Depakin Chrono 500 mg, 30 pcs.

 1 tab. Sodium valproate ** 333 mg valproic acid ** 145 mg

Excipients:

silicon dioxide colloidal anhydrous - 4 mg,

methylhydroxypropyl cellulose 4000 MPa.s (hypromellose) - 176 mg,

ethyl cellulose (20 MPa.s) - 12 mg,

sodium saccharin - 10 mg,

silicon dioxide colloidal hydrated - 50 mg,

methyl hydroxypropyl cellulose 6 MPa.s (hypromellose) - 7.2 mg,

30% polyacrylate dispersion - 24 mg,

macrogol 6000 - 7.2 mg,

talc - 7.2 mg

titanium dioxide - 1.2 mg.

** Corresponds to 500 mg of valproic acid in 1 tab.

The drug has a central muscle relaxant and sedative effect. It exhibits antiepileptic activity in all types of epilepsy.

The main mechanism of action, apparently, is associated with the effect of valproic acid on the GABA-ergic system: the drug increases the GABA content in the central nervous system and activates the GABA-ergic transmission.

Pharmacokinetics

Suction

The bioavailability of sodium valproate and valproic acid when administered is close to 100%.

When taking Depakin® Chrono 500 mg tablets at a dose of 1000 mg / day, Cmin in plasma is 44.7 ± 9.8 μg / ml, and Cmax in plasma is 81.6 ± 15.8 μg / ml. Tmax in plasma is 6.58 ± 2.23 h. Css in plasma is achieved within 3-4 days of regular administration of the drug.

The average therapeutic range of serum concentrations of valproic acid is 50-100 mg / L. If it is justified to achieve higher concentrations of valproic acid in blood plasma, the ratio of the expected benefit and the risk of side effects, especially dose-dependent, should be carefully weighed, because when the concentration of valproic acid is more than 100 mg / l, an increase in side effects is expected until the development of intoxication. With a plasma concentration of valproic acid of more than 150 mg / l, a dose reduction is required.

Compared to the enteric-coated dosage form, the sustained-release tablet formulation in equivalent doses is characterized by the absence of latent absorption time, prolonged absorption, identical bioavailability, lower Cmax value (Cmax decrease by about 25%), but with a more stable phase plateau from 4 to 14 hours after administration, a more linear correlation between the dose and the concentration of the drug in plasma.

Distribution

Binding to plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturated.

Vd depends on age and is usually 0.13-0.23 l / kg body weight or in young people 0.13-0.19 l / kg body weight.

Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding plasma concentration.

Valproic acid passes into breast milk in nursing mothers. In equilibrium, the concentration of valproic acid in breast milk is 1-10% of its concentration in plasma.

Metabolism

It is metabolized by beta, omega and omega-1 oxidation and conjugation with glucuronic acid. More than 20 metabolites were isolated, metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on the isoenzymes of the P450 cytochrome system: unlike most other antiepileptic drugs, valproic acid does not affect the degree of both its own metabolism and the degree of metabolism of other drugs, such as estrogens, progestogens and indirect anticoagulants.

Breeding

It is excreted mainly in urine after beta oxidation and conjugation. T1 / 2 is 15-17 hours. Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml / min.

Pharmacokinetics in special clinical cases

In elderly patients, patients with renal and hepatic insufficiency, binding to plasma proteins is reduced. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid can increase to 8.5-20%.

With hypoproteinemia, the total concentration of valproic acid (free + fraction bound to blood plasma proteins) may not change, but it may also decrease due to an increase in the metabolism of the free (non-bound blood plasma fraction) valproic acid fraction.

When combined with antiepileptic drugs that induce microsomal liver enzymes, the plasma clearance of valproic acid increases and T1 / 2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

T1 / 2 values ​​in children over 2 months of age are close to those in adults.

In patients with liver disease, valproic acid T1 / 2 increases.

With an overdose, an increase in T1 / 2 to 30 hours was observed.

Only the free fraction of valproic acid in the blood is subjected to hemodialysis (10%)

Features of pharmacokinetics during pregnancy

With an increase in Vd of valproic acid in the III trimester of pregnancy, its renal and hepatic clearance increase. Moreover, despite taking the drug in a constant dose, a decrease in the concentration of valproic acid in the plasma is possible. In addition, during pregnancy, a change in the degree of binding of valproic acid to plasma proteins is possible, which can lead to an increase in the serum content of the free (therapeutically active) fraction of valproic acid.

In adults, as monotherapy or in combination with other antiepileptic drugs:

• treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic);
• Lennox-Gastaut syndrome;
• treatment of partial epileptic seizures (partial seizures with or without secondary generalization);
• treatment and prevention of bipolar affective disorders.

In children, as monotherapy or in combination with other antiepileptic drugs:

• treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic);
• Lennox-Gastaut syndrome;
• treatment of partial epileptic seizures (partial seizures with or without secondary generalization).

During pregnancy, the development of generalized tonic-clonic epileptic seizures, epileptic status with the development of hypoxia can be a risk factor for death for both the mother and the fetus.

In experimental studies of reproductive toxicity in mice, rats, and rabbits, the teratogenic effects of valproic acid have been shown.

Available clinical data confirm that in children born to mothers with epilepsy who received valproic acid, an increased frequency of occurrence of intrauterine developmental disorders of varying severity (neural tube defects; craniofacial deformities; malformations of the extremities, cardiovascular system; a also multiple intrauterine malformations affecting different organ systems) compared with the frequency of their occurrence when pregnant women take some other antiepileptic drugs.

Based on available data, it is assumed that there is a relationship between the intrauterine exposure to valproic acid and the risk of developmental delay (especially speech development) in children born to mothers with epilepsy who took valproic acid. Delayed development is often combined with malformations and phenomena of dysmorphism. However, in cases of developmental delay in such children, it is difficult to establish a causal relationship with valproic acid intake due to the possibility of simultaneous exposure to other factors, such as low intelligence of the mother or both parents; genetic, social factors, environmental factors; lack of effectiveness of treatment aimed at preventing maternal epileptic seizures during pregnancy.

The development of various autistic disorders in children exposed to intrauterine exposure to valproic acid has also been reported.

Both valproic acid monotherapy and combination therapy with valproic acid are associated with an unfavorable pregnancy outcome, but combined antiepileptic therapy including valproic acid has been reported to be associated with a higher risk of an adverse pregnancy outcome compared to valproic acid monotherapy.

In connection with the foregoing, Depakin® chrono should not be used during pregnancy and in women of childbearing age unless absolutely necessary. Its use is possible, for example, in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

The question of whether Depakin® chrono should be used or the possibility of refusal to use it should be decided before the use of the drug is started or reviewed if a woman receiving Depakin® chrono is planning a pregnancy.

Women of childbearing age should use effective methods of contraception during treatment with Depakin® chrono. Women of childbearing age should be informed about the risks and benefits of using valproic acid during pregnancy. When prescribing the drug, pregnancy must be excluded.

If a woman is planning a pregnancy or is diagnosed with pregnancy, then the need for valproic acid treatment should be reassessed, depending on the indications:

• in bipolar disorder, consideration should be given to stopping treatment with valproic acid;
• with epilepsy, the question of continuing treatment with valproic acid or its cancellation is resolved after reassessment of the ratio of benefit and risk. If, after reviewing the ratio of benefits and risks, a decision has been made to continue treatment with Depakin® chrono during pregnancy, it is recommended to use it in the minimum effective daily dose, divided into several doses. It should be noted that during pregnancy, the use of sustained release dosage forms is preferred.

One month before conception and within 2 months after it, folic acid (at a dose of 5 mg / day) should be added to antiepileptic treatment, because this can minimize the risk of neural tube malformations.

Continuous special prenatal monitoring should be carried out to identify possible malformations of the neural tube or other fetal malformations.

It was reported about the development of isolated cases of hemorrhagic syndrome of newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with hypofibrinogenemia and is possibly due to a decrease in the content of blood coagulation factors. Fatal afibrinogenemia has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

Therefore, in newborns born to mothers who received valproic acid, it is necessary to determine the number of platelets in the blood, the plasma concentration of fibrinogen, coagulation factors and a coagulogram.

Cases of hypoglycemia have been reported in newborns whose mothers took valproic acid during the third trimester of pregnancy.

The excretion of valproic acid with breast milk is low, its concentration in breast milk is 1-10% of its plasma concentration. Based on literature data and little clinical experience, with monotherapy with Depakin® Chrono, mothers can plan breastfeeding, but the profile of side effects of the drug, especially the hematological disorders caused by it, should be taken into account.

Use in children

For children aged 6 years and older, the average daily dose is 30 mg / kg.

• hypersensitivity to sodium valproate, valproic acid, semisodium valproate, valpromide, or to any of the auxiliary components of the drug;
• acute hepatitis;
• chronic hepatitis;
• severe liver diseases (especially drug hepatitis) in the history of the patient and his close blood relatives;
• severe fatal liver damage with valproic acid in close blood relatives of the patient;
• severe dysfunction of the liver or pancreas;
• severe pancreatic dysfunction;
• hepatic porphyria;
• combination with mefloquine;
• combination with drugs of St. John's wort perforated;
• children under 6 years of age (risk of ingestion of the pill by swallowing).

Carefully

• a history of liver and pancreas;
• pregnancy;
• congenital fermentopathies;
• inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
• renal failure (dose adjustment required);
• patients receiving multiple anticonvulsants (due to an increased risk of liver damage);
• concomitant use of drugs that provoke convulsive seizures or lower the threshold of convulsive readiness, such as tricyclic antidepressants, selective serotonin reuptake inhibitors; phenothiazine derivatives, derivatives of buterophenone, chloroquine, bupropion, tramadol (risk of convulsive seizures);
• simultaneous administration of antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (the possibility of potentiating their effects);
• concomitant use of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine (due to the pharmacokinetic interaction of blood plasma levels or possibly a change in plasma metabolism or drugs and / or valproic acid);
• concomitant use with carbamazepine (risk of potentiation of the toxic effects of carbamazepine and a decrease in the plasma concentration of valproic acid);
•  
• concomitant use with topiramate (risk of developing encephalopathy).

Use for impaired liver function

The drug is contraindicated in cases of impaired liver function.

Use for impaired renal function

When using Depakine Chrono in patients with renal failure, it may be necessary to reduce the dose of the drug.

Use in elderly patients

In elderly patients, the dose should be set in accordance with their clinical condition.

Determination of the frequency of adverse reactions (WHO): very often (≥10%), often (≥1% and

From the hemopoietic system: often - thrombocytopenia; rarely - pancytopenia, anemia, leukopenia, disorders of bone marrow hematopoiesis, including isolated aplasia of red blood cell cells; agranulocytosis.

From the blood coagulation system: an isolated decrease in blood fibrinogen content and lengthening of the prothrombin time, usually not accompanied by clinical manifestations, were reported, especially when used in high doses (valproic acid has an inhibitory effect on the second phase of platelet aggregation).

From the nervous system: infrequently - ataxia; very rarely - dementia, combined with cerebral atrophy, reversible within a few weeks or months after discontinuation of the drug, several cases of stupor and lethargy (sometimes leading to transient coma / encephalopathy; they can be isolated or combined with an increase in seizures (despite treatment), which become less common with drug withdrawal or dose reduction; these cases were mainly observed during combination therapy, in particular with phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid), extrapyramidal disorders (may be irreversible) including reversible parkinsonism, transient and / or dose-related mild postural tremor and drowsiness, hyperammonemia,

From the psyche: infrequently - irritability, hyperactive state, confusion, especially at the beginning of treatment; rarely - changes in behavior, moods, depression, tiredness, aggressiveness, psychosis, unusual arousal, motor anxiety, dysarthria; frequency unknown - hallucinations.

On the part of the hearing organ: rarely - reversible or irreversible deafness.

From the side of the organ of vision: the frequency is unknown - diplopia, nystagmus, flickering of "flies" in front of the eyes.

From the digestive system: often - at the beginning of treatment, nausea, vomiting, epigastric pain, diarrhea, which with continued use of the drug usually disappear after a few days; rarely - liver damage; very rarely - pancreatitis, sometimes fatal.

From the urinary system: very rarely - enuresis. There were several separate reports on the development of reversible Fanconi syndrome, the mechanism of development of which is still unclear.

On the part of the skin and subcutaneous tissue: often - transient or dose-dependent alopecia; very rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash.

From the side of metabolism: often - isolated and moderate hyperammonemia in the absence of changes in liver function tests and neurological manifestations, not requiring drug withdrawal; very rarely - hyponatremia, ADH secretion disorder syndrome, weight gain (since obesity is a risk factor for the development of polycystic ovary syndrome, patients with weight gain should be closely monitored).

From the vessels: vasculitis.

General disorders: very rarely - small peripheral edema.

On the part of the immune system: angioedema, drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome), allergic reactions, such as urticaria.

From the reproductive system: the frequency is unknown - amenorrhea and dysmenorrhea, male infertility.

The effect of valproic acid on other drugs

Valproic acid can potentiate the effects of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (clinical monitoring is recommended and, if necessary, dose adjustment of the corresponding drug).

Valproic acid does not affect serum lithium concentration.

Valproic acid increases the concentration of phenobarbital in plasma (due to a decrease in its hepatic metabolism), in connection with which the development of the sedative effect of the latter is possible, especially in children. Therefore, careful medical monitoring of the patient during the first 15 days of combination therapy with an immediate reduction in the dose of phenobarbital in case of sedation and, if necessary, determination of the plasma concentration of phenobarbital is recommended.

Valproic acid increases the concentration of primidone in plasma, which leads to an increase in its side effects (such as sedation); with prolonged treatment, these symptoms disappear. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy with dose adjustment of primidone, if necessary.

Valproic acid reduces the total concentration of phenytoin in plasma. In addition, valproic acid increases the concentration of the phenytoin free fraction with the possibility of developing overdose symptoms (valproic acid displaces phenytoin from its association with blood plasma proteins and slows down its hepatic metabolism). Therefore, careful clinical monitoring of the patient and determination of the concentration of phenytoin and its free fraction in the blood are recommended.

With the simultaneous use of valproic acid and carbamazepine, clinical manifestations of toxicity of carbamazepine have been reported, because valproic acid may potentiate the toxic effects of carbamazepine. Careful clinical monitoring of such patients is recommended, especially at the beginning of combination therapy with the correction, if necessary, of the dose of carbamazepine.

Valproic acid slows down the metabolism of lamotrigine in the liver and increases T1 / 2 of lamotrigine almost 2 times. This interaction can lead to increased toxicity of lamotrigine, in particular to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical observation and, if necessary, correction (reduction) of the dose of lamotrigine is recommended.

Valproic acid can increase plasma concentrations of zidovudine, which leads to an increase in the toxicity of zidovudine.

Valproic acid can lower average felbamate clearance by 16%.

Strengthening the hypotensive effect of nimodipine (for oral administration and, by extrapolation, for parenteral administration) due to an increase in its plasma concentration (inhibition of nimodipine metabolism by valproic acid).

The effect of other drugs on valproic acid

Antiepileptic drugs that can induce microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine) reduce the plasma concentration of valproic acid. In the case of combination therapy, the dose of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

With the combination of felbamate and valproic acid, the clearance of valproic acid decreases by 22-50% and, accordingly, the plasma concentration of valproic acid increases. The plasma concentration of valproic acid should be monitored.

Mefloquine accelerates the metabolism of valproic acid and is capable of causing seizures, therefore, with their simultaneous use, an epileptic seizure may develop.

With the simultaneous use of valproic acid and Hypericum perforatum preparations, a decrease in the anticonvulsant effectiveness of valproic acid is possible.

In the case of the simultaneous use of valproic acid and drugs having a high and strong bond with plasma proteins (acetylsalicylic acid), an increase in the concentration of the free fraction of valproic acid is possible.

With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of the prothrombin index is required.

The concentration of valproic acid in blood plasma may increase with the simultaneous use of cimetidine or erythromycin (as a result of a slowdown in its hepatic metabolism).

A decrease in the concentration of valproic acid in the blood when it is used simultaneously with carbapenems (panipenem, meropenem, imipenem), leading to a 60-100% decrease in the concentration of valproic acid in the blood plasma in 2 days of joint therapy, which was sometimes combined with the occurrence of seizures. The simultaneous use of carbapenems in patients with a selected dose of valproic acid should be avoided due to their ability to quickly and intensively reduce the concentration of valproic acid in plasma. If treatment with carbapenems cannot be avoided, careful monitoring of valproic acid concentrations in the blood should be carried out.

Rifampicin can reduce the concentration of valproic acid in the blood, which leads to the loss of the therapeutic effect of Depakin® chrono. Therefore, it may be necessary to increase the dose of Depakin® chrono while using rifampicin.

Other interaction

The simultaneous use of valproic acid and topiramate was accompanied by encephalopathy and / or hyperammonemia. Patients receiving this combination need careful medical supervision for the development of symptoms of hyperammonemic encephalopathy.

Valproic acid does not have the ability to induce liver enzymes and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen drugs in women using hormonal contraception.

When ethanol and other potentially hepatotoxic drugs are taken at the same time as valproic acid, the hepatotoxic effect of valproic acid may be enhanced.

The simultaneous use of clonazepam with valproic acid can in rare cases lead to an increase in the severity of the abscess status.

With the simultaneous use of drugs with myelotoxic effect, with valproic acid, the risk of inhibition of bone marrow hematopoiesis is increased.

Depakin® chrono is intended only for adults and children over 6 years old with a body weight of more than 17 kg!

Depakin® chrono is a slow release dosage form, this avoids sharp increases in the concentration of valproic acid in the blood after taking the drug and for a longer time maintains a constant concentration of valproic acid in the blood during the day.

Long-acting tablets Depakin® Chrono 300 mg or 500 mg can be divided to facilitate the administration of an individually selected dose.

Tablets are taken without crushing or chewing them.

Epilepsy

The doctor selects the daily dose individually.

To prevent the development of epilepsy attacks, the drug should be used in the minimum effective dose (especially during pregnancy).

The daily dose is set in accordance with the age and body weight of the patient. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached.

No clear association was found between the daily dose, plasma concentration, and therapeutic effect. Therefore, the optimal dose should be determined mainly by the clinical response. Determination of plasma valproic acid levels may complement clinical observation if epilepsy is not controlled or if side effects are suspected. The range of therapeutic concentrations in the blood is usually 40-100 mg / L (300-700 μmol / L).

With monotherapy, the initial dose is usually 5-10 mg of valproic acid per kg of body weight, then this dose is gradually increased every 4-7 days at the rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control over epilepsy attacks.

Average daily doses (with prolonged use):

for children 6-14 years old (body weight 20-30 kg) - 30 mg of valproic acid / kg body weight (600-1200 mg);

for adolescents (body weight 40-60 kg) - 25 mg of valproic acid / kg body weight (1000-1500 mg);

for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg of valproic acid / kg of body weight (1200-2100 mg).

Although the daily dose is determined depending on the age and body weight of the patient, a wide range of individual sensitivity to valproate should be taken into account.

If epilepsy cannot be controlled at such doses, they can be increased under the control of the patient's condition and the concentration of valproic acid in the blood. In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, you should not increase the daily dose above the recommended average daily dose earlier than this period.

The daily dose can be divided into 1-2 doses, preferably with meals.

Application in one step is possible with well-controlled epilepsy.

Most patients who are already taking Depakin® in a non-prolonged dosage form can be transferred to Depakin® chrono immediately or within a few days, while patients should continue to take the previously selected daily dose.

For patients who have previously taken antiepileptic drugs, the transfer to the administration of Depakin® chrono should be carried out gradually, reaching the optimal dose of the drug within about 2 weeks. In this case, you should immediately reduce the dose of the antiepileptic drug that the patient took earlier, especially if it is phenobarbital. The withdrawal of the antiepileptic drug that the patient took ear