

Paediatric population:

Over 20kg:

Initial dosage should be 400mg/day (irrespective of weight) with spaced increases 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 35mg/kg body weight per day.

Under 20kg:

An alternative formulation of Depakine should be used in this group of patients, due to the tablet size and need for dose titration. Among the oral pharmaceutical forms, the following formulations are more appropriate for administration to children less than 11 years (syrup, oral solution, and granules).

Elderly:

Although the pharmacokinetics of Depakine 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 in patients with renal insufficiency to decrease the dosage, or to increase the dosage in patients on haemodialysis. Sodium valproate is dialysable (see section 4.9). Dosing should be modified according to clinical monitoring of the patient (see section 4.4).

Combined Therapy

When starting Depakine in patients already on other anticonvulsants, these should be tapered slowly; initiation of Depakine 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 to 10mg/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 Depakine. 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 40mg/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 Pharmacokinetic Properties).

Signs and symptoms

Signs of acute massive overdose usually include a coma, with muscular hypotonia, hyporeflexia, miosis, impaired respiratory functions metabolic acidosis, hypotension and circulatory collapse/shock.

Deaths have occurred following massive overdose; nevertheless, a favourable outcome is usual.

Symptoms may however be variable, and seizures have been reported in the presence of very high plasma levels. Cases of hypertension intracranial related to cerebral edema have been reported.

The presence of sodium content in the valproate formulations may lead to hepernatraemia when taken in overdose.

Management

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

Naloxone has been successfully used in a few isolated cases. In case of massive overdose, hemodialysis and hemoperfusion have been used successfully.

36 months.

Store away from humidity and below 30°C.

Bottle of 30 prolonged-release tablets.

No special requirements.