Depakine chrono 500 atx code. Depakine chrono instructions for use, contraindications, side effects, reviews

inside.

This drug is intended only for adults and children over 6 years of age weighing more than 17 kg!

Depakine ® chrono is a form of delayed release of the active substance from the Depakine ® group of drugs. Sustained release avoids sharp rises in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood for a longer period of time.

Depakine ® chrono 300/500 mg extended-release tablets can be divided to facilitate the administration of an individually adjusted dose.

Tablets are taken without crushing or chewing them.

Dosing regimen for epilepsy

The minimum effective dose to prevent the development of epileptic seizures should be selected (especially during pregnancy). The daily dose should be adjusted according to age and body weight. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached. A clear relationship between daily dose, plasma concentration and therapeutic effect has not been established. Therefore, the optimal dose should be determined primarily by clinical response. Determination of the level of valproic acid in plasma can serve as an addition to clinical observation if epilepsy is not controlled or there is a suspicion of the development of side effects. The range of therapeutic concentration in the blood is usually 40-100 mg/l (300-700 µmol/l).

With monotherapy, the initial dose is usually 5-10 mg / kg, which is then 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 of epileptic seizures.

Average daily doses (with prolonged use):

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

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

For adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg valproic acid / kg (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 is not 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, do not increase the daily dose above the recommended average daily dose before this time.

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

One-shot use is possible with well-controlled epilepsy.

Most patients who are already taking a non-prolonged-release dosage form of Depakine ® can be transferred to the dosage form of this drug of prolonged action 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 drug Depakine ® chrono should be carried out gradually, reaching the optimal dose of the drug within about 2 weeks. At the same time, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, blood levels of valproic acid should be monitored within 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), the daily dose of valproic acid should be reduced. . If necessary, the combination of valproic acid with other antiepileptic drugs should be added to the treatment gradually (see "Interaction").

Dosing regimen for manic episodes in bipolar disorders

adults

The daily dose is selected by the attending physician individually.

The recommended starting daily dose is 750 mg. In addition, in clinical studies, the initial dose of 20 mg of sodium valproate per kg of body weight also showed an acceptable safety profile.

Sustained release formulations can be taken once or twice a day. The dose should be increased as rapidly as possible until the minimum therapeutic dose that produces the desired clinical effect is reached. The average value of the daily dose is in the range of 1000-2000 mg of sodium valproate. Patients receiving a daily dose above 45 mg/kg/day should be under close medical supervision.

Continuation of treatment of manic episodes in bipolar disorder should be carried out by taking an individually adjusted minimum effective dose.

Children and teenagers

The efficacy and safety of the drug in the treatment of manic episodes in bipolar disorders in patients under 18 years of age have not been evaluated.

The use of the drug in patients of special groups

In patients with renal insufficiency and/or hypoproteinemia the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and if necessary, reduce the dose of valproic acid, focusing on the selection of the dose, mainly on the clinical picture, and not on the total content of valproic acid in the blood serum (free fraction and fraction associated with plasma proteins) to avoid possible errors in dose selection.

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Instructions for medical use

medicinal product

DEPAKIN® CHRONO

Tradename

Depakine Chrono

International non-proprietary name

Valproic acid

Dosage form

Film-coated tablets, prolonged release, divided, 500 mg

Compound

One tablet contains

active substances: sodium valproate 333 mg

Valproic acid 145 mg,

Excipients: hypromellose 4000 (3000 mPa.s), ethylcellulose 20 mPa.s, sodium saccharinate, colloidal anhydrous silicon dioxide, colloidal silicon dioxide aqueous,

Shell composition: hypromellose (6 mPa.s), macrogol 6000, talc, titanium dioxide (E171), polyacrylate 30% dispersion or dry extract.

Description

Oblong-shaped tablets with hemispherical edges, almost white color with a biconvex surface, film-coated, scored on both sides, practically odorless or with a slight odor.

Pharmacotherapeutic group

Antiepileptic drugs. Fatty acid derivatives.

ATC code N03AG01

Pharmacological properties

Pharmacokinetics

The bioavailability of valproate in the blood when taken orally is close to 100%. The drug is distributed mostly into the systemic circulation and into the extracellular fluid. Valproate penetrates into the cerebrospinal fluid and brain tissue. The half-life is 15-17 hours. For a therapeutic effect, a minimum serum concentration of 40-50 mg / l is required, ranging from 40-100 mg / l. If a higher plasma concentration is required, the benefit must be weighed against the risk of adverse effects, especially dose-dependent ones. Despite this, when concentrations persist at levels above 150 mg/l, the dose should be reduced. Steady-state plasma concentration is reached in 3-4 days. Binding to blood proteins is dose-dependent and saturable. Valproate is metabolized by glucuron-conjugation and beta-oxidation, then excreted, mainly in the urine. Can be dialyzed, however, hemodialysis is effective only against the free fraction of valproate in the blood (approximately 10%). Valproate does not induce enzymes involved in the cytochrome P450 metabolic system. Unlike most other antiepileptic drugs, it does not accelerate its own degradation, nor that of other substances such as estrogen-progestogens and oral anticoagulants.

When compared to the gastro-resistant formulation of valproate, the sustained release formulation at the same doses showed no absorption lag, prolonged absorption, identical bioavailability, lower total maximum concentration and plasma concentration of free substance (Cmax lower by about 25% with a relatively stable plateau 4-14 hours after injection); this “peak-flattening” effect provides a more constant and more evenly distributed concentration of valproic acid over a 24-hour period: after administration of the same dose twice a day, the amplitude of fluctuations in plasma concentrations is halved, a linear relationship between dose and plasma concentration (total and free substance) is more pronounced.

Pharmacodynamics

Depakine Chrono acts primarily on the central nervous system. The anticonvulsant effect of Depakine Chrono is manifested in relation to various types of convulsive seizures of epilepsy in humans.

Depakine Chrono has two types of anticonvulsant action: the first type is a direct pharmacological effect associated with the concentrations of Depakine Chrono in plasma and brain tissues, the second type of action is indirect and is probably associated with valproate metabolites located in the brain tissues, or with changes neurotransmitters or direct action on the membrane. The most widely accepted hypothesis is related to the level of gamma-aminobutyric acid (GABA), which increases after the use of Depakine Chrono.

Depakine Chrono reduces the duration of the intermediate phase of sleep with a simultaneous increase in its slow-wave component.

Indications for use

Treatment of epilepsy in adults and children as monotherapy or in combination with other antiepileptic drugs in both generalized seizures (clonic, tonic, tono-clonic, absences, myoclonic and atonic seizures; Lennox-Gastaut syndrome) and focal epilepsy (focal seizures with secondary generalization or without it)

Treatment in adults of manic syndrome in bipolar disorders and prevention of relapses, manic episodes in which amenable to treatment with Depakine Chrono.

Dosage and administration

Depakine Chrono is an extended release dosage form of Depakine with a reduced maximum plasma concentration, providing a more even plasma concentration over a 24-hour period.

Based on the amount of active substance, this medicinal product is intended for use by adults and children weighing more than 17 kg.

This dosage form is not suitable for children under 6 years of age (risk of inhalation).

Mode of application

For ingestion. The daily dose should be taken 1 time per day or divided into 2 doses per day, preferably taken with meals.

A single dose per day is possible if epilepsy is well controlled.

The tablet is swallowed whole, without biting or chewing.

Dosage for generalized and focal epilepsy

The initial daily dose is 10-15 mg / kg, then the dose is increased to the optimum (see "Start of treatment"). Average dose: 20 - 30 mg/kg per day. However, if the seizures do not respond to these doses, then with strict supervision of the patient, the dose can be increased.

For children aged 6 and over: The average dose is 30 mg/kg per day.

For adults: the average dose is 20 - 30 mg/kg per day.

In elderly patients, the dose should be adjusted according to the clinical condition.

The daily dose should be prescribed based on age and body weight, while taking into account the wide range of individual sensitivity to valproate.

The exact relationship between daily dose, blood concentration and therapeutic effect has not been established: the dose is selected based on the clinical response. In the case of seizures that cannot be controlled or if adverse reactions are suspected, along with clinical monitoring, measurement of plasma levels of valproic acid may be required. The therapeutic effect is usually observed at concentrations of 40-100 mg/l (300-700 µmol/l).

Start of treatment

Patients in whom appropriate seizure control is provided with the help of dosage forms of Depakine immediate release, the daily dose remains unchanged when it is replaced with Depakine® Chrono.

For patients already on treatment and taking another antiepileptic drug, Depakine® Chrono is administered gradually in order to reach the optimal dose after about 2 weeks; then - if necessary - reduce concomitant treatment depending on the effectiveness of treatment.

In patients not taking other antiepileptic drugs, it is advisable to increase the dose in stages, every 2-3 days in order to reach the optimal dose in about one week.

If necessary, the additional appointment of other antiepileptic drugs is carried out gradually.

Dosage for the treatment of manic syndrome in bipolar disorders

The recommended starting dose is 20 mg/kg/day. This dose should be increased as soon as possible in order to reach the minimum therapeutic dose that will provide the desired clinical effect. This effect can usually be obtained at plasma levels of valproate in the range between 45 and 125 µg/ml. The recommended maintenance dose for bipolar disorder is 1000-2000 mg per day. In exceptional cases, the dose can be increased to a maximum of 3000 mg per day. The dose is selected based on the individual clinical response. The duration of the course is determined individually by the doctor.

Dosage to Prevent Relapse of Manic Syndrome in Bipolar Disorders

In order to avoid relapse, the dose to be administered should be the lowest dose that provides adequate control of the acute symptoms of mania in the individual patient. Do not exceed the maximum daily dose of 3000 mg.

Side effects

Congenital, familial or genetic disorders due to teratogenic risk (see section "Special Instructions")

Bone marrow aplasia and true erythrocyte aplasia

Agranulocytosis

Dose-dependent thrombocytopenia observed without any clinical consequences

For asymptomatic thrombocytopenia, reducing the dose of this drug alone, if possible based on platelet count and in the context of effective epilepsy control, will usually resolve the thrombocytopenia.

Temporary and/or dose-dependent adverse effects: fine postural tremor and drowsiness

Confusion or convulsions

Stupor or lethargy, sometimes leading to a temporary coma (encephalopathy), either isolated or associated with a paradoxical increase in seizures with valproate, regressing on discontinuation of treatment or after dose reduction

Such conditions occur most often with drug polytherapy (especially with phenobarbital or topiramate) or after a sharp increase in the dose of valproate.

Hyperammonemia, occurring with neurological symptoms (up to coma) and requiring additional tests

Headache

The appearance of gastrointestinal disorders at the beginning of treatment (nausea, vomiting, stomach pain, diarrhea), which usually resolve after a few days without discontinuation of the drug

Temporary and/or dose-dependent hair loss

Skin reactions such as exanthematous rash

Syndrome of inappropriate secretion of antidiuretic hormone (SIAH)

Weight gain, which is a risk factor for polycystic ovary syndrome - careful monitoring of body weight of patients is necessary

Angioedema, drug rash syndrome with eosinophilia and systemic symptoms (LSESS syndrome), or hypersensitivity syndrome

Liver disease

Amenorrhea, menstrual irregularities

Especially, with drug polytherapy, isolated moderate hyperammonemia without changes in laboratory tests of liver functions, which does not require discontinuation of the drug

Ataxia

Reversible Parkinson's Syndrome

Very rarely

Cognitive impairment with a latent and progressive onset that may progress to complete dementia and is reversible weeks or months after treatment is discontinued

Pancreatitis requiring early discontinuation of treatment, sometimes fatal

Enuresis and urinary incontinence

Hyponatremia

Peripheral edema in mild form

In exceptional cases

Reversible and irreversible hearing loss

Lyell's syndrome, Stevens-Johnson syndrome and erythema multiforme

Kidney damage

A decrease in the level of fibrinogen or an increase in bleeding time, usually without associated clinical symptoms, when taking large doses of Depakine® Chrono, has an inhibitory effect on the second phase of platelet aggregation. Cases of anemia, macrocytosis, leukopenia and, in exceptional cases, pancytopenia have been reported less frequently.

Contraindications

Hypersensitivity to valproate, divalproate, valpromide or to any of the components of the drug in history

Acute and chronic hepatitis

Cases of severe hepatitis in the patient's personal or family history, including those caused by drugs

Hepatic porphyria

Combination with mefloquine

Combined reception with St. John's wort

Children's age up to 6 years

Drug Interactions

The concomitant use of drugs that provoke convulsions or drugs that lower the threshold of excitability of the brain should be taken into account with all seriousness in view of the severity of the potential danger. These include most antidepressants (imipramines, selective serotonin reuptake inhibitors), antipsychotics (phenothiazines and butyrophenones), mefloquine, chloroquine, bupropion, and tramadol.

Contraindicated combinations

Mefloquine (an antimalarial drug) increases the metabolism of valproic acid and may cause seizures. Therefore, epileptic seizures may occur during combination therapy.

St. John's wort causes a risk of reducing the concentration of valproic acid in the blood plasma and its therapeutic efficacy.

Lamotrigine: increased risk of severe skin reactions (Lyell's syndrome).

In addition, it is possible to increase the concentration of lamotrigine in the blood plasma (its metabolism is slowed down by sodium valproate). If the combination proves necessary, careful clinical monitoring is required.

Combinations requiring special precautions

Aztreonam, imipenem, meropenem cause the risk of seizures, due to a decrease in the concentration of valproic acid in the blood serum. Clinical observation, determination of the concentration of drugs in the blood plasma and, possibly, a revision of the dosage of valproic acid during treatment with antibacterial drugs and after their withdrawal are required.

Carbamazepine: Depakine Chrono causes an increase in plasma concentrations of the active metabolite of carbamazepine with signs of overdose. In addition, a decrease in plasma concentrations of valproic acid is possible as a result of stimulation of hepatic metabolism by carbamazepine. Clinical monitoring, determination of plasma concentrations and, if necessary, dose adjustment of both anticonvulsants is recommended.

Felbamate causes an increase in the concentration of valproic acid in the blood serum, the risk of overdose. Clinical monitoring and laboratory monitoring are required, and possibly a revision of the dosage of Depakine® Chrono during treatment with felbamate and after its withdrawal.

Phenobarbital (and by exprapolation - primidone): an increase in phenobarbital in blood plasma with signs of overdose in children. In addition, plasma concentrations of valproic acid are reduced due to increased hepatic metabolism under the influence of phenobarbital.

Therefore, clinical monitoring is recommended during the first 15 days of combined treatment with an immediate reduction in the dose of phenobarbital when signs of drowsiness appear. If necessary, determine the level of both drugs in plasma in the blood.

Phenytoin (and by extrapolation - fosphenytoin): change in the concentration of phenytoin in the blood plasma. In addition, the risk of a decrease in the concentration of valproic acid in the blood plasma as a result of an increase in its metabolism by phenytoin in the liver. Therefore, clinical monitoring, measurement of plasma concentrations and dose adjustments of both anticonvulsants are recommended.

Topiramate: risk of developing hyperammonemia or encephalopathy, usually associated with valproic acid, when administered simultaneously with topiramate. It is necessary to strengthen the clinical and laboratory control of ammonemia at the beginning of treatment in the event of the appearance of symptoms indicating it.

Rifampicin: Risk of seizures due to increased hepatic metabolism of valproate by rifampicin. Clinical and laboratory monitoring is recommended, and dose adjustment of the anticonvulsant drug is possible during treatment with rifampicin and after its withdrawal.

Zidovudine: the risk of increased adverse reactions to zidovudine, in particular hematological effects, due to a decrease in metabolism under the influence of valproic acid. Regular clinical and laboratory monitoring is required. The blood picture for the detection of anemia should be checked during the first two months of using the combination.

Combinations to consider

Nimodipine (for oral and, by extrapolation, injection):

The risk of enhancing the hypotensive effect of nimodipine due to an increase in its concentration in the blood plasma (valproic acid inhibits its metabolism).

Other forms of interaction

Oral contraceptives: Depakine Chrono does not have an enzyme-inducing effect and, therefore, does not reduce the effectiveness of estrogen-progestogenic hormonal contraceptives.

special instructions

In rare cases (regardless of the spontaneous fluctuations observed in some types of epilepsy), an increase in seizures or the development of a new type of seizures may occur after taking an antiepileptic drug. This may be the result of a pharmacokinetic interaction of two or more antiepileptic drugs used simultaneously, a manifestation of toxicity (due to impaired liver function or encephalopathy) or overdose.

Since this drug is converted to valproic acid in the body, it should not be used concomitantly with other drugs that undergo the same transformation to avoid an overdose of valproic acid (eg, divalproate, valpromide).

Liver dysfunction

Conditions of occurrence: there are exceptional cases of liver damage with severe and sometimes fatal outcome. Infants and children under 3 years of age with severe epilepsy associated with brain damage, mental retardation and/or congenital metabolic disorder or degenerative disease are at increased risk. At the age of over 3 years, the frequency of such complications decreases significantly.

In the vast majority of cases, this liver injury occurs in the first 6 months of treatment, usually between weeks 2 and 12, and usually during polytherapy with antiepileptic drugs.

Signs-harbingers: early diagnosis is based mainly on the clinical picture of the disease. In particular, you should pay attention to two types of symptoms that may precede the development of jaundice, especially in patients at risk (see "Conditions"):

First, non-specific systemic signs, usually with sudden onset, such as asthenia, anorexia, loss of strength, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;

Secondly, relapses of epileptic seizures, despite the exact adherence to treatment.

It is recommended to inform the patient or his family, if this is a child, that they should immediately consult a doctor if this type of clinical picture develops. In addition to the physical examination, laboratory analysis of liver function should be performed immediately.

Detection: during the first 6 months of treatment, periodic monitoring of liver function is necessary.

Among the standard tests, the most important are analyzes that reflect the state of protein synthesis and, in particular, prothrombin time (PT). If pathologically low PT values are confirmed, especially if there are other abnormal laboratory parameters (significant decrease in fibrinogen and blood coagulation factors, increased bilirubin levels, increased transaminase activity), it is required to stop treatment (and as a precaution, stop treatment salicylate derivatives, if they are administered simultaneously, since their metabolism is carried out in the same way).

pancreatitis

Extremely rare cases of pancreatitis are known, sometimes with a fatal outcome. Pancreatitis can occur regardless of the patient's age and duration of treatment, with young children at highest risk.

Pancreatitis with an unfavorable outcome is usually observed in young children and in patients with severe epilepsy, with brain damage or against the background of polytherapy with antiepileptic drugs.

The risk of death is higher with pancreatitis associated with liver failure.

With the appearance of acute abdominal pain, nausea, vomiting and / or anorexia, the possibility of developing pancreatitis should be considered; in the event of an increase in the levels of pancreatic enzymes, treatment should be discontinued and other necessary treatment should be prescribed.

Suicide risk

Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for some indications. A meta-analysis of data from randomized, placebo-controlled clinical trials of antiepileptic drugs also showed a slight increase in the risk of suicidal thoughts and behavior. The reasons for this risk are unknown, and the available data do not rule out an increased risk associated with the use of valproate.

Therefore, careful monitoring of signs of suicidal thoughts and behavior in patients is necessary, and appropriate treatment may be required. Patients (and their caregivers) should seek medical attention if suicidal thoughts and behavior occur.

Interaction with other drugs

Co-administration of this drug with lamotrigine is not recommended.

Precautions for use

Before starting treatment, a laboratory analysis of liver function should be carried out, then, during the first 6 months, periodically repeated, especially in patients at risk.

As with most antiepileptic drugs, isolated, transient and mild transaminase elevations can be observed without any clinical symptoms, especially at the start of treatment.

In such cases, it is recommended to conduct a more complete laboratory examination (in particular, the determination of prothrombin time) in order to revise the dosage if necessary; analyzes are repeated depending on the results obtained.

In children under 3 years of age, the use of sodium valproate is recommended only as monotherapy after weighing the therapeutic benefit / risk of liver damage and pancreatitis in patients of this age group. In addition, not all dosage forms are applicable in children: see the section "Method of administration and doses".

Before starting treatment, as well as before any surgical operation and in cases of hematomas or spontaneous bleeding, it is recommended to do a blood test (complete blood count, including platelet count, bleeding time and blood coagulation parameters).

Avoid concomitant administration of salicylate derivatives to children due to possible hepatotoxicity and risk of bleeding.

In renal insufficiency, an increase in the concentration of valproic acid in the blood should be taken into account and, therefore, it is necessary to reduce the dose.

Patients with a deficiency of urea cycle enzymes are not recommended to take this drug. In such patients, several cases of hyperammonemia occurring with stupor or coma have been described.

In children with a history of hepatic and gastrointestinal disorders of unknown etiology (anorexia, vomiting, cases of cytolysis) with episodes of lethargy or coma, mental retardation, or with a family history of death of a newborn child or infant, before starting treatment with valproate, it is necessary to conduct a metabolic examination, in particular, the presence of ammonemia on an empty stomach and after eating.

Despite the recognition that this drug causes immune system disorders only in exceptional cases, in patients with systemic lupus erythematosus, the benefit should be weighed against the risk.

When starting treatment, the patient should be informed about the possible weight gain and about the appropriate measures, mainly dietary, that he should take to minimize this effect. You should also exclude pregnancy in women of childbearing age and use effective contraception before starting treatment.

The risk of malformations caused by valproate is 3-4 times higher in pregnant women taking this drug than the risk found in the general population, which is 3%. The most commonly observed malformations are neural tube closure defects (approximately 2-3%), facial dysmorphias, facial clefts, craniostenosis, cardiac malformations, kidney and urinary tract malformations, and limb deformities.

Doses greater than 1000 mg/day and combination with other anticonvulsants are important risk factors for fetal malformations.

Current epidemiological data do not indicate a decrease in the overall intelligence factor of children with exposure to sodium valproate in utero.

However, these children have been described to have some reduction in verbal ability and/or more frequent visits to speech therapists or extracurricular activities. In addition, several cases of autism and related disorders have been reported in children exposed to sodium valproate in utero. More research is needed to confirm or refute these results.

When planning a pregnancy

If you plan to become pregnant, you should definitely decide on the use of other medications.

If the use of sodium valproate is unavoidable (i.e., there is no other alternative), it is recommended to prescribe the minimum effective daily dose. Sustained release dosage forms should be used or, if this is not possible, the daily dose should be divided into several doses. This is necessary in order to avoid peak peak plasma concentrations of valproic acid.

There are currently no data to support the efficacy of folic acid supplementation in women exposed to sodium valproate during pregnancy. However, given its beneficial effects in other conditions, folic acid supplementation at 5 mg/day 1 month before conception and 2 months after conception may be suggested. An examination aimed at identifying malformations should be the same for everyone, regardless of whether the pregnant woman is taking folic acid or not.

During pregnancy:

If the choice of another drug is absolutely impossible, and it is necessary to continue treatment with sodium valproate, it is recommended to prescribe the lowest effective dose. Doses in excess of 1000 mg/day should be avoided whenever possible. Regardless of folic acid intake, screening for fetal malformations is essential for all pregnant women.

Before delivery, a coagulogram should be done, in particular, the number of platelets, the level of fibrinogen and the time of blood clotting (activated partial thromboplastin time, APTT).

newborns

Depakine Chrono can cause the development of hemorrhagic syndrome in newborns, not associated with vitamin K deficiency.

Normal indicators of maternal hemostasis do not exclude the possibility of pathology in the newborn. Therefore, the newborn should have platelet count, fibrinogen levels, and activated partial thromboplastin time (APTT) measured. Newborns have also reported cases of hypoglycemia in the first week of life.

Lactation

Valproate is excreted in breast milk in small amounts. However, in connection with data on reduced verbal abilities in young children, patients should be advised to stop breastfeeding.

The peculiarity of the influence on the ability to drive a vehicle or potentially dangerous mechanisms

The patient should be warned about the risk of drowsiness, especially in the case of combined anticonvulsant therapy or the combination of Depakine® Chrono with drugs that can increase drowsiness.

Overdose

Symptoms: coma with muscular hypotension, hyporeflexia, miosis, impaired respiratory function and metabolic acidosis. Rare cases of intracranial hypertension resulting from cerebral edema have been described.

Treatment: gastric lavage, maintaining effective diuresis, monitoring the state of the cardiovascular and respiratory systems. In very severe cases, if necessary, extrarenal dialysis can be performed.

As a rule, the prognosis of such poisoning is favorable. Despite this, several deaths have been reported.

inside.

This drug is intended only for adults and children over 6 years of age weighing more than 17 kg!

Depakine ® chrono 300/500 mg extended-release tablets can be divided to facilitate the administration of an individually adjusted dose.

Tablets are taken without crushing or chewing them.

Dosing regimen for epilepsy

Average daily doses (with prolonged use):

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

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

For adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg valproic acid / kg (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 is not 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.

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

One-shot use is possible with well-controlled epilepsy.

Dosing regimen for manic episodes in bipolar disorders

adults

The daily dose is selected by the attending physician individually.

The recommended starting daily dose is 750 mg. In addition, in clinical studies, the initial dose of 20 mg of sodium valproate per kg of body weight also showed an acceptable safety profile.

Continuation of treatment of manic episodes in bipolar disorder should be carried out by taking an individually adjusted minimum effective dose.

Children and teenagers

The efficacy and safety of the drug in the treatment of manic episodes in bipolar disorders in patients under 18 years of age have not been evaluated.

The use of the drug in patients of special groups

Instructions for use Depakine Chrono
Buy Depakine Chrono tb 500mg
Dosage forms
prolonged-release film-coated tablets 500mg
Manufacturers
Sanofi Winthrop Industry (France)
Group
Anticonvulsants - valproates
Compound
Active ingredients: sodium valproate - 199.8 mg, valproic acid - 87.0 mg.
International non-proprietary name
Valproic acid
Synonyms
Acediprol, Valparin XP, Depakine, Depakine Chronosphere, Depakine enteric 300, Konvuleks, Konvulsofin, Enkorat
pharmachologic effect
Pharmacodynamics. An antiepileptic drug that has a central muscle relaxant and sedative effect. Shows antiepileptic activity in various types of epilepsy. The main mechanism of action seems to be associated with the effect of valproic acid on the GABAergic system: an increase in the content of gamma-aminobutyric acid (GABA) in the central nervous system (CNS) and activation of GABAergic transmission. Pharmacokinetics. Absorption. The bioavailability of sodium valproate and valproic acid when taken orally is close to 100%. When taking tablets at a dose of 1000 mg / day, the minimum plasma concentration is 44.7 ± 9.8 μg / ml, and the maximum plasma concentration is 81.6 ± 15.8 μg / ml. The time to reach the maximum concentration is 6.58±2.23 hours. The equilibrium concentration is reached 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 there is a reasonable need to achieve higher plasma concentrations, the ratio of the expected benefit and the risk of side effects, especially dose-dependent ones, should be carefully weighed, since at concentrations above 100 mg / l, an increase in side effects is expected up to the development of intoxication. At plasma concentrations above 150 mg / l, a dose reduction is required. Distribution. The volume of distribution 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. Communication with blood plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, the relationship with blood plasma proteins decreases. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid may increase to 8.5-20%. With hypoproteinemia, the total concentration of valproic acid (free + plasma protein-bound fraction) may not change, but may also decrease due to an increase in the metabolism of the free (non-plasma protein-bound) fraction of valproic acid. Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in the CSF is 10% of the corresponding concentration in the blood serum. Valproic acid passes into the breast milk of nursing mothers. In the state of reaching the equilibrium concentration of valproic acid in the blood serum, its concentration in breast milk is from 1% to 10% of its concentration in the blood serum. Metabolism. Metabolism is carried out in the liver by glucuronidation, as well as beta-, omega-, and omega-1 oxidation. More than 20 metabolites have been identified, metabolites after omega-oxidation have a hepatotoxic effect. Valproic acid does not have an inducing effect on enzymes that are part of the cytochrome P450 metabolic 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 substances, such as estrogens, progestogens and indirect anticoagulants. Withdrawal. Valproic acid is predominantly excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted by the kidneys unchanged. The plasma clearance of valproic acid in patients with epilepsy is 12.7 ml/min. The half-life is 15-17 hours. When combined with antiepileptic drugs that induce microsomal liver enzymes, the plasma clearance of valproic acid increases, and the half-life decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs. The half-life values in children older than 2 months of age are close to those in adults. In patients with liver disease, the half-life of valproic acid is increased. In case of overdose, an increase in the half-life up to 30 hours was observed. Only the free fraction of valproic acid in the blood (10%) is subjected to hemodialysis. Features of pharmacokinetics during pregnancy. With an increase in the volume of distribution of valproic acid in the third trimester of pregnancy, its renal clearance increases. At the same time, despite taking the drug at a constant dose, a decrease in serum concentrations of valproic acid is possible. In addition, during pregnancy, the relationship of valproic acid with blood plasma proteins may change, which can lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum. Compared to the enteric-coated form, the extended-release form at equivalent doses is characterized by the following: no absorption delay time after ingestion; prolonged absorption; identical bioavailability; lower maximum concentration, (decrease in maximum concentration by about 25%), but with a more stable plateau phase from 4 to 14 hours after ingestion; more linear correlation between dose and plasma drug concentration.
Indications for use
In adults. For the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoconic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs). For the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs). For the treatment and prevention of bipolar affective disorders. In children. For the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoconic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs). For the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs).
Contraindications
Hypersensitivity to valproate, sodium, valproic acid, seminatrium valproate, valpromide or any of the components of the drug; acute hepatitis; chronic hepatitis; severe liver disease (especially drug-induced hepatitis) in the anamnesis of the patient and his close blood relatives; severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient; severe violations of the liver or pancreas; hepatic porphyria; combination with mefloquine; combination with St. John's wort; children under 6 years of age (risk of getting the tablet into the respiratory tract when swallowing).
Side effect
Congenital, hereditary and genetic disorders. Teratogenic risk. Blood and lymphatic disorders. Frequent: thrombocytopenia; rare: pancytopenia, anemia, leukopenia, disorders of bone marrow hematopoiesis, including isolated aplasia of red blood cells; agranulocytosis. An isolated decrease in the content of fibrinogen in the blood and a prolongation of the prothrombin time have been reported, usually not accompanied by clinical manifestations, especially when using high doses (valproic acid has an inhibitory effect on the second phase of platelet aggregation). Nervous system disorders. Uncommon: ataxia; very rare: dementia associated 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 the frequency of seizures (despite treatment), which decreases when the drug is discontinued or the dose is reduced. 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, which may be irreversible, including reversible parkinsonism. Transient and / or dose-dependent mild postural tremor and drowsiness. Hyperammonemia, combined with neurological symptoms (in this case, the patient requires additional examination). Hearing disorders and labyrinth disorders. Rare: reversible or irreversible deafness. Violations of the organ of vision. Unknown frequency: diplopia, nystagmus, flashing "flies" before the eyes. Gastrointestinal disorders; frequent: at the beginning of treatment, nausea, vomiting, epigastric pain, diarrhea, which, with continued use of the drug, usually disappear after a few days; very rare: pancreatitis, sometimes fatal. Renal and urinary tract disorders. Very rare: enuresis. There have been several separate reports of the development of reversible Fanconi syndrome, the mechanism of which is still unclear. Skin and subcutaneous tissue disorders. Frequent: transient or dose-dependent alopecia; Very rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash. Metabolic and nutritional disorders. Frequent: isolated and moderate hyperammonemia in the absence of changes in liver function tests and neurological manifestations, which does not require discontinuation of the drug; very rare: hyponatremia. Syndrome of impaired secretion of antidiuretic hormone. Vascular disorders. Vasculitis. General disorders. Very rare: slight peripheral edema. Increase in body weight. Since obesity is a risk factor for the development of polycystic ovary syndrome, patients should be carefully monitored with weight gain. Immune system disorders. Angioedema, drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome), allergic reactions such as urticaria. Liver and biliary tract disorders. Rare: liver damage. Violations of the genital organs and the mammary gland. Frequency not known: amenorrhea and dysmenorrhea. male infertility. Mental disorders. Infrequent: irritability, hyperactivity, confusion, especially at the beginning of treatment; rare: changes in behavior, mood, depression, fatigue, aggressiveness, psychosis, unusual agitation, restlessness, dysarthria. Unknown frequency. hallucinations.
Interaction
Effect of valproic acid on other drugs. Antipsychotics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines. Valproic acid may potentiate the action of other psychotropic drugs such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, when they are used simultaneously with the drug, careful medical supervision and, if necessary, dose adjustment is recommended. lithium preparations. Valproic acid does not affect serum lithium concentrations. Phenobarbital. Valproic acid increases plasma concentrations of phenobarbital (by reducing its hepatic metabolism), and therefore the development of a 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 is recommended, with an immediate reduction in the dose of phenobarbital in the event of a sedative effect and, if necessary, the determination of plasma concentrations of phenobarbital. Primidon. Valproic acid increases plasma concentrations of primidone with 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. Phenytoin. Valproic acid reduces total plasma concentrations of phenytoin. In addition, valproic acid increases the concentration of the free fraction of phenytoin 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 concentrations of phenytoin and its free fraction in the blood is recommended. Carbamazepine. With the simultaneous use of valproic acid and carbamazepine, clinical manifestations of carbamazepine toxicity have been reported, since valproic acid can potentiate the toxic effects of carbamazepine. Careful clinical monitoring of such patients is recommended, especially at the beginning of combination therapy with correction, if necessary, of the dose of carbamazepine. Lamotrigine. Valproic acid slows down the metabolism of lamotrigine in the liver and increases the half-life of lamotrigine by 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, dose adjustment (reduction) of lamotrigine is recommended. Zidovudine. Valproic acid may increase plasma concentrations of zidovudine, resulting in increased zidovudine toxicity. Felbamat. Valproic acid can reduce the mean clearance of felbamate by 16%. Nimodipine (for oral administration and, by extrapolation, a solution for parenteral administration). Strengthening the hypotensive effect of nimodipine due to an increase in its plasma concentration (inhibition of the metabolism of nimodipine by valproic acid). Effect of other drugs on valproic acid. Antiepileptic drugs that can induce microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine) reduce plasma concentrations of valproic acid. In the case of combination therapy, the doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood. Felbamat. With the combination of felbamate and valproic acid, the clearance of valproic acid is reduced by 22-50% and, accordingly, plasma concentrations of valproic acid increase. Plasma concentrations of valproic acid should be monitored. Mefloquine. Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing convulsions, therefore, with their simultaneous use, the development of an epileptic seizure is possible. St. John's wort preparations. With the simultaneous use of valproic acid and preparations of St. John's wort, a decrease in the anticonvulsant effectiveness of valproic acid is possible. Drugs that have a high and strong connection with blood plasma proteins (acetylsalicylic acid). In the case of simultaneous use of valproic acid and drugs that have a high and strong connection with blood plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free fraction of valproic acid. Indirect anticoagulants. With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of the prothrombin index is required. Pimetidine, erythromycin. Serum concentrations of valproic acid may increase in the case of simultaneous use of cimetidine or erythromycin (as a result of slowing down its hepatic metabolism). Carbapenems (panipenem, meropenem, imipenem). A decrease in the concentration of valproic acid in the blood when it is used simultaneously with carbapenems, leading to a 60-100% decrease in the concentration of valproic acid in the blood over two 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 the blood. If treatment with carbapenems cannot be avoided, blood levels of valproic acid should be closely monitored. Rifampicin. Rifampicin can reduce the concentration of valproic acid in the blood, which leads to the loss of the therapeutic effect of the drug. Therefore, it may be necessary to increase the dose of the drug while using rifampicin. Other interactions. With topiramate. The simultaneous use of valproic acid and topiramate has been associated with encephalopathy and/or hyperammonemia. Patients receiving these two drugs at the same time should be under close medical supervision for the development of symptoms of hyperammoniemic encephalopathy. With estrogen-progestogenic drugs. Valproic acid does not have the ability to induce liver enzymes and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogenic drugs in women using hormonal contraceptive methods. With ethanol and other potentially hepatotoxic drugs. When they are used simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid. with clonazepam. The simultaneous use of clonazepam with valproic acid can lead in isolated cases to an increase in the severity of the absence status. With myelotoxic drugs. With their simultaneous use with valproic acid, the risk of inhibition of bone marrow hematopoiesis increases.
Method of application and dosage
This drug is intended only for adults and children over 6 years of age weighing more than 17 kg. This dosage form is not recommended for children under 6 years of age (risk of inhalation of the tablet if swallowed). The drug is a form of delayed release of the active substance from the Depakine group of drugs. Sustained release avoids sharp rises in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood for a longer period of time. The extended-release tablets may be divided to facilitate individual dose adjustment. Dosing regimen for epilepsy. The daily dose is selected by the attending physician individually. The minimum effective dose to prevent the development of epileptic seizures should be selected (especially during pregnancy). The daily dose should be adjusted according to age and body weight. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached. A clear relationship between daily dose, plasma concentration and therapeutic effect has not been established. Therefore, the optimal dose should be determined primarily by clinical response. Determination of the level of valproic acid in plasma can serve as an addition to clinical observation if epilepsy is not controlled or there is a suspicion of the development of side effects. The range of therapeutic concentration 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, which is then 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 of epileptic seizures. Average daily doses (with long-term use): for children 6-14 years old (body weight 20-30 kg) - 30 mg valproic acid / kg body weight (600-1200 mg); for adolescents (body weight 40-60 kg) - 25 mg 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 is not 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, do not increase the daily dose above the recommended average daily dose before this time. The daily dose may be divided into 1-2 doses, preferably with meals. Most patients who are already taking the dosage form of the drug Depakine ("long-acting" can be transferred to the dosage form of this drug of prolonged action immediately or within a few days, while patients should continue to take the previously selected daily dose. For patients who previously took antiepileptic means, the transfer to the drug Depakine chrono should be carried out gradually, reaching the optimal dose of the drug within about 2 weeks.At the same time, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced.If the previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.So as other antiepileptic drugs can reversibly induce microsomal liver enzymes, it is necessary to monitor the concentration of valproic acid in the blood within 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), reduce the daily dose of valproic acid. If necessary, the combination of valproic acid with other antiepileptic drugs should be added to the treatment gradually. Dosing regimen for manic episodes in bipolar disorders. Adults. The daily dose is selected by the attending physician individually. The recommended starting daily dose is 750 mg. In addition, in clinical studies, the initial dose of 20 mg of sodium valproate per kg of body weight also showed an acceptable safety profile. Sustained release formulations can be taken once or twice a day. The dose should be increased as rapidly as possible until the minimum therapeutic dose that produces the desired clinical effect is reached. The average value of the daily dose is in the range of 1000-2000 mg of sodium valproate. Patients receiving a daily dose above 45 mg/kg/day should be under close medical supervision. Continuation of treatment of manic episodes in bipolar disorder should be carried out by taking an individually adjusted minimum effective dose. Children and teenagers. The efficacy and safety of the drug in the treatment of manic episodes in bipolar disorders in patients under 18 years of age have not been evaluated. The use of the drug in patients of special groups. In patients with renal insufficiency and / or hypoproteinemia, the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be considered, and if necessary, reduce the dose of valproic acid, focusing on dose selection, mainly on the clinical picture, and not on the total content valproic acid in serum (free fraction and fraction associated with plasma proteins) to avoid possible errors in dose selection.
Overdose
Clinical manifestations of acute massive overdose usually occur in the form of a coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis. Cases of intracranial hypertension associated with cerebral edema have been described. With a massive overdose, a fatal outcome is possible, but the prognosis for an overdose is usually favorable. Symptoms of overdose may vary; seizures have been reported at very high plasma concentrations of valproic acid. Emergency care for overdose in the hospital should be as follows: gastric lavage, which is effective for 10-12 hours after taking the drug, monitoring the state of the cardiovascular and respiratory system and maintaining effective diuresis. Naloxone has been used successfully in some cases. In very severe cases of massive overdose, hemodialysis and hemoperfusion have been effective.
special instructions
Carefully. With diseases of the liver and pancreas in history. During pregnancy. With congenital fermentopathy. With oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia). With renal failure (dose adjustment required). With hypoproteinemia. In patients receiving multiple anticonvulsants due to an increased risk of liver damage. Concomitant use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, buterophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures). With the simultaneous use of antipsychotics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines (the possibility of potentiating their effects). With the simultaneous use of phenobarbital, primidone, phenytoid, lamotrid, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenemes, rifampicin, nimodipine (due it is possible to change plasma concentrations or these drugs and / or valproic acid, for more details see the section "Interaction with other drugs"). With the simultaneous use of carbamazepine, the risk of potentiation of the toxic effects of carbamazepine and a decrease in the plasma concentration of valproic acid). With the simultaneous use of topiramate (risk of developing encephalopathy). Pregnancy and lactation period. Pregnancy. The risk associated with the development of epileptic seizures during pregnancy. During pregnancy, the development of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia may pose a particular risk for both the mother and the fetus due to the possibility of death. The risk associated with the use of the drug during pregnancy. Experimental reproductive toxicity studies in mice, rats, and rabbits have demonstrated that valproic acid is teratogenic. Available clinical data confirm that children born to mothers with epilepsy treated with valproic acid have an increased incidence of intrauterine developmental disorders of varying severity (neural tube malformations; 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. Available data suggest an association between 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. Developmental delay is often combined with malformations and dysmorphic phenomena. However, in cases of developmental delay in such children, it is difficult to accurately establish a causal relationship with the use of valproic acid due to the possibility of simultaneous influence of other factors, such as the low level of intelligence of the mother or both parents; genetic, social factors, environmental factors; insufficient effectiveness of treatment aimed at preventing epileptic seizures in the mother during pregnancy. Various autistic disorders have also been reported in children exposed to valproic acid in utero. Both valproic acid monotherapy and combination therapy with valproic acid inclusion are associated with poor pregnancy outcomes, but combination antiepileptic therapy with valproic acid has been reported to be associated with a higher risk of adverse pregnancy outcomes compared with valproic acid monotherapy. In connection with the foregoing, the drug 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 the need to use the drug or the possibility of refusing to use it should be decided before starting the use of the drug or reconsidered if the woman receiving the drug is planning a pregnancy. Women of childbearing age should use effective contraception during treatment with the drug. Women of childbearing age should be informed about the risks and benefits of using valproic acid during pregnancy. If a woman is planning a pregnancy or she is diagnosed with pregnancy, then the need for treatment with valproic acid should be reassessed depending on the indication. When bipolar disorder is indicated, consideration should be given to discontinuing treatment with valproic acid. When epilepsy is indicated, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the benefit-risk ratio. If, after a reassessment of the balance of benefits and risks, treatment with the drug should still be continued during pregnancy, then 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 slow-release dosage forms of the drug is preferable. One month before conception and within 2 months after it, folic acid (at a dose of 5 mg per day) should be added to antiepileptic treatment, as this can minimize the risk of neural tube defects. Continuous special prenatal monitoring should be carried out to identify possible malformations of the neural tube or other malformations of the fetus. risk for newborns. It was reported about the development of isolated cases of hemorrhagic syndrome in 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 clotting 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 treated with valproic acid, it is imperative to determine the number of platelets in the blood, plasma fibrinogen concentration, blood clotting factors and a coagulogram. Cases of hypoglycemia have been reported in newborns whose mothers took valproic acid during the third trimester of pregnancy. breastfeeding period. Excretion of valproic acid into breast milk is low, its concentration in milk is 1-10% of its concentration in blood serum. Based on literature data and little clinical experience, mothers may plan to breastfeed when monotherapy with the drug, but the side effect profile of the drug, especially the hematological disorders caused by it, should be taken into account. Severe liver damage. predisposing factors. Clinical experience shows that patients at risk are patients receiving several antiepileptic drugs at the same time, children under three years of age with severe seizures, especially against the background of brain damage, mental retardation and / or congenital metabolic or degenerative diseases. After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the age of the patient increases. In most cases, liver damage occurred within the first 6 months of treatment. Symptoms suggestive of liver damage. For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, attention should be paid to the appearance of the following symptoms, which may precede the onset of jaundice, especially in patients at risk: non-specific symptoms, especially those of sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by recurrent vomiting and abdominal pain; recurrence of seizures in patients with epilepsy. Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of the symptoms to the attending physician. In the event of their occurrence, patients should immediately conduct a clinical examination and laboratory tests of liver function tests. Identification. Determination of liver function tests should be carried out before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative studies reflect the state of the protein-synthetic function of the liver, especially the prothrombin index. Confirmation of a deviation from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of transaminases) requires discontinuation of the drug. As a precaution, if patients received salicylates at the same time, their intake should also be discontinued, since they are metabolized along the same metabolic pathway as valproic acid. Pancreatitis. Children are at an increased risk of developing pancreatitis, with increasing age of the child the risk decreases. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for developing pancreatitis. Liver failure associated with pancreatitis increases the risk of death. Patients who develop severe abdominal pain, nausea, vomiting, and/or anorexia should be evaluated immediately.