Depakin chrono 500 by code atx. 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 slow-release form of the active substance from the Depakine ® group of drugs. Slow release avoids sudden increases in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood throughout the day for a longer period of time.

Extended-release tablets Depakine ® Chrono 300/500 mg can be divided to facilitate the administration of an individually selected dose.

The tablets are taken without crushing or chewing them.

Dosage regimen for epilepsy

The minimum dose effective to prevent the development of epileptic attacks should be selected (especially during pregnancy). The daily dose should be set according to age and body weight. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached. No clear relationship has been established between daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined primarily by clinical response. Determination of plasma valproic acid levels can serve as an addition to clinical monitoring if epilepsy is uncontrolled or if side effects are suspected. The therapeutic blood concentration range is usually 40-100 mg/L (300-700 µmol/L).

For 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 valproic acid per kg body weight to the dose required 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 (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 60 kg and above) - an average of 20 mg of valproic acid / kg (1200-2100 mg).

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

If epilepsy is not controlled at these doses, they can be increased under monitoring 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, the daily dose should not be increased above the recommended average daily dose before this date.

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

One-time use is possible for well-controlled epilepsy.

Most patients who are already taking the non-extended-release dosage form of Depakine ® can be switched to the extended-release dosage form of this drug 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 transition to taking the drug Depakine ® Chrono should be carried out gradually, reaching the optimal dose of the drug within approximately 2 weeks. In this case, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previously taken antiepileptic drug is discontinued, its withdrawal should be carried out gradually.

Since other antiepileptic drugs can reversibly induce liver microsomal enzymes, the concentrations of valproic acid in the blood should be monitored for 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 it is necessary to combine valproic acid with other antiepileptic drugs, they should be added to treatment gradually (see “Interaction”).

Dosage regimen for manic episodes in bipolar disorders

Adults

The daily dose is selected individually by the attending physician.

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

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

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

Children and teenagers

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

Use of the drug in patients of special groups

In patients with renal failure 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 when selecting a 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 blood plasma proteins) to avoid possible errors in dose selection.

APPROVED

By order of the chairman

Committee for Control of Medical and

Pharmaceutical activities

Ministry of Health

Republic of Kazakhstan

From "__"____________20

№ ____________

Instructions for medical use

Medicine

DEPAKIN® CHRONO

Tradename

Depakin Chrono

International nonproprietary name

Valproic acid

Dosage form

Film-coated tablets, extended release, divisible, 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 silicon dioxide anhydrous, colloidal silicon dioxide aqueous,

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

Description

Tablets are oblong in shape with hemispherical edges, almost white in 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.

PBX 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 higher plasma concentrations are required, the benefits must be weighed against the risk of adverse effects, especially dose-related ones. Despite this, if concentrations persist at levels above 150 mg/l, the dose should be reduced. Steady-state concentrations in blood plasma are achieved within 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 on 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 either its own degradation or that of other substances such as estrogen-progestogens and oral anticoagulants.

When compared with the gastroresistant dosage form of valproate, the extended release dosage form at the same doses is characterized by the disappearance of the absorption lag period, prolonged absorption, identical bioavailability, lower total maximum concentration and plasma concentration of free substance (Cmax lower by approximately 25% with a relatively stable plateau 4-14 hours after administration); 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 daily, the amplitude of fluctuations in plasma concentrations is reduced by half, 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 against 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 brain tissues, or with changes neurotransmitters or direct effects on the membrane. The most widely accepted hypothesis relates 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 while simultaneously increasing its slow-wave component.

Indications for use

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

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

Directions for use and doses

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 (respiratory hazard).

Mode of application

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

Once daily dosing 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, subsequently the dose is increased to the optimal dose (see “Start of treatment”). Average dose: 20 - 30 mg/kg per day. However, if seizures cannot be treated with these doses, then with strict monitoring of the patient, the dose can be increased.

For children aged 6 years and older: Average dose is 30 mg/kg per day.

For adults: average dose 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, taking into account the wide range of individual sensitivity to valproate.

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

Start of treatment

For patients in whom adequate control of seizures is achieved using immediate-release dosage forms of Depakine, the daily dose remains unchanged when replacing it with Depakine Chrono.

For patients already under treatment and taking another antiepileptic drug, Depakin Chrono is administered gradually so that the optimal dose is reached after approximately 2 weeks; then, if necessary, reduce concomitant treatment depending on the effectiveness of treatment.

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

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

Dosage for the treatment of mania in bipolar disorders

The recommended starting dose is 20 mg/kg/day. This dose should be increased as soon as possible to achieve the minimum therapeutic dose that will provide the desired clinical effect. This effect can generally be obtained at plasma valproate levels between 45 and 125 mcg/mL. The recommended maintenance dose for bipolar disorders 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 individual clinical response. The duration of the course is determined individually by the doctor.

Dosage for preventing relapse of mania in bipolar disorders

To avoid relapse, the dose to be prescribed should be the lowest dose that provides adequate control of the acute symptoms of mania in the individual patient. The maximum daily dose of 3000 mg should not be exceeded.

Side effects

Congenital, familial or genetic disorders, due to teratogenic risk (see section “Special instructions”)

Bone marrow aplasia and true red cell aplasia

Agranulocytosis

Dose-dependent thrombocytopenia observed without any clinical consequences

For asymptomatic thrombocytopenia, simply reducing the dose of this drug, if possible based on platelet counts and providing effective epilepsy control, will usually resolve the thrombocytopenia.

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

Confusion or convulsions

Stupor or lethargy, sometimes leading to temporary coma (encephalopathy), either isolated or associated with a paradoxical increase in seizures with valproate, regressing when treatment is stopped or when the dose is reduced

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 stopping the drug

Temporary and/or dose-dependent hair loss

Skin reactions such as exanthematous rash

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

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

Quincke's edema, drug eruption syndrome with eosinophilia and systemic symptoms (LSESS syndrome) or hypersensitivity syndrome

Liver diseases

Amenorrhea, menstrual irregularities

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

Ataxia

Reversible Parkinson's syndrome

Very rarely

Cognitive impairment with an insidious and progressive onset, which can progress to full dementia and is reversible after a few weeks or months after discontinuation of treatment

Pancreatitis requiring premature cessation of treatment, sometimes fatal

Enuresis and urinary incontinence

Hyponatremia

Mild peripheral edema

In exceptional cases

Reversible and irreversible hearing loss

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

Kidney damage

A decrease in fibrinogen levels 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. Less frequently reported cases of anemia, macrocytosis, leukopenia and, in exceptional cases, pancytopenia.

Contraindications

History of hypersensitivity to valproate, divalproate, valpromide or any of the components of the drug

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

Combination with St. John's wort

Children under 6 years old

Drug interactions

The simultaneous use of drugs that provoke seizures or drugs that lower the threshold of brain excitability should be taken into account with all seriousness due to 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) increases the metabolism of valproic acid and may cause seizures. Therefore, during combination therapy, epileptic seizures may occur.

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

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, close clinical monitoring is required.

Combinations requiring special precautions

Aztreonam, imipenem, meropenem cause a risk of seizures due to a decrease in the concentration of valproic acid in the blood serum. Clinical observation, determination of drug concentrations in blood plasma and, possibly, a revision of the dosage of valproic acid during treatment with antibacterial drugs and after their discontinuation 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 carbamazepine stimulation of hepatic metabolism. Clinical monitoring, determination of plasma concentrations and, if necessary, dose adjustment of both anticonvulsants are recommended.

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

Phenobarbital (and by extrapolation - primidone): increased 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 combination treatment, with immediate reduction of the phenobarbital dose if signs of drowsiness occur. If necessary, determine the plasma levels of both drugs in the blood.

Phenytoin (and by extrapolation - fosphenytoin): changes in the concentration of phenytoin in blood plasma. In addition, there is a risk of decreased plasma concentrations of valproic acid as a result of phenytoin enhancing its metabolism in the liver. Therefore, clinical monitoring, measurement of plasma concentrations and dose adjustment of both anticonvulsants is recommended.

Topiramate: There is a risk of developing hyperammonemia or encephalopathy, usually associated with valproic acid, when administered concomitantly with topiramate. It is necessary to strengthen clinical and laboratory monitoring of ammonemia at the beginning of treatment if symptoms indicating it appear.

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 discontinuation.

Zidovudine: there is a risk of increased adverse reactions to zidovudine, in particular hematological effects, due to decreased metabolism under the influence of valproic acid. Regular clinical and laboratory monitoring is necessary. Blood counts should be checked to detect anemia during the first two months of use of the combination.

Combinations to Consider

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

The risk of increasing the hypotensive effect of nimodipine due to an increase in its concentration in the blood plasma (valproic acid suppresses 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-progestogen hormonal contraceptives.

special instructions

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

Because this drug is converted to valproic acid in the body, it should not be used at the same time as other drugs that undergo the same transformation to avoid overdose of valproic acid (eg, divalproate, valpromide).

Liver dysfunction

Conditions of occurrence: There are exceptional cases of liver damage with severe and sometimes fatal outcomes. Infants and children under 3 years of age with severe epilepsy associated with brain damage, mental retardation, and/or an inborn error of metabolism or degenerative disease are at increased risk. Over the age of 3 years, the frequency of such complications decreases significantly.

In the vast majority of cases, such liver damage is observed in the first 6 months of treatment, usually between 2 and 12 weeks, and, as a rule, during polytherapy with antiepileptic drugs.

Precursor signs: 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 of occurrence”):

First, nonspecific systemic signs, usually with a sudden onset, such as asthenia, anorexia, loss of energy, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;

Secondly, relapses of epileptic seizures, despite strict adherence to treatment.

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

Identification: During the first 6 months of treatment, periodic monitoring of liver function is necessary.

Among the standard tests, the most important are those 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 abnormalities in laboratory parameters (significant decrease in the level of fibrinogen and blood coagulation factors, increased bilirubin levels, increased transaminase activity), it is necessary to stop treatment (and, as a precaution, stop treatment salicylate derivatives, if they are prescribed simultaneously, since their metabolism occurs in the same way).

Pancreatitis

There are extremely rare cases of pancreatitis, sometimes fatal. Pancreatitis can occur regardless of the patient's age or duration of treatment, with young children being at highest risk.

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

The risk of death is higher with pancreatitis against the background of liver failure.

If acute abdominal pain, nausea, vomiting and/or anorexia occur, the possibility of pancreatitis should be considered; If pancreatic enzyme levels increase, treatment should be discontinued and other appropriate treatment given.

Risk of suicide

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

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

Interaction with other drugs

Concomitant use of this drug with lamotrigine is not recommended.

Precautions for use

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

As with most antiepileptic drugs, an isolated, temporary and moderate increase in transaminase levels can be observed without any clinical symptoms, especially at the beginning of treatment.

In such cases, it is recommended to conduct a more complete laboratory examination (in particular, 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 the development of pancreatitis in patients in this age group. In addition, not all dosage forms are applicable in children: see section “Dosage and Administration”.

Before starting treatment, as well as before any surgery 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 case of renal failure, 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.

This drug is not recommended for patients with carbamide cycle enzyme deficiency. In such patients, several cases of hyperammonemia accompanied by 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, it is necessary before starting treatment with valproate. conduct a metabolic examination, in particular, the presence of ammonemia on an empty stomach and after meals.

Although it is recognized that this drug causes immune system dysfunction only in exceptional cases, the benefit versus risk should be weighed in patients with systemic lupus erythematosus.

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

The risk of malformations caused by valproate is 3 to 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 dysmorphia, facial clefts, craniostenosis, cardiac defects, renal and urinary tract malformations, and limb deformities.

Doses exceeding 1000 mg/day and combination with other anticonvulsants are important risk factors for the formation of malformations in the fetus.

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

However, some decrease in verbal abilities and/or more frequent use of speech therapists or additional classes have been described in such children. In addition, several cases of autism and related disorders have been reported in children exposed to sodium valproate in utero. Additional studies are needed to confirm or refute these results.

When planning a pregnancy

If pregnancy is planned, 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 peaks in the maximum concentrations of valproic acid in the blood plasma.

There is currently no evidence to support the effectiveness of folic acid supplementation in women exposed to sodium valproate during pregnancy. However, given its beneficial effects in other conditions, supplemental folic acid at a dose of 5 mg/day can be suggested 1 month before conception and for 2 months after it. Screening for birth defects should be the same for everyone, regardless of whether the pregnant woman is taking folic acid or not.

During pregnancy:

If choosing another drug is absolutely impossible and treatment with sodium valproate must be continued, it is recommended to prescribe the minimum effective dose. Doses exceeding 1000 mg/day should be avoided whenever possible. Regardless of folic acid intake, screening for fetal abnormalities is necessary for all pregnant women.

Before delivery, a coagulation test should be performed, including platelet count, fibrinogen level and clotting time (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's platelet count, fibrinogen level, and activated partial thromboplastin time (aPTT) should be determined. Hypoglycemia has also been reported in newborns in the first week of life.

Lactation

Valproate is excreted in breast milk in small quantities. However, due to data on reduced verbal abilities in young children, patients should be advised not to breastfeed.

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

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

Overdose

Symptoms: coma with muscle hypotonia, 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, extrarenal dialysis can be performed if necessary.

As a rule, the prognosis for 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!

Extended-release tablets Depakine ® Chrono 300/500 mg can be divided to facilitate the administration of an individually selected dose.

The tablets are taken without crushing or chewing them.

Dosage regimen for epilepsy

Average daily doses (with long-term 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 60 kg and above) - an average of 20 mg of valproic acid / kg (1200-2100 mg).

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

If epilepsy is not controlled at these doses, they can be increased under monitoring of the patient's condition and the concentration of valproic acid in the blood.

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

One-time use is possible for well-controlled epilepsy.

Dosage regimen for manic episodes in bipolar disorders

Adults

The daily dose is selected individually by the attending physician.

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

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

Children and teenagers

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

Use of the drug in patients of special groups

Instructions for use Depakine Chrono
Buy Depakine Chrono TB 500mg
Dosage forms
film-coated tablets, prolonged action 500 mg
Manufacturers
Sanofi Winthrop Industry (France)
Group
Anticonvulsants - valproate
Compound
Active ingredients: sodium valproate - 199.8 mg, valproic acid - 87.0 mg.
International nonproprietary name
Valproic acid
Synonyms
Acediprol, Valparin HR, Depakin, Depakin Chronosphere, Depakin Enteric 300, Convulex, Convulsofin, Encorat
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 appears to be related to the effect of valproic acid on the GABAergic system: increasing the content of gamma-aminobutyric acid (GABA) in the central nervous system (CNS) and activating 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 mcg/ml, and the maximum plasma concentration is 81.6 ± 15.8 mcg/ml. The time to reach maximum concentration is 6.58±2.23 hours. Equilibrium concentration is achieved within 3-4 days of regular use of the drug. The average therapeutic range for serum concentrations of valproic acid is 50-100 mg/L. If there is a justified need to achieve higher concentrations in the blood plasma, 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 reduction in the dose of the drug 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. The connection 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 connection with blood plasma proteins decreases. 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 plasma proteins) may not change, but may decrease due to an increase in the metabolism of the free (not bound to plasma proteins) fraction of valproic acid. Valproic acid penetrates the cerebrospinal fluid and the brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding concentration in the blood serum. Valproic acid passes into the breast milk of nursing mothers. In the state of achieving equilibrium concentration of valproic acid in the blood serum, its concentration in breast milk ranges from 1% to 10% of its concentration in the blood serum. Metabolism. Metabolism occurs in the liver through 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 included in the metabolic system of cytochrome P450: 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. Excretion. Valproic acid is primarily excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted unchanged by the kidneys. 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 liver microsomal 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 liver microsomal enzymes by other antiepileptic drugs. The half-life values in children over 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 to 30 hours was observed. Only the free fraction of valproic acid in the blood (10%) is subject to hemodialysis. Features of pharmacokinetics during pregnancy. As the volume of distribution of valproic acid increases in the third trimester of pregnancy, its renal clearance increases. In this case, despite taking the drug in a constant dose, a decrease in serum concentrations of valproic acid is possible. In addition, during pregnancy, the connection 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 with the enteric-coated form, the extended-release form in equivalent doses is characterized by the following: no absorption delay after administration; prolonged absorption; identical bioavailability; lower maximum concentration (decrease in maximum concentration by approximately 25%), but with a more stable plateau phase from 4 to 14 hours after administration; 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, absence seizures, 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, absence seizures, 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, semisodium valproate, valpromide or any of the components of the drug; acute hepatitis; chronic hepatitis; a history of severe liver disease (especially drug-induced hepatitis) in 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 dysfunction of the liver or pancreas; hepatic porphyria; combination with mefloquine; combination with St. John's wort; children under 6 years of age (risk of tablets entering the respiratory tract when swallowed).
Side effect
Congenital, hereditary and genetic disorders. Teratogenic risk. Disorders of the blood and lymphatic system. Common: thrombocytopenia; rare: pancytopenia, anemia, leukopenia, disorders of bone marrow hematopoiesis, including isolated red blood cell aplasia; agranulocytosis. An isolated decrease in fibrinogen levels in the blood and an increase in 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 combined with brain 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 increased frequency of convulsive seizures (despite treatment), which decreases when the drug is discontinued or its dose is reduced. These cases were mainly observed during combination therapy (particularly with phenobarbital or topiramate) or after a sharp increase in the dose of valproic acid. Extrapyramidal disorders that 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 and labyrinth disorders. Rare: reversible or irreversible deafness. Violations of the organ of vision. Unknown frequency: diplopia, nystagmus, flashing “floaters” before the eyes. Gastrointestinal disorders; frequent: at the beginning of treatment, nausea, vomiting, epigastric pain, diarrhea, which usually disappear after a few days with continued use of the drug; very rare: pancreatitis, sometimes fatal. Renal and urinary tract disorders. Very rare: enuresis. There have been several isolated reports of the development of reversible Fanconi syndrome, the mechanism of development of which is still unclear. Disorders of the skin and subcutaneous tissues. Common: 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. Because obesity is a risk factor for the development of polycystic ovary syndrome, patients should be closely monitored for weight gain. Immune system disorders. Angioedema, drug eruption syndrome with eosinophilia and systemic symptoms (DRESS syndrome), allergic reactions such as urticaria. Disorders of the liver and biliary tract. Rare: liver damage. Disorders of the genital organs and breast. Unknown frequency: amenorrhea and dysmenorrhea. Male infertility. Mental disorders. Uncommon: irritability, hyperactivity, confusion, especially at the beginning of treatment; rare: changes in behavior, mood, depression, feeling tired, aggressiveness, psychosis, unusual agitation, restlessness, dysarthria. Unknown frequency. Hallucinations.
Interaction
Effect of valproic acid on other drugs. Neuroleptics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines. Valproic acid may potentiate the effect of other psychotropic drugs such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; Therefore, when used simultaneously with the drug, careful medical supervision and, if necessary, dose adjustment are 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 sedative effect of the latter may develop, especially in children. Therefore, careful medical monitoring of the patient is recommended 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 plasma concentrations of phenobarbital. Primidon. Valproic acid increases plasma concentrations of primidone with increased side effects (such as sedation); with long-term 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 binding to 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 are recommended. Carbamazepine. Clinical manifestations of carbamazepine toxicity have been reported with concomitant use of valproic acid and carbamazepine, as 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 adjustment, 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 may result in increased toxicity of lamotrigine, particularly severe skin reactions including toxic epidermal necrolysis. Therefore, careful clinical monitoring and, if necessary, dose adjustment (reduction) of lamotrigine are recommended. Zidovudine. Valproic acid may increase plasma concentrations of zidovudine, resulting in increased zidovudine toxicity. Felbamate. Valproic acid may reduce the mean clearance of felbamate by 16%. Nimodipine (for oral administration and, by extrapolation, solution for parenteral administration). Increased hypotensive effect of nimodipine 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 liver microsomal enzymes (including phenytoin, phenobarbital, carbamazepine) reduce plasma concentrations of valproic acid. In the case of combination therapy, doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood. Felbamate. When felbamate and valproic acid are combined, the clearance of valproic acid is reduced by 22-50% and plasma concentrations of valproic acid increase accordingly. 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. Preparations of St. John's wort. With the simultaneous use of valproic acid and St. John's wort preparations, 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. When valproic acid and indirect anticoagulants are used simultaneously, careful monitoring of the prothrombin index is required. Pimetidine, erythromycin. Serum concentrations of valproic acid may increase with simultaneous use of cimetidine or erythromycin (as a result of slowing its hepatic metabolism). Carbapenems (panipenem, meropenem, imipenem). A decrease in the concentration of valproic acid in the blood when used simultaneously with carbapenems, leading to a 60-100% decrease in the concentration of valproic acid in the blood within two days of joint therapy, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems should be avoided in patients receiving a dose of valproic acid due to their ability to rapidly and intensely reduce valproic acid blood concentrations. If treatment with carbapenems cannot be avoided, close monitoring of valproic acid blood concentrations should be performed. Rifampicin. Rifampicin may reduce the concentration of valproic acid in the blood, which leads to 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. Concomitant use of valproic acid and topiramate has been associated with encephalopathy and/or hyperammonemia. Patients receiving these two drugs simultaneously should be closely monitored for the development of symptoms of hyperammonemic encephalopathy. With estrogen-progestogen 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-progestogen drugs in women using hormonal methods of contraception. With ethanol and other potentially hepatotoxic drugs. When used simultaneously with valproic acid, the hepatotoxic effect of valproic acid may be enhanced. With clonazepam. The simultaneous use of clonazepam with valproic acid can lead in isolated cases to increased severity of absence status. With myelotoxic drugs. When used simultaneously with valproic acid, the risk of suppression of bone marrow hematopoiesis increases.
Directions for use 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 the tablet entering the respiratory tract when swallowed). The drug is a slow-release form of the active substance from the Depakine group of drugs. Slow release avoids sudden increases in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood throughout the day for a longer period of time. Extended-release tablets may be divided to facilitate individual administration of the dose. Dosage regimen for epilepsy. The daily dose is selected individually by the attending physician. The minimum dose effective to prevent the development of epileptic attacks should be selected (especially during pregnancy). The daily dose should be set according to age and body weight. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached. No clear relationship has been established between daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined primarily by clinical response. Determination of plasma valproic acid levels can serve as an addition to clinical monitoring if epilepsy is uncontrolled or if side effects are suspected. The therapeutic blood concentration range is usually 40 - 100 mg/L (300 - 700 µmol/L). For monotherapy, the initial dose is usually 5-10 mg valproic acid per kg body weight, which is then gradually increased every 4-7 days at a rate of 5 mg valproic acid per kg body weight to the dose required 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 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; The wide range of individual sensitivity to valproate should be taken into account. If epilepsy is not controlled at these doses, they can be increased under monitoring 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, the daily dose should not be increased above the recommended average daily dose before this date. The daily dose can be divided into 1-2 doses, preferably with meals. Most patients who are already taking the long-acting dosage form of Depakine can be switched to the long-acting dosage form of this drug immediately or within a few days, and patients should continue to take the previously selected daily dose. For patients who have previously taken antiepileptic drugs funds, the transfer to taking the drug Depakine Chrono should be carried out gradually, reaching the optimal dose of the drug within approximately 2 weeks. In this case, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previously taken antiepileptic drug is discontinued, then its withdrawal should be carried out gradually. So As other antiepileptic drugs can reversibly induce liver microsomal enzymes, the concentrations of valproic acid in the blood should be monitored for 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 it is necessary to combine valproic acid with other antiepileptic drugs, they should be added to treatment gradually. Dosage regimen for manic episodes in bipolar disorders. Adults. The daily dose is selected individually by the attending physician. The recommended initial daily dose is 750 mg. In addition, in clinical studies, an initial dose of 20 mg sodium valproate per kg body weight also showed an acceptable safety profile. Slow-release formulations can be taken once or twice daily. The dose should be increased as quickly as possible until the minimum therapeutic dose that produces the desired clinical effect is reached. The average daily dose is in the range of 1000-2000 mg sodium valproate. Patients receiving a daily dose higher than 45 mg/kg/day should be under close medical supervision. Continuation of treatment of manic episodes in bipolar disorders should be carried out by taking an individually selected minimum effective dose. Children and teenagers. The effectiveness and safety of the drug in the treatment of manic episodes in bipolar disorder in patients under 18 years of age have not been evaluated. Use of the drug in patients of special groups. In patients with renal failure 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 dose selection, mainly on the clinical picture, and not on the total content valproic acid in blood serum (free fraction and fraction bound to 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 hypotonia, hyporeflexia, miosis, respiratory depression, and metabolic acidosis. Cases of intracranial hypertension associated with cerebral edema have been described. With a massive overdose, death is possible, but usually the prognosis for an overdose is favorable. Symptoms of overdose may vary, and seizures have been reported at very high plasma concentrations of valproic acid. Emergency care in case of overdose in a hospital should be as follows: gastric lavage, which is effective within 10-12 hours after taking the drug, monitoring the state of the cardiovascular and respiratory systems and maintaining effective diuresis. Naloxone has been used with success in some cases. In very severe cases of massive overdose, hemodialysis and hemoperfusion have been effective.
special instructions
Carefully. With a history of liver and pancreas diseases. During pregnancy. For congenital enzymopathies. When bone marrow hematopoiesis is suppressed (leukopenia, thrombocytopenia, anemia). In case of renal failure (dose adjustment required). With hypoproteinemia. In patients receiving multiple anticonvulsants due to an increased risk of liver damage. While taking 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). When taking antipsychotics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines simultaneously (possibility of potentiating their effects). When taking phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine simultaneously (due to pharmacokinetic interactions at the level of metabolism or plasma protein binding, plasma concentrations or these drugs and/or valproic acid, for more details see the section “Interaction with other drugs”). With simultaneous use of carbamazepine, there is a risk of potentiation of the toxic effects of carbamazepine and a decrease in plasma concentrations of valproic acid). With simultaneous use of topiramate (risk of developing encephalopathy). Pregnancy and lactation period. Pregnancy. 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. Risk associated with using the drug during pregnancy. Experimental reproductive toxicity studies conducted in mice, rats and rabbits have demonstrated that valproic acid is teratogenic. Available clinical data confirm that children born to mothers with epilepsy who received valproic acid have an increased incidence of intrauterine developmental disorders of varying severity (neural tube malformations; craniofacial deformities; malformations of the limbs, cardiovascular system; and also multiple malformations of intrauterine development, 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 prenatal exposure to valproic acid and the risk of developmental delays (especially language development) in children born to mothers with epilepsy who took valproic acid. Developmental delay is often combined with developmental defects and dysmorphism. However, in cases of developmental delay in such children, it is difficult to accurately establish a cause-and-effect relationship with valproic acid due to the possibility of simultaneous influence of other factors, such as low intelligence level 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. The development of various autistic disorders has also been reported in children exposed to valproic acid in utero. Both valproic acid monotherapy and combination therapy containing valproic acid are associated with adverse pregnancy outcomes, but combination antiepileptic therapy containing valproic acid is reported to be associated with a higher risk of adverse pregnancy outcome compared with valproic acid monotherapy. In connection with the above, 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 cannot tolerate them. The question of whether it is necessary to use the drug or the possibility of refusing to use it should be decided before starting to use the drug or reviewed if the woman receiving the drug is planning a pregnancy. Women of childbearing potential should use effective methods of 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 has been diagnosed with pregnancy, the need for treatment with valproic acid should be re-evaluated depending on the indications. If bipolar disorder is indicated, discontinuation of treatment with valproic acid should be considered. When epilepsy is indicated, the question of continuing treatment with valproic acid or its discontinuation is decided after reassessing the benefit-risk ratio. If, after reassessing the balance of benefit and risk, treatment with the drug must still be continued 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, it is preferable to use slow-release dosage forms of the drug. One month before conception and for 2 months after it, folic acid (at a dose of 5 mg per day) should be added to antiepileptic treatment, as this may minimize the risk of neural tube defects. Constant special prenatal monitoring should be carried out to identify possible defects in the formation of the neural tube or other malformations of the fetus. Risk to newborns. The development of isolated cases of hemorrhagic syndrome has been reported in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with hypofibrinogenemia and may be 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 receiving valproic acid, it is necessary to determine the number of platelets in the blood, plasma fibrinogen concentration, blood coagulation factors and 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 serum. Based on the literature data and limited clinical experience, mothers can plan to breastfeed when using the drug alone, but the side effect profile of the drug, especially the hematological disorders it causes, should be taken into account. Severe liver damage. Predisposing factors. Clinical experience shows that patients at risk include patients receiving multiple antiepileptic drugs at the same time, children under three years of age with severe seizures, especially in the presence of brain damage, mental retardation and/or congenital metabolic or degenerative diseases. After the age of three, the risk of liver damage decreases significantly and decreases progressively as the patient ages. In most cases, liver damage occurred during the first 6 months of treatment. Symptoms suspicious for liver damage. For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, you should pay attention to the appearance of the following symptoms that may precede the onset of jaundice, especially in patients at risk: nonspecific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain; resumption 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 symptoms to their doctor. If they occur, patients should immediately undergo clinical examination and laboratory testing of liver function tests. Identification. Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative are studies reflecting the state of the protein-synthetic function of the liver, especially the prothrombin index. Confirmation of deviations from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory parameters (significant decrease in the content of fibrinogen and blood coagulation factors, increase in bilirubin concentration and increase in transaminase activity) requires discontinuation of the drug. As a precaution, if patients were concomitantly receiving salicylates, their use should also be discontinued, since they are metabolized through the same metabolic pathway as valproic acid. Pancreatitis. Children are at increased risk of developing pancreatitis, and the risk decreases as the child ages. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for developing pancreatitis. Liver failure combined with pancreatitis increases the risk of death. Patients who experience severe abdominal pain, nausea, vomiting and/or anorexia should be evaluated immediately