Eftil® retard 500 tablets film-coated
(Sodium Valproate +Valproic Acid)

N03AG02

Antiepileptic

Sastav:
Each retard 500 tablet film-coated tablet contains:
Valproic acid.................………..145 mg
Sodium valproate........................333 mg

Excipients contained in the tablets film-coated tablets include: hipromelose 4000 (3000 mPas); silicone-dioxide, colloid, hydrate; ethyl cellulose 20 mPas; saccharine sodium; silicone-dioxide, colloid, anhydrate. Excipients in the film coating of tablets include: hipromelose
(6 mPas); macrogel 6000; polyacrylate, dispersion 30%; talcum and titanium-dioxide (E 171).

Dejstvo:
Valproates (valproic acid and sodium valproate) are antiepileptic agents characterized with wide anticonvulsant spectrum, primarily effective in prevention and treatment of generalized forms of epilepsy. Besides, they as are used stabilizers of mood valproates for prevention and treatment of mania in bipolar affective disorder. The mechanism of action of valproate on the central nervous system is complex, the main component being increase of GABA (gamma-amino butyric acid), inhibitory neurotransmitter in the brain, reduction of its degradation or increase of its synthesis. Besides, valproates reduce excitatory neurotransmitters (gamma-hydroxybutyric amino acid, glutamic acid) manifesting direct action on neuron membranes and modulating conduction through sodium and potassium channels. Thus, valproates lead to anticonvulsive action and reduce the symptoms of acute manic phase in bipolar affective disorder.

Farmakokinetika:
Eftil® retard 500 tablet film-coated tablet is associated with excellent pharmacokinetic properties. These are: gradual resorption, stable plasma levels without major fluctuations, prolonged action; the drug is taken once or twice a day, which is more patient-friendly. After resorption from the gastrointestinal tract, peak plasma levels are reached in 9-10 h, amounting to 40 and 100 mg/l remaining stable over 24 h. Valproate levels in the cerebrospinal fluid reaches 10% of the corresponding plasma levels; biological half-life is 8-17 h which is, however, shortened with concomitant administration with other antiepileptic agents. Over 90% of valproates bind to plasma, between 70 and 80% of the administered dose are eliminated in the urine, and only a small part via the lungs and bile. Valproates cross into the fetal circulation and are excreted in the breast milk.

Indikacije:
I. Treatment of epilepsy
Eftil® retard 500 tablets film-coated) is indicated for children. It is the first choice drug in cases of primary generalized epilepsy, such as:

- Absence attacks (petit mal epilepsy)

- Myoclonic attacks

- Generalized tonic-clonic seizures (grand mal epilepsy)

- Atonic or akinetic attacks

Sodium valproate is the second choice drug in partial attacks:

- Simple (temporal, psychomotor, Jacksonian epilepsy

- Complex (with loss of consciousness)

- Secondary generalized convulsions

- Mixed forms (generalized and partial)

II. Treatment and prevention of mania in affective bipolar disorder


Doziranje i način primene:
Eftil® retard 500 tablets film-coated are administered orally to adults and children over the age of 15.
Doses are individually adjusted. Therapeutic plasma levels are between 40 and 100 mcg/ml (280-700 micromole/l). For successful control of seizures, as well as for prevention and treatment of mania in bipolar disorders, blood levels should be determined; it is also mandated in cases of unsatisfactory therapeutic effect or when serious side effects are suspected.
The same doses are applied for treatment of epilepsy and mania in bipolar affective disorder. The usual initial dose is 15 mg/kg day, which is gradually increased by 5-10 mg day in 2-3 day intervals, until the optimum dose has been reached over one week. The dose sufficient to control seizures and reduce symptoms of mania in bipolar disorders is usually 20-30 mg/kg day, which is taken as an individual dose or divided into two daily doses. If the underlying condition cannot be controlled by this dose, it may be increased up to 50 mg/kg/day, with careful monitoring of the patient and regular measurements of the blood levels. If a patient was treated with other antiepileptic medication, the retard tablet dose is gradually increased over two weeks until the optimum dosage has been reached, with concomitant reduction of other medication. Discontinuation of Eftil® retard 500 tablets film-coated or transfer to other antiepileptic or mood stabilizer has to be gradual, since abrupt discontinuation may induce exacerbation of the underlying disease.


Neželjena dejstva:
The most severe adverse effect is hepatic impairment that usually develops in the course of the first six months, more frequently in children and with combined anticonvulsive therapy. Symptoms of hepatotoxicity of valproate may be non specific including weakness, lethargy, edema, anorexia, vomiting, abdominal pain, somnolence, jaundice. These symptoms indicate immediate termination of therapy. In case of doubt, prothrombin time should be measured, which is a reliable test for valproate-induced hepatic impairment.
Elevation of hepatic enzymes is not uncommon in the course of valproate therapy; it is usually transitory and may be corrected with dose adjustment (elevation of transaminase (SGOT, SGPT), LDH and bilirubin. Most common side effects at the outset of therapy include gastrointestinal, nausea, vomiting, abdominal pain; they are all transient, while diarrhea, abdominal cramps and constipation are less common. In case of acute pancreatitis, the therapy is terminated. Sedative effect of sodium valproate is observed rarely, and is more common in combination with other antiepileptic medication. Other adverse effects include: tremor, ataxia, headache, somnolence, prolonged bleeding time, thrombocytopenia, petechial bruising, rarely leukopenia, anemia, transient hair loss, skin rash and hyperammoniemia.

Kontraindikacije:
- Pregnancy and lactation

- Hypersensitivity to sodium valproate

- Acute and chronic hepatitis and other active hepatic diseases

- History of severe, familial hepatic dysfunction, particularly drug-
induced

- Hepatic porphyria

Upozorenje:
Before initiation of sodium valproate and before dose increase, functional liver tests should be performed together with determination of blood coagulation time, fibrinogen level and platelet aggregation.
Valproate may be hepatotoxic inducing major liver failure, so that care should be taken in patients with hepatic dysfunction and children below the age of 3, particularly with congenital metabolic diseases, organic brain diseases and mental retardation. The risk of hepatotoxicity is increased when valproate is combined with other antiepileptic medication.
In case of hepatic dysfunction the therapy is discontinued or even not started at all in case fibrinogen impairment, blood coagulation disorder, triple transaminase elevation, elevation of alkaline phosphatase, bilirubin and hyperammoniemia. In patients receiving valproate therapy, hematological parameters should be controlled before any surgical procedure.
Caution is also necessitated in cases of renal failure because of possible raise of valproic acid plasma levels.
Sodium valproate is partially eliminated in the urine as keto-metabolites, which may be incorrectly interpreted as positive ketonic test.

Trudnoća i dojenje:
Valproates have been associated with teratogenic effect in experimental animals (like other antiepileptic medication), leading to malformations of the skeleton and internal organs of the fetus 2-3 times more often than it is the case in general population. The risk of teratogenic action is higher when more drugs are used in comparison with monotherapy.
If a woman receiving antiepileptic therapy insists on pregnancy, special treatment is undertaken implying monotherapy, minimum effective daily dose in several divided doses, etc. The risks for the newborn include hemorrhagic syndrome due to reduced fibrinogen and coagulation factors. Therefore, in newborns of mothers receiving valproates in pregnancy regular monitoring of platelets, fibrinogen levels and coagulation factors is needed.
Valproates are excreted breast milk in the concentration ranging from 1-10% of the maternal serum levels.

Uticaj na sposobnost upravljanja motornim vozilima i mašinama:
The drug impairs psychophysical competencies, induces somnolence. It is forbidden to drive and operate machinery during the valproate therapy.

Interakcije:
Concomitant administration of valproate with other antiepileptic medication (phenobarbiton, phenytoin, primidone, ethosuximide, carbamazepin etc.) determination of blood levels of all these drugs and subsequent dose adjustment are mandated.

- Valproates elevate phenobarbiton serum levels and with concomitant administration severe CNS depression may ensue, so that dose reduction is required.

- Valproate push out phenytoin from plasma protein binding sites, increase their free blood fraction lading to symptoms of overdose.

- Valproates increase primidone plasma levels, so that marked sedation may ensue.

- Concomitant administration of valproate and clonazepam may induce Absence status, while concomitant administration of valproate and ethosuximide leads to changed concentrations of both drugs.

- Valproate potentiates the effect of neuroleptic agents, MAO inhibitors and other antidepressants.

- Valproate reduce warfarin plasma protein binding, so that caution is required with concomitant administration with anticoagulants and antiaggregation drugs (aspirin).

- Valproate potentiates central depressive action of alcohol.


Predoziranje:
With concentrations exceeding the therapeutic doses five times, the first symptoms of overdose are nausea, vomiting and somnolence. In case of massive overdose, when valproate plasma levels are ten or more times over the therapeutic ones, with clinical picture of acute intoxication, severe CNS and respiration depression ensue, and seizures may develop. The therapy is not specific and includes gastric lavage, osmotic diuresis, maintenance of respiration and cardiac action. In most severe cases, hemodialysis may be used.

Način izdavanja:
Prescription only.

Način cuvanja:
Eftil® retard 500 tablets film-coated should be stored at temperatures below 25˚C, protected from light and out of reach of children.

Rok upotrebe:
3 years. The drug should not be used after the date marked on the packages.

Pakovanje:
Box with 30 tablets film-coated