Expiration date: 05/2025

Structure and Composition: 

Depakine enteric 300

Film-coated tablets, soluble in the gut Table 1. (425 mg)

Sodium valproate 300 mg

Excipients:

Core (weight 335 mg): povidone K90 - 8 mg of hydrated calcium silicate - talc 15 mg - magnesium stearate 9 mg - 3 mg

?1 film coating: methacrylic acid - methyl methacrylate (1: 1) - approximately 19.63 mg of talc - approximately 19.63 mg Opaspray White K1-7000 - approximately 16.82 mg of diethyl phthalate - approximately 3.92 mg

film coating ?2: cellulose acetate phthalate - about 20 mg of diethyl phthalate - about 5 mg

film coating ?3: cellulose acetate phthalate - approximately 3.22 mg of diethyl phthalate - approximately 0.81 mg Opaspray White K1-7000 - approximately 0.97 mg

in blister 10 pcs. 10 blisters per box.

Description pharmaceutical form:

Pharmacokinetics:

Bioavailability - about 100%. The volume of distribution is limited primarily by blood and extracellular fluid. The concentration of valproate in the cerebrospinal fluid is close to the free plasma concentrations. Depakine cross the placenta, excreted in breast milk in very low concentrations (1-10% of the total serum concentration). Stable plasma concentration is reached quickly (3-4 days) after oral application at on / in the equilibrium concentration can be achieved within a few minutes, and then maintained in / infusion. Depakine is well bound to plasma proteins, protein binding is dose-dependent and saturable. The drug is excreted by dialysis, but only in free form (approximately 10%). Unlike other antiepileptic drugs do not affect the Depakine enzymes including cytochrome P450, and therefore does not alter the metabolism of other drugs. T1 / 2 - 8-20 hours in children - shorter. Depakine predominantly excreted in the urine after metabolism by glyukuronirovaniya and beta-oxidation.

Description of the pharmacological actions:

The antiepileptic drug broad spectrum. It has a central muscle relaxant and sedative properties. It improves mood and mental state of patients.

Depakine acts primarily on the central nervous system, showing anti-epileptic activity at the different types of epilepsy (generalized and focal forms).

The main mechanism of action, apparently associated with increased content of GABA in the central nervous system, resulting in decreased anxiety and convulsive readiness of motor areas of the brain.

Indications:

• generalized or focal epilepsy, especially with the following types of seizures: myoclonic, tonic-clonic, atonic, mixed
  
• focal epilepsy: simple or more complex seizures, secondary generalized seizures
  
• specific syndromes (West, Lennox-Gastaut syndrome).
  

Contraindications:

Depakine enteric 300: idiosyncrasy of sodium valproate, acute hepatitis, chronic hepatitis, cases of severe hepatitis in a patient or his family, particularly those caused by drugs, pancreatic function disorder, thrombocytopenia, bleeding diathesis, hepatic porphyria, children's age up to 3 years.

Application of pregnancy and breastfeeding:

Pregnancy

The total risk of malformations in the fetus while taking valproate in the I trimester of pregnancy is not higher than when taking other anti-epileptic drugs. There are cases of facial dysmorphia.

There were rare cases of multiple malformations, especially the limbs.

The frequency of these effects is still uncertain. In addition, sodium valproate mainly causes a disturbance of the embryonic neural tube: myelomeningocele, spina bifida. The frequency of these complications - 1-2%.

In connection with this drug is not recommended in the I trimester of pregnancy.

If a woman is planning pregnancy, should be revised indications for antiepileptic therapy is recommended to consider the introduction of additional folic acid.

Appointment of the drug during pregnancy is possible when the expected benefit to the mother outweighs the potential risk to the fetus.

During pregnancy should not interrupt treatment antiepileptic drug valproic acid, if it is effective. In such cases monotherapy.

The risk for a newborn

individual cases of hemorrhagic syndrome in newborns have been described whose mothers took during pregnancy, sodium valproate. This haemorrhagic syndrome is associated with hypofibrinogenemia afibrinogenemia has also been described, which can lead to death. Gipofibrinogenemia in this case, may be associated with decreased levels of coagulation factors. However, this syndrome must be distinguished from the reduction of vitamin K-dependent factors, caused by phenobarbital and other inducers of microsomal enzymes.

Therefore, infants should be investigated coagulation, to assess the platelet count, fibrinogen level in plasma, bleeding time and blood clotting time.

Lactation

Valproate in small amounts are excreted in breast milk, valproic acid concentration in human milk is 1-10% from its level in the blood serum. So far, the children (whose mothers received Depakine) receiving breast milk, have been monitored in the neonatal period, was not observed any marked adverse clinical manifestations. However, breast-feeding is not recommended.

Side effect:

Described rare cases of liver dysfunction, teratogenic risk (see. "Pregnancy").

Neurological disorders: confusion, ataxia, tremors, drowsiness, lethargy, coma. Most often, these cases are described in the complex treatment (in particular with phenobarbital) or after a sharp increase in the dose of valproate.

We describe the very rare cases of dementia.

Some patients in the early treatment often develop gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, stomach pain), which usually resolves on its own within a few days without discontinuation.

There are quite frequent reports of temporary and / or dose-dependent side effects: hair loss, drowsiness.

Hematologic side effects are described some cases lowering fibrinogen level or increase bleeding time, usually without associated clinical symptoms, and particularly at high doses (sodium valproate has an inhibitory effect on platelet aggregation second step) (see "Pregnancy".).

Often - thrombocytopenia, rarely - anemia, pancytopenia or leykotsitopeniya.

Described rare cases of pancreatitis, sometimes leading to death, vasculitis.

Can meet frequently isolated and moderate hyperammonemia without change in liver function assays that do not require discontinuation of therapy.

There are also reports an increase in body weight of patients, amenorrhea and menstrual cycle regularity violation.

Described rare cases of hearing loss, both reversible and irreversible, but its causes and dependence on the drug have not been established.

When using valproate may experience allergic skin reactions such as exanthematous rash, urticaria, angioedema. In extremely rare cases, described the occurrence of toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema poliformnoy.

There are some reports of a reversible Fanconi syndrome associated with valproate therapy.

Drug Interactions:

Depakine may potentiate the effects of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines.

Phenobarbital. Depakine increases phenobarbital concentration in blood plasma.

Primidone. Depakine primidone concentration increases in blood plasma.

Phenytoin. Depakine alter the total concentration of phenytoin in plasma. Moreover, increasing the amount of free Depakine phenytoin forms with the possible appearance of signs of overdose (phenytoin, valproic acid substitutes due to plasma proteins and reduces its catabolism in the liver).

Carbamazepine. Valproate may potentiate toxic effects of carbamazepine.

Lamotrigine. Valproate may slow the metabolism of lamotrigine and increases the half-life.

Zidovudine. Valproate can increase the concentration of AZT in the plasma, leading to increased toxicity latter.

Antiepileptic drugs having enzyme-inducing action (phenytoin, phenobarbital, carbamazepine) reducing the concentration of valproate in serum.

On the other hand, the combination of felbamate and valproate may increase serum concentrations of valproate.

Mefloquine increases the metabolism of valproic acid and can cause seizures. Therefore, the combination therapy may occur seizures.

In the case of concurrent use of valproate and agents strongly binding to blood proteins (acetylsalicylic acid), the concentration of free valproate in serum may increase.

In the case of joint use with a vitamin K-dependent anticoagulant should be carried out strict control of prothrombin index.

The level of serum valproate can increase (as a result of reduced hepatic metabolism) in case of simultaneous use with cimetidine or erythromycin.

Panipenem / meropenem: decrease of valproic acid levels in the blood was observed with the combination of medication with antibiotics panipenemom or meropenem.

Valproate has usually not enzyme-inducing action as a result, does not reduce the effectiveness of valproate-estrogen oral progestational hormonal contraceptives.

Dosage and administration:

Inside, during or immediately after a meal, without chewing. The initial daily dose with body weight more than 25 kg - usually 10-15 mg / kg, followed by doses gradually increased to 5-10 mg / kg per week. The maximum dose - 30 mg / kg / day (the dose may be increased under the control of the concentration in plasma of up to 60 mg / kg / day). Adults - at an initial dose of 300 mg 2 times a day with a gradual increase to 200 mg / day with a 3-day intervals until clinical effect (usually up to 1000-1600 mg / day, sometimes up to 2600 mg / day). Children with body weight less than 25 kg average daily dose - 20-30 mg / kg, the maximum daily dose - 50 mg / kg.

Depakine enteric drug may be administered twice a day.

Overdose:

Symptoms: coma with hypotonia of muscles, hyporeflexia, miosis, respiratory depression seizures (at very high concentrations). Cases of increased intracranial pressure due to cerebral edema.

Treatment: gastric lavage (after oral administration, no later than 10-12 hours), activated charcoal method, providing an osmotic diuresis, continuous monitoring of the state of the cardiovascular and respiratory systems, hemodialysis.

Precautionary measures:

Be wary designate children, especially up to 3 years (the highest risk of hepatotoxicity), women of childbearing age (obligatory reliable contraception). During treatment should be deleted alcohol intake.

To carry out certain functions of the liver before starting treatment ( "Contra" cm.) And periodically during the first 6 months of treatment, especially in patients at risk (see. "Special Instructions").

In the treatment of Depakine as other antiepileptic drugs, isolated and temporary increase in the level of liver enzymes in the blood serum can be observed, especially at the beginning of treatment.

it is recommended to conduct a blood test (to determine blood count, including platelet count, bleeding time and coagulation tests) before starting therapy or surgery, in case of spontaneous bruising or bleeding (see. "Side effects").

Patients with renal failure can be necessary to reduce the dose. The dosage should be adjusted according to clinical response (cm. "Pharmacokinetics").

Although Depakine during treatment were noted only extremely rare disorders of the immune system, it should be possible to weigh the advantages of drug administration to patients suffering from systemic lupus erythematosus, as compared with the potential risk.

In acute abdominal pain syndrome is recommended prior to surgery to investigate the levels of pancreatic enzymes, as there are reports of rare cases of pancreatitis.

If there is a suspicion of urea cycle enzyme deficiency, there should be appropriate laboratory testing prior to treatment.

The patient should be made aware of the risk of drowsiness, especially in the case of combined anticonvulsant therapy (see. "Interaction").

Use caution when performing work that requires quickness of psychomotor reactions.

Special instructions:

When unknown correlation between daily dose of valproate in serum concentration and therapeutic effect, the optimal dose should be determined according to the clinical results. Determination of valproic acid concentration in blood plasma can be regarded as an additional criterion when only prevent clinical achieve adequate control or when side effects are manifested. Effective level Depakin according to sources is usually 40-100 mg / liter (300-700 umol / L).

Abnormal liver function

Terms of occurrence

risk group consists of patients receiving anticonvulsant therapy complex, high-risk group - infants and children up to 3 years. At the age of 3 years, the frequency of such complications is greatly reduced, and then gradually decreases with increasing age.

In most cases, the reaction expressed by the liver was observed during the first 6 months of treatment.

Possible signs

Early diagnosis is based mainly on clinical examination. It should be taken into consideration symptoms that may precede jaundice, particularly for patients at-risk (cm. "The conditions of occurrence").

Non-specific symptoms such as fatigue, anorexia, extreme fatigue, drowsiness, usually appear suddenly, sometimes accompanied by repeated vomiting and abdominal pain.

Recurrence of epileptic seizures.

It is recommended to inform the patient, and if it is a child, his family, that the development of clinical symptoms should be cause for immediate consultation, which, in addition to clinical examination should include an immediate study of the liver.

Diagnostics

At the beginning and during the first 6 months of treatment should be periodically check liver function. The most important tests that reflect the protein-synthetic function of the liver, and especially prothrombin index. In the case of abnormally low levels of prothrombin, especially accompanied by a significant decrease in the level of fibrinogen and other blood coagulation factors, increased levels of transaminases and bilirubin, therapy should be suspended Depakine.

As a precaution, you should stop treatment with salicylates, if they were included in the treatment regimen, because they use the same metabolic pathway.