Valproic acid (Depakine chrono, Encorate chrono, Convulex, Valparin)

Indications

Adults
As monotherapy or in combination with other antiepileptic drugs:

- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic);

- Lennox-Gastaut syndrome;

- treatment of partial epileptic seizures (partial seizures with or without secondary generalization).

Treatment and prevention of bipolar affective disorders.

Children

As monotherapy or in combination with other antiepileptic drugs:

- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic);

- Lennox-Gastaut syndrome;

- treatment of partial epileptic seizures (partial seizures with or without secondary generalization).

PsyAndNeuro.ru

We present to your attention a review translation of the first clinical recommendations in the history of psychiatry for the treatment of mixed conditions in bipolar affective disorder of the World Federation of Societies of Biological Psychiatry, prepared jointly by the scientific Internet portal “Psychiatry & Neuroscience” and the Clinic of Psychiatry and Addiction Medicine Doctor SAN.

Mixed conditions have attracted the attention of specialists only recently. The interest is largely due to their high prevalence and poor prognosis. 70% of patients with manic symptoms also have symptoms of depression. Observations of such mixed states support the idea that bipolar disorder is by no means “madness in two forms,” an illness in which two polar states—manic and depressive—are clearly separated.

It's time to create a guideline that focuses exclusively on mixed disorders. Current recommendations include extrapolations from studies that have examined cases of pure mania. Based on these extrapolations, recommendations were made for mixed conditions. However, mixed depression (depression with hypo/manic symptoms) was rarely taken into account.

The presence of depressive symptoms in the manic phase was noted at the beginning of the 19th century. German scientists. In the middle of the 19th century. transition states observed at the end of depression and the onset of mania have been described. In transitional states, the symptoms of mania and depression are mixed.

The first systematic description of mixed states was made by Kraepelin and Weingandt in 1899. Their description proceeds from the fact that between pure mania and pure depression there are subtypes in which the features of depression and mania are mixed in different combinations.

The main problem in treating mixed conditions is that there is still no common definition of what they are. The diagnostic criteria of DSM-IV, ICD-10 and DSM-V are summarized in Table 1. This guideline, which is based on the diagnostic criteria of DSM-IV, refers to the following situations:

• immediate treatment of a manic episode with three or more depressive symptoms, including anxiety, irritability, and agitation
• immediate treatment of a bipolar depressive episode with three or more hypomanic or manic symptoms
• continuation of treatment and prevention of recurrence of a mixed episode
• preventing a mixed episode after a manic or depressive episode

Due to the lack of a common understanding of mixed conditions, data on their prevalence varies greatly. Mixed conditions are noted to become more frequent as bipolar disorder progresses, especially in women. The gender proportion, according to some sources, appears to be 60:40 in favor of women. Manic patients with mixed conditions are more likely to be admitted to the hospital and spend more time there. It has also been noted that patients with mixed conditions are more likely to abuse substances.

Table 1. Diagnostic criteria for mixed conditions

A – Strong evidence from controlled studies

A category is assigned if there are: two or more double-blind, parallel group, randomized controlled trials (RCTs) showing superiority over placebo (or in the case of psychotherapy, superiority to “psychological placebo”), or one or more positive RCTs showing superior to or as effective as a comparator, with three groups of participants and a placebo control, or in a well-designed experiment (where a standard comparator exists).

If there are studies that are negative (studies that do not show superiority over placebo or that show inferior efficacy compared to the comparator), each study must have at least two additional studies with positive results or a meta-analysis of all available studies showing superiority over placebo and higher efficacy compared to the comparator drug. Research must meet established methodological standards.

B – Limited strength of evidence from controlled studies

A category is assigned if there is: one or more RCTs showing superiority over placebo (or in the case of psychotherapy, superiority over “psychological placebo”) or a randomized controlled comparison with standard treatment without placebo control with a sample size sufficient for the experiment or an a priori designed analysis subgroup included in the study protocol, and for every one negative result (studies not showing superiority over placebo or showing inferior efficacy compared with the comparator) there must be at least one additional positive result or a meta-analysis of all available studies showing superiority over placebo and higher efficacy compared to the comparator drug.

C – Evidence from uncontrolled studies or case reports, expert opinion, post hoc analysis of RCTs

A category is assigned if there are: one or more naturalistic open-label studies with a positive result (with a minimum number of patients evaluated) or a comparison with a reference product in a sample of insufficient size for a comparative experiment and no controlled studies with a negative result or clinical cases: one or more than one positive result and there are no controlled studies with a negative result or there is a post hoc analysis of an RCT (not planned a priori as part of the study protocol) or there are expert opinions

D - Conflicting results

RCTs with positive results are inferior or approximately equal in number to RCTs with negative results.

E – Negative evidence

Most RCTs or exploratory studies show no superiority over placebo (or, in the case of psychotherapy, superiority over “psychological placebo”) or lower efficacy compared to the comparator.

F – Lack of evidence

No studies have been conducted to demonstrate effectiveness or ineffectiveness.

Recommendation levels (RG):

1 – Category of evidence A and good risk/benefit ratio

2 – Category of evidence A and average risk/benefit ratio

3 – Category of evidence B

4 – Evidence category C

5 – Evidence category D

Additional Evidence (FE)

++ – Some supporting additional evidence, such as a meta-analysis or studies with a positive result, that do not meet the criteria for an “A” or “B” category of evidence

+ – Some supporting additional evidence, such as limited data from open studies

0 – Inconsistent data or missing data

(-) – Some disconfirming additional evidence, such as limited disconfirming data from open-label studies/Some disconfirming additional evidence, such as a negative meta-analysis or studies with a negative result that do not meet the criteria for an “A” or “B” evidence category ”

Safety and Tolerability (ST)

++ – Very good

+ – Good

0 – Advantages and disadvantages equal or no data

(-) – There are problems/Serious problems

Table 2. CE and RG for immediate treatment of mixed conditions

MM: mixed manic; DM: mixed depressive; MS: manic symptoms; DS: depressive symptoms; M: mania; D: depression; Mx: mixed episode; MIE: first manic episode; DIE: first depressive episode; MxIE: first episode of mixed state; CE: category of evidence; FE: additional evidence; ST: safety and tolerability; RG: recommendation level.

Table 3. CE and RG for maintenance therapy after a mixed episode and for its prevention

MM: mixed manic; DM: mixed depressive; M: mania; D: depression; Mx: mixed episode; MIE: first manic episode; DIE: first depressive episode; MxIE: first episode of mixed state; CE: category of evidence; FE: additional evidence; ST: safety and tolerability; RG: recommendation level.

Several drugs are effective in treating patients with mixed conditions. But none of these drugs works equally well at all stages of treatment or in all subgroups of patients. There are still more questions than answers regarding the treatment of mixed conditions.

For the immediate treatment of mixed mania, olanzapine, paliperidone, and aripiprazole are the best proven medications. For mixed bipolar depression, ziprasidone alone has been shown to be effective in combination therapy (levels of recommendation 1-3). Level 4 recommendation categories include carbamazepine, lurasidone, olanzapine, and ECT.

Thus, for mixed bipolar depression, there are no drugs with convincing evidence. Additionally, ziprasidone has only been studied in bipolar II disorder.

Quetiapine, lithium and olanzapine (as monotherapy and in combinations) are best suited to prevent a new episode of mixed conditions.

Little is known about how to prevent a mixed episode after a primary manic, mixed, or depressive episode. But at least valproic acid, olanzapine and lithium show some effectiveness.

As a result, it turns out that olanzapine (as monotherapy and in combination) is the drug that is suitable for most situations and subgroups of patients. It can also be assumed that combination therapy is more effective than monotherapy in the treatment of mixed conditions.

It is believed that valproic acid is more effective than lithium in mixed conditions. In the absence of reliable data on lithium, it can be assumed, although with a low recommendation category, that this is true for immediate treatment. As with mania and depression, clozapine and ECT are options that should be considered when all other treatments have failed.

The material was prepared with the support of the Doctor SAN clinic, a leading private psychiatric clinic and one of the best drug treatment hospitals in the North-West region.

Translation: Filippov D.S.

Translation editor: Kasyanov E.D.

Contraindications

- hypersensitivity to sodium valproate, valproic acid, semisodium valproate, valpromide or to any of the auxiliary components of the drug;

- acute hepatitis;

- chronic hepatitis;

- severe liver disease (especially drug-induced hepatitis) in the patient’s and his close blood relatives’ history;

- severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;

- severe liver dysfunction;

- severe dysfunction of the pancreas;

- hepatic porphyria;

- established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), for example, Alpers-Huttenlocher syndrome, and suspected diseases caused by defects in γ-polymerase in children under 2 years of age (applies to the use of drugs forms of the drug Depakine intended for children);

— patients with established disorders of the carbamide cycle (urea cycle);

- combination with mefloquine;

- combination with St. John's wort preparations;

- children under 6 years of age (risk of tablets entering the respiratory tract when swallowed).

Carefully

- history of liver and pancreas diseases;

- pregnancy;

— congenital enzymopathies;

- inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);

- renal failure (dose adjustment required);

- hypoproteinemia;

- simultaneous use of several anticonvulsants (due to an increased risk of liver damage);

- simultaneous use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors; phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures);

- simultaneous use of antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiating their effects);

- simultaneous use of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, olanzapine, propofol, aztreonam, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, rufinamide (especially in children), protease inhibitors (lopinavir a, ritonavir ), cholestyramine (due to pharmacokinetic interactions at the level of metabolism or binding to plasma proteins, changes in plasma concentrations of either these drugs and/or valproic acid are possible);

- simultaneous use with carbamazepine (risk of potentiation of the toxic effects of carbamazepine and a decrease in plasma concentrations of valproic acid);

- simultaneous use with topiramate (risk of developing encephalopathy);

- in patients with existing carnitine palmitoyltransferase (CPT) type II deficiency (higher risk of developing rhabdomyolysis when taking valproic acid).

Depakine®

Before starting to use the drug and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed.

As with the use of most antiepileptic drugs, when using valproic acid, a slight increase in the activity of “liver” transaminases is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In such patients, it is necessary to conduct a more thorough study of biological parameters, including the prothrombin index. It may be necessary to adjust the dose of the drug, and, if necessary, repeat clinical and laboratory examination.

Before starting therapy or before surgery, as well as in the event of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine the bleeding time and the number of formed elements in the peripheral blood, including platelets.

Severe liver damage

Predisposing factors

Isolated cases of severe liver damage, sometimes fatal, have been described. Clinical experience shows that those at risk include patients taking multiple antiepileptic drugs at the same time, children under 3 years of age with severe seizures, especially against the background of brain damage, mental retardation and/or congenital metabolic or degenerative diseases; patients concomitantly taking salicylates (since salicylates are metabolized through the same metabolic pathway as valproic acid).

After 3 years, the risk of liver damage decreases significantly and decreases progressively as the patient ages. In most cases, such liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually when valproic acid was used as part of combination antiepileptic therapy.

Suspicion of liver damage

For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, you should pay attention to the following symptoms that may precede the onset of jaundice, especially in patients at risk:

- nonspecific symptoms, especially those that began suddenly, 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 pediatric patients) should be warned that they should immediately report the occurrence of any of these symptoms to their doctor. Patients should immediately undergo clinical examination and laboratory testing of liver function tests.

Revealing

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 determination of the prothrombin index. Confirmation of deviation from the norm of the prothrombin index in the direction of its decrease, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood clotting factors, an increase in the concentration of bilirubin and an increase in the activity of “liver” transaminases), as well as the appearance of other symptoms indicating for liver damage, requires discontinuation of the drug. As a precaution, if patients were taking salicylates concomitantly, their use should also be discontinued.

Pancreatitis

There are rare reported cases of severe forms of pancreatitis in children and adults, which developed regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis have been observed with rapid progression of the disease from the first symptoms to death.

Children are at increased risk of developing pancreatitis, and this risk decreases with increasing age of the child. Risk factors for developing pancreatitis may include severe seizures, neurological disorders, or anticonvulsant therapy. Liver failure combined with pancreatitis increases the risk of death.

If severe abdominal pain, nausea, vomiting and/or anorexia occur, patients should be evaluated immediately. If pancreatitis is confirmed, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment should be started.

Suicidal thoughts and attempts

Suicidal thoughts and attempts have been reported in patients taking antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a 0.19% increase in the risk of suicidal thoughts and attempts in all patients taking antiepileptic drugs (including a 0.24% increase in this risk in patients taking antiepileptic drugs for for epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown.

Therefore, patients taking the drug should be constantly monitored for suicidal thoughts and attempts. if they occur, appropriate treatment must be carried out. Patients and caregivers are advised to seek immediate medical attention if a patient experiences suicidal thoughts or attempts.

Carbapenems

The simultaneous use of carbapenems is not recommended (see section “Interaction with other drugs”, “With caution”).

Patients with known or suspected mitochondrial diseases

Valproic acid can initiate or aggravate the manifestations of mitochondrial diseases in the patient, caused by mutations in mitochondrial DNA, as well as in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding γ-polymerase (POLG), such as patients with Alpers-Huttenlocher syndrome, a higher incidence of acute liver failure and liver-related deaths was associated with the use of valproic acid. outcomes. Diseases due to γ-polymerase defects may be suspected in patients with a family history of such diseases or symptoms suggestive of their presence, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura and others. In accordance with current clinical practice, testing for mutations in the polymerase γ gene (POLG) should be performed to diagnose such diseases (see section "Contraindications").

Paradoxical increase in the frequency and severity of seizures (including the development of status epilepticus) or the emergence of new types of seizures

As with other antiepileptic drugs, when taking valproic acid, instead of improvement, some patients experienced a reversible increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures. If seizures worsen, patients should immediately consult their doctor (see section "Side effects").

Female children and adolescents, women of childbearing potential and pregnant women

Pregnancy Prevention Program

Valproic acid has a high teratogenic effect; the use of valproic acid leads to a high risk of congenital malformations and developmental disorders of the central nervous system in the fetus.

The use of valproic acid is contraindicated:

- during pregnancy for epilepsy, except in cases of absence of alternative treatment methods (see sections “Special instructions”, “Use during pregnancy and breastfeeding”);

— during pregnancy in the treatment and prevention of bipolar affective disorders;

- in women of childbearing potential, unless all the conditions of the Pregnancy Prevention Program are met (see sections “Special Instructions”, “Use during Pregnancy and Breastfeeding”).

When prescribing drugs containing valproic acid, you must:

— conduct an individual assessment of the circumstances of prescribing the drug in each individual case, discuss possible methods of therapy and make sure that the patient understands the potential risks and the need for measures taken to minimize them;

— make sure that the patient has childbearing potential;

— make sure that the patient understands the nature and magnitude of the risks of using valproic acid during pregnancy, in particular, the risks of teratogenic effects, as well as the risks of disorders of the mental and physical development of the child;

— make sure that the patient understands the need to conduct a pregnancy test before starting and during treatment;

- explain the necessary methods of contraception, make sure that the patient uses reliable methods of contraception continuously during treatment with drugs containing valproic acid;

— make sure that the patient understands the need to regularly contact a specialist in the treatment of epilepsy and bipolar affective disorders (at least once a year) to re-analyze the prescribed therapy;

- make sure that the patient understands the need to contact her doctor if she is planning a pregnancy in order to promptly assess the possibility of switching to alternative therapy before stopping the use of contraception;

- inform about the need for immediate consultation with your doctor if you suspect pregnancy;

— ensure that the patient has received all the necessary explanations about the risks and necessary precautions.

The above information is also relevant for women who are not currently sexually active, unless the attending physician is satisfied that there is no childbearing potential.

Female pediatric patients

When prescribing drugs containing valproic acid, you must:

— make sure that female pediatric patients/their legal representatives understand the need to consult with their doctor upon the onset of menarche;

— ensure that female pediatric patients who have reached menarche, or their legal representatives, receive detailed information about the risks of congenital malformations and disorders of the central nervous system in the fetus.

The treating physician should re-evaluate the prescribed valproic acid therapy annually and evaluate the possibility of prescribing alternative therapy. If medications containing valproic acid are the treatment of choice, ensure that reliable methods of contraception are used and that the Pregnancy Prevention Program is followed. Before puberty, the possibility of switching patients to alternative treatment methods should be constantly considered.

Pregnancy test

Before starting treatment with drugs containing valproic acid, it is necessary to exclude pregnancy. Therapy with drugs containing valproic acid cannot be prescribed to women of childbearing potential unless a negative pregnancy test (pregnancy blood test) has been confirmed by a health care professional, in order to exclude the use of the drug during pregnancy.

Contraception methods

Female patients of childbearing potential who are prescribed therapy with drugs containing valproic acid should use reliable methods of contraception continuously throughout the entire treatment period.

Female patients of childbearing potential should be provided with detailed information about methods of preventing pregnancy, and such patients may also seek advice from their physician if they are not using a reliable method of contraception.

You must use at least one reliable method of contraception (preferably simultaneously with methods such as an intrauterine system or implant) or two complementary methods of contraception, including barrier methods. When prescribing a contraceptive method to a patient, it is necessary to take an individualized approach and discuss all possible contraceptive options with the patient to ensure that the patient adheres to and adheres to the regimen. In case of amenorrhea, the patient should also be warned about the use of effective methods of contraception.

Annual analysis of prescribed therapy

At least once a year, the treating physician should evaluate whether medications containing valproic acid are the treatment of choice. The risks associated with therapy should be discussed when prescribing the drug and at each annual review of the prescribed therapy, and ensure that the patient understands all risks.

Planning a pregnancy

If a patient is planning to become pregnant, a specialist in the treatment of epilepsy and bipolar affective disorder should evaluate therapy with drugs containing valproic acid and consider alternative therapy. Every effort should be made to switch the patient from therapy with drugs containing valproic acid before conception and until contraception is discontinued (see section “Use during pregnancy and breastfeeding”). If alternative therapy is not available, the patient should be advised of the risks associated with the use of drugs containing valproic acid for the unborn child to help make an informed decision about family planning.

What to do if you become pregnant?

If you become pregnant, you should contact your healthcare provider immediately to evaluate your treatment and consider alternative therapy.

The health worker must ensure that:

— patients understand all the risks described above;

— patients received recommendations not to stop therapy with valproic acid and to immediately contact their doctor when planning pregnancy.

Concomitant use with estrogen-containing drugs

Valproic acid does not reduce the therapeutic effectiveness of hormonal contraceptives. However, drugs containing estrogen, including estrogen-containing hormonal contraceptives, may increase the clearance of valproic acid, which may lead to a decrease in its serum concentration and, consequently, a decrease in its effectiveness. It is necessary to monitor the concentration of valproic acid in the blood serum and clinical effectiveness (seizure control and mood control) when prescribing or discontinuing estrogen-containing drugs (see section "Interaction with other drugs").

Children (information refers to dosage forms of the drug that can be taken by children under 3 years of age)

In children under 3 years of age, if it is necessary to use the drug, it is recommended to use it in monotherapy and in the dosage form recommended for children. In this case, before starting treatment, the ratio of the potential benefit from the use of valproic acid and the risk of liver damage and the development of pancreatitis when using it should be assessed.

In children under 3 years of age, the simultaneous use of valproic acid and salicylates should be avoided due to the risk of liver toxicity.

Kidney failure

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. If it is impossible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Enzyme deficiency of the carbamide cycle (urea cycle)

If an enzymatic deficiency of the carbamide cycle is suspected, the use of valproic acid is contraindicated. Several cases of hyperammonemia with stupor or coma have been described in such patients. In these cases, metabolic studies should be carried out before starting treatment with valproic acid (see section "Contraindications").

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or child, metabolic studies should be performed before initiating treatment with valproic acid, in particular, determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after meals (see section “Contraindications”).

Patients with systemic lupus erythematosus

Despite the fact that during treatment with the drug, dysfunction of the immune system is extremely rare, the potential benefits of its use must be compared with the potential risks when using the drug in patients with systemic lupus erythematosus.

Weight gain

Patients should be warned about the risk of weight gain at the start of treatment and measures, mainly diet, should be taken to minimize this phenomenon.

Patients with diabetes mellitus

Given the possibility of adverse effects of valproic acid on the pancreas, when using the drug in patients with diabetes mellitus, blood glucose concentrations should be carefully monitored. When testing urine for the presence of ketone bodies in patients with diabetes, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partly in the form of ketone bodies.

Patients infected with human immunodeficiency virus (HIV)

In vitro studies have shown that valproic acid stimulates HIV replication under certain experimental conditions. The clinical significance of this fact is unknown. In addition, the significance of data obtained from in vitro studies for patients receiving maximally suppressive antiretroviral therapy has not been established. However, these data should be taken into account when interpreting the results of continuous viral load monitoring in HIV-infected patients taking valproic acid.

Patients with existing carnitine palmitoyltransferase (CPT) type II deficiency

Patients with existing CPT type II deficiency should be warned of the increased risk of rhabdomyolysis when taking valproic acid.

Ethanol

During treatment with valproic acid, ethanol consumption is not recommended.

Other special instructions

The inert matrix of the drug (extended release drug), due to the nature of its excipients, is not absorbed in the gastrointestinal tract; after the release of the active substances, the inert matrix is ​​excreted by the intestines.

Dosage

Depakine Chrono is intended only for adults and children over 6 years of age weighing more than 17 kg.

Depakine Chrono is a slow-release dosage form, which 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 mg or 500 mg can be divided to facilitate the administration of an individually selected dose.

The tablets are taken without crushing or chewing them.

Epilepsy

The doctor selects the daily dose individually.

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

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

No clear 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 of valproic acid per kg of body weight, then this dose is gradually increased every 4-7 days at the rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control 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 teenagers (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)

- on average 20 mg of valproic acid/kg body weight (1200-2100 mg).

Although the daily dose is determined by 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 Depakine in a non-extended-release dosage form can be switched to Depakine chrono immediately or within a few days, while patients must 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, you should immediately reduce the dose of the antiepileptic drug that the patient was taking previously, especially if it is phenobarbital. The withdrawal of an antiepileptic drug that the patient was previously taking should be done gradually.

Because other antiepileptic drugs can reversibly induce liver microsomal enzymes, the plasma concentration of valproic acid 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.

Manic episodes in bipolar disorders

Adults

The doctor selects the daily dose individually.

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

Depakine Chrono can be taken 1 or 2 times a day. The dose should be increased as quickly as possible until the minimum effective therapeutic dose that produces the desired clinical effect is achieved.

The average daily dose is in the range of 1000-2000 mg sodium valproate.

Patients receiving a daily dose of more than 45 mg/kg/day should be under close medical supervision.

When continuing treatment of manic episodes in bipolar disorders, the drug is used in 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.

Special patient groups

Female children and adolescents, women of childbearing potential and pregnant women:

Treatment with Depakine Chrono should be started under the supervision of a specialist with experience in the treatment of epilepsy and bipolar disorders. Treatment should only be started if other treatments are ineffective or not tolerated, and the balance of benefit and risk should be carefully re-evaluated when treatment is regularly reviewed. It is preferable to use Depakine drugs for monotherapy and in the lowest effective doses and, if possible, in extended-release dosage forms. During pregnancy, the daily dose should be divided into at least 2 single doses.

Although in elderly patients

There are changes in the pharmacokinetics of valproic acid, they are of limited clinical significance, and the dose of valproic acid in elderly patients should be adjusted in accordance with achieving control of epileptic seizures.

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.

Depakin 300 enteric tablet p/o col.sol. 300 mg 100 pcs

Before starting the use of Depakine® Enteric 300 and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed. As with the use of most antiepileptic drugs, when using valproic acid, a slight increase in the activity of liver enzymes is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In these patients, a more detailed study of biological parameters, including the prothrombin index, is necessary, and dose adjustment of the drug may be required, and, if necessary, repeated clinical and laboratory examinations. Before starting therapy or before surgery, in case of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine the bleeding time and the number of formed elements in the peripheral blood, including platelets. Severe liver damage

Predisposing factors: clinical experience shows that patients at risk are patients taking several 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; patients concomitantly taking salicylates (since salicylates are metabolized through the same metabolic pathway as valproic acid). After the age of three, the risk of liver damage decreases significantly and decreases progressively as the patient ages. In most cases, such liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually when valproic acid was used as part of combination antiepileptic therapy. 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, which may precede the onset of jaundice, especially in patients at risk (see above): non-specific symptoms, especially those of 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 of these symptoms to their doctor. Patients should immediately undergo clinical examination and laboratory testing of liver function tests.

Detection: 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 determination of the prothrombin index. Confirmation of an abnormal prothrombin index, especially in combination with abnormalities in 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 “liver” transaminases), as well as the appearance of other symptoms indicating liver damage ( see above), requires discontinuation of use of the drug Depakine® Enteric 300. For precautionary purposes, if patients were taking salicylates at the same time, their use should also be discontinued.

Pancreatitis

There are rare reported cases of severe forms of pancreatitis in children and adults, which developed regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis have been observed with rapid progression of the disease from the first symptoms to death. Children are at increased risk of developing pancreatitis, and this risk decreases as the child ages. Risk factors for developing pancreatitis may include severe seizures, neurological disorders, or anticonvulsant therapy. 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. If pancreatitis is confirmed, in particular with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment should be initiated.

Suicidal thoughts and attempts

Suicidal thoughts and attempts have been reported in patients taking antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a 0.19% increase in the risk of suicidal ideation and attempts in all patients taking antiepileptic drugs (including a 0.24% increase in this risk in patients taking antiepileptic drugs for epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown. Therefore, patients taking Depakine® Enteric 300 should be constantly monitored for suicidal thoughts and attempts, and, if they occur, appropriate treatment should be provided. Patients and caregivers are advised to seek immediate medical attention if a patient experiences suicidal thoughts or attempts.

Carbapenems

Concomitant use of carbapenems is not recommended (see section “Interaction with other drugs”).

Patients with known or suspected mitochondrial diseases

Valproic acid can initiate or aggravate the manifestations of the patient's mitochondrial diseases caused by mutations in mitochondrial DNA, as well as in the nuclear gene encoding the mitochondrial enzyme polymerase gamma (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding polymerase gamma (POLG); for example, in patients with Alpers-Huttenlocher syndrome, valproic acid was associated with a higher incidence of acute liver failure and liver-related deaths. Diseases due to gamma polymerase defects may be suspected in patients with a family history of such diseases or symptoms suspicious for their presence, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura and others. In accordance with current clinical practice, testing for mutations in the polymerase gamma gene (POLG) should be performed to diagnose such diseases (see section “Contraindications”).

Women of childbearing potential, pregnant women

Depakine® Enteric 300 should not be used in female children and adolescents, women of childbearing potential and pregnant women, unless alternative treatments are ineffective or not tolerated. This limitation is associated with a high risk of teratogenicity and mental and physical development disorders in children who were exposed to valproic acid in utero. The balance of benefits and risks should be carefully re-evaluated in the following cases: during regular review of treatment, when a girl reaches puberty and, urgently, if a woman taking valproic acid plans or becomes pregnant. During treatment with valproic acid, women of childbearing potential should use reliable methods of contraception, and they should be informed of the risks associated with taking Depakine® Enteric 300 during pregnancy (see section "Use during pregnancy and breastfeeding") . To help the patient understand these risks, the physician prescribing valproic acid should provide the patient with comprehensive information about the risks associated with taking Depakine® Enteric 300 during pregnancy. In particular, the doctor prescribing valproic acid must make sure that the patient understands: the nature and magnitude of the risks when using valproic acid during pregnancy, in particular, the risks of teratogenicity, as well as the risks of disorders of the mental and physical development of the child; the need to use effective contraception; the need for regular review of treatment; the need to urgently consult her doctor if she suspects that she is pregnant or when she suspects the possibility of pregnancy. A woman planning a pregnancy should definitely try, if possible, to switch to an alternative treatment before she attempts to conceive (see section “Use during pregnancy and breastfeeding”). Treatment with valproic acid should be continued only after a physician experienced in the treatment of epilepsy and bipolar disorders has re-evaluated the benefits and risks of treatment.

Children (the information applies to dosage forms of the drug Depakine, which can be taken by children under three years of age) In children under three years of age, if the use of the drug is necessary, it is recommended to use it in monotherapy and in the dosage form recommended for children. However, before starting treatment, you should weigh the ratio of the potential benefits of using valproic acid and the risk of liver damage and the development of pancreatitis when using it. In children under 3 years of age, the simultaneous use of valproic acid and salicylates should be avoided due to the risk of liver toxicity.

Kidney failure

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. If it is impossible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Enzyme deficiency of the urea cycle (urea cycle) If enzymatic deficiency of the urea cycle is suspected, the use of valproic acid is contraindicated. Several cases of hyperammonemia with stupor or coma have been described in such patients. In these cases, metabolic studies should be carried out before starting treatment with valproic acid (see section "Contraindications"). In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, with mental retardation, or a family history of death of a newborn or child, metabolic studies should be carried out before starting treatment with valproic acid, in particular, determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after meals (see section “Contraindications”).

Patients with systemic lupus erythematosus

Although it has been shown that during treatment with Depakine® Enteric 300, dysfunction of the immune system is extremely rare, the potential benefits of its use must be compared with the potential risks when using the drug in patients with systemic lupus erythematosus

Weight gain

Patients should be warned about the risk of weight gain at the beginning of treatment, and measures, mainly dietary, should be taken to minimize this phenomenon.

Patients with diabetes mellitus

Given the possibility of adverse effects of valproic acid on the pancreas, when using the drug in patients with diabetes mellitus, blood glucose concentrations should be carefully monitored. When testing urine for the presence of ketone bodies in patients with diabetes, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partly in the form of ketone bodies.

Patients infected with human immunodeficiency virus (HIV) In vitro, valproic acid has been shown to stimulate HIV replication under certain experimental conditions. The clinical significance of this fact, if any, is unknown. Additionally, the significance of these in vitro data for patients receiving maximally suppressive antiretroviral therapy has not been established. However, these data should be taken into account when interpreting the results of continuous viral load monitoring in HIV-infected patients taking valproic acid.

Patients with existing carnitine palmitoyltransferase (CPT) type II deficiency Patients with existing CPT type II deficiency should be warned of the higher risk of developing rhabdomyolysis when taking valproic acid.

Ethanol

During treatment with valproic acid, ethanol consumption is not recommended.

Impact on the ability to drive vehicles or engage in other potentially hazardous activities

Patients should be warned about the risk of developing drowsiness, especially in the case of combined anticonvulsant therapy or when combining the drug Depakine® enteric 300 with benzodiazepines (see section “Interaction with other drugs”).

Side effects

Determination of the frequency of adverse reactions (WHO classification): very often (≥10%), often (≥1% and <10%), infrequently (≥0.1% and <1%), rarely (≥0.01% and <0.1%), very rare (<0.01%),

frequency unknown (cannot be determined from available data).

Congenital, hereditary and genetic disorders:

teratogenic risk.

From the hematopoietic system:

often - anemia, thrombocytopenia; uncommon - pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can occur with or without depression of bone marrow hematopoiesis. After discontinuation of the drug, the blood picture returns to normal.

From the blood coagulation system:

often - bleeding and hemorrhage; rarely - a decrease in the content of blood coagulation factors (at least one), deviation from the norm of blood coagulation parameters (such as an increase in prothrombin time, an increase in aPTT, an increase in thrombin time, an increase in MHO). The appearance of spontaneous ecchymosis and bleeding requires discontinuation of the drug and clinical and laboratory examination.

From the nervous system:

very often - tremor; often - extrapyramidal disorders, stupor*, drowsiness, convulsions*, memory impairment, headache, nystagmus, dizziness (may occur a few minutes after IV injection and disappear spontaneously within a few minutes); uncommon - coma*, encephalopathy*, lethargy*, reversible parkinsonism, ataxia, paresthesia, increased severity of seizures; rarely - reversible dementia combined with reversible brain atrophy, cognitive disorders; frequency unknown - sedation.

*stupor and lethargy sometimes led to transient coma/encephalopathy and were either isolated or combined with an increase in convulsive attacks during treatment, and also decreased when the drug was discontinued or its dose was reduced. Most of these cases have been described during combination therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

From the mental side:

infrequently - a state of confusion, aggressiveness**, agitation**, impaired attention**, depression (when valproic acid is combined with other anticonvulsants); rarely - behavioral disorders**, psychomotor hyperactivity**, learning disabilities**, depression (with monotherapy with valproic acid).

**adverse reactions, mainly observed in pediatric patients.

From the senses:

often - reversible and irreversible deafness; frequency unknown - diplopia.

From the digestive system:

very often - nausea; often - vomiting, gum changes (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhea (which often occurs in some patients at the beginning of treatment, but usually disappears after a few days and does not require cessation of therapy); uncommon - pancreatitis, sometimes fatal (the development of pancreatitis is possible during the first 6 months of treatment; in case of acute abdominal pain, it is necessary to monitor the activity of serum amylase); frequency unknown - abdominal cramps, anorexia, increased appetite. Frequent reactions from the digestive system can be reduced by taking the drug during or after meals.

From the liver and biliary tract:

often - liver damage, which is accompanied by deviations from the norm in indicators of the functional state of the liver, such as a decrease in the prothrombin index, especially in combination with a significant decrease in the content of fibrinogen and blood clotting factors, an increase in the concentration of bilirubin and an increase in the activity of liver transaminases in the blood; liver failure, in exceptional cases with death. It is necessary to monitor patients for possible liver dysfunction.

From the respiratory system:

infrequently - pleural effusion.

From the urinary system:

uncommon - renal failure; rarely - enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of renal tubular damage with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is still unclear.

From the immune system:

often - hypersensitivity reactions, for example, urticaria; uncommon - angioedema; rarely - drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

For the skin and subcutaneous tissues:

often - transient or dose-dependent alopecia (including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary syndrome, as well as alopecia against the background of developed hypothyroidism), disorders of the nails and nail bed; uncommon - rash, hair disorders (such as disruption of the normal hair structure, change in hair color, abnormal hair growth [disappearance of wavy and curly hair or, conversely, the appearance of curly hair in persons with initially straight hair]); rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme).

From the musculoskeletal system and connective tissue:

infrequently - a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients taking valproic acid for a long time (the mechanism of the effect of valproic acid on bone metabolism has not been established); systemic lupus erythematosus.

From the endocrine system:

uncommon - syndrome of inadequate ADH secretion, hyperandrogenism (hirsutism, virilization, acne, male pattern alopecia and/or increased concentrations of androgens in the blood); rarely - hypothyroidism.

From the side of metabolism:

often - hyponatremia, weight gain (since weight gain is a factor contributing to the development of polycystic ovary syndrome); rarely - hyperammonemia*, obesity.

* cases of isolated and moderate hyperammonemia may occur without changes in liver function tests and the need to discontinue treatment. Hyperammonemia has also been reported, accompanied by the appearance of neurological symptoms, incl. development of encephalopathy, vomiting, ataxia), which required discontinuation of valproic acid and additional examination.

From the side of blood vessels:

infrequently - vasculitis.

From the reproductive system:

often - dysmenorrhea; infrequently - amenorrhea; rarely - male infertility, polycystic ovary syndrome; frequency unknown - dysmenorrhea, breast enlargement, galactorrhea.

Benign, malignant and unspecified tumors (including cysts and polyps):

rarely - myelodysplastic syndrome.

Common disorders:

infrequently - hypothermia, mild peripheral edema.

Laboratory and instrumental data:

rarely - biotin deficiency/biotinidase deficiency.

Instructions for use DEPAKINE CHRONO

The use of antiepileptic drugs may in rare cases be accompanied by the recurrence and development of more severe seizures or the episodic appearance of a new type of seizure in patients, these seizures are not dependent on the spontaneous fluctuations established in these patients. This primarily concerns simultaneously administered antiepileptic therapy, pharmacokinetic interactions with other drugs, toxicity, and overdose.

To avoid overdose, you should not use simultaneously other drugs whose metabolism produces valproic acid (including divalproate, valpromide).

There are extremely rare reports of severe and fatal cases of liver disease. In the vast majority of cases, such liver damage occurs within the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combination therapy with antiepileptic drugs. At increased risk are infants and children under 3 years of age with severe epilepsy, especially those associated with brain damage, mental retardation, and/or congenital metabolic or degenerative diseases. Over the age of 3 years, the frequency of such complications decreases significantly and gradually decreases with age.

Early diagnosis of liver lesions is based primarily on clinical examination. In particular, you should take into account 2 types of symptoms that may precede jaundice, especially in patients at risk:

• on the one hand, nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;
• on the other hand, relapse of epileptic seizures, despite adequate treatment.

It is recommended to inform the patient, and if it is a child, then his family, that if these clinical symptoms develop, you should immediately consult a doctor. In such cases, in addition to clinical examination, a liver function test should be immediately performed.

In order to timely detect liver dysfunction, it is necessary to periodically monitor liver function during the first 6 months of treatment, especially in patients at risk. Among the standard parameters, the most important are tests reflecting the protein-synthetic function of the liver and especially the prothrombin index. If a pathologically low level of prothrombin is detected, especially in combination with other laboratory test results (significant decrease in the level of fibrinogen and blood coagulation factors, increase in the level of bilirubin and transaminases), treatment with Depakin Chrono should be suspended. If the patient has been prescribed salicylates (concomitant therapy), as a precautionary measure, their use should also be discontinued, since they are metabolized along the same route.

In extremely rare cases, severe forms of pancreatitis were observed, which in some cases led to death. These cases were observed regardless of the patient's age or duration of treatment, although younger children appear to be at increased risk.

Pancreatitis with an unfavorable outcome was usually observed in young children, in patients with severe epilepsy, brain damage, or when using complex anticonvulsant therapy. Insufficiency of liver function in pancreatitis increases the risk of death.

When treating with Depakine Chrono, as with other antiepileptic drugs, a slight, isolated and temporary increase in transaminase levels may be observed, especially at the beginning of treatment in the absence of any clinical symptoms. In this case, it is recommended to do a more complete laboratory examination (including determination of the prothrombin index), if necessary, adjust the dose and repeat the tests depending on changes in parameters.

For asymptomatic thrombocytopenia, reducing the dose of sodium valproate usually achieves regression of thrombocytopenia if the platelet count and epilepsy control allow.

The condition of patients who experience an increase in body weight during therapy with Depakine Chrono should be monitored, because this is a risk factor for the development of polycystic ovary syndrome.

Patients should be warned about the risk of weight gain early in treatment and the need to follow an appropriate diet.

Before starting therapy or surgery in the case of hematomas or spontaneous bleeding, it is recommended to conduct a hematological blood test (determine the blood count, including platelet count, bleeding time and coagulation tests).

In patients with renal failure, it is recommended to take into account the increased concentration of free form of valproic acid in the serum and reduce the dose.

In case of acute abdominal pain and gastrointestinal symptoms (nausea, vomiting and/or anorexia), it is necessary to conduct diagnostic tests for the presence of pancreatitis and, in case of elevated levels of pancreatic enzymes, discontinue the drug and prescribe alternative therapy.

Sodium valproate is not recommended for use in patients with carbamide cycle enzyme deficiency. In such patients, several cases of hyperammonemia accompanied by stupor and/or coma have been described.

Although it has been shown that during treatment with Depakine Chrono, dysfunction of the immune system is extremely rare, the potential benefits of therapy and the risks should be assessed if it is necessary to use the drug in patients suffering from SLE.

Patients should be warned about the risk of weight gain early in treatment; To minimize this effect, the patient should follow an appropriate diet.

Use in pediatrics

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or young child, metabolic studies, especially ammonemia, should be performed before initiating treatment with sodium valproate. on an empty stomach and after meals.

The simultaneous administration of salicylate derivatives to children should be avoided due to possible hepatotoxicity.

Impact on the ability to drive vehicles and operate machinery

During treatment, patients should be warned about the possible occurrence of temporary drowsiness and the need to be careful when driving vehicles and other activities that require high concentration and speed of psychomotor reactions (especially when using combined anticonvulsant therapy).

Overdose

Symptoms:

coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive decrease in blood pressure, vascular collapse/shock. Cases of intracranial hypertension associated with cerebral edema have been described. The presence of sodium in valproic acid preparations in case of overdose can lead to the development of hypernatremia. Symptoms may vary, and seizures have been reported with very high plasma concentrations of valproic acid. With a significant overdose, death is possible, but the prognosis is usually favorable.

Treatment:

in the hospital - gastric lavage, which is effective within 10-12 hours after taking the drug orally. To reduce the absorption of valproic acid, taking activated carbon, incl. its administration through a nasogastric tube. Monitoring and correction of the functional state of the cardiovascular and respiratory systems and maintenance of effective diuresis are required.

It is necessary to monitor the functions of the liver and pancreas. If respiratory depression occurs, mechanical ventilation may be required.

Naloxone has been used with success in some cases. In very severe cases of significant overdose, hemodialysis and hemoperfusion have been effective.

Psychiatry Psychiatry and psychopharmacotherapy named after. P.B. Gannushkina No. 1 2004 Appendix

TO

At the turn of the millennium, sufficient evidence has accumulated indicating that epileptic discharge activity in functionally significant areas of the brain leads to permanent non-seizure disorders in patients with epilepsy in the form of behavioral, mental, and neuropsychological disorders.
With foci in the left hemisphere, changes in language and speech functions predominate, such as receptive and expressive aphasia, agraphia, acalculia, alexia, and speech dyspraxia. In right-hemispheric cases, the changes are complemented by auditory and visuospatial nonverbal agnosia, dyscopia, aprosody and disarticulation. Orbitofrontal, cingulate foci, involvement of nonspecific midline structures are accompanied by severe behavioral disorders, autism, mutism, aspontaneity, asociality, aggression, and eccentricity. Involvement of hippocampal structures and the amygdala is manifested by impairment of either socially motivated (left) or primary emotions (right) and specific verbal and nonverbal memory and learning [2–5, 8, 9, 11, 13, 27, 29]. The result of the generalization of these data was the introduction by the Working Group on Classification and Terminology of the International League Against Epilepsy into the draft of a new classification of epileptic syndromes of an extensive category of epileptic encephalopathies
[3, 7, 17, 19, 27, 43, 44]. This section of the classification includes epilepsies and epileptic syndromes, “in which epileptiform disorders lead to progressive brain dysfunction.” This, in particular, includes two syndromes: Landau-Kleffner epileptic aphasia and epilepsy with constant spike-wave complexes during slow-wave sleep, which in a significant number of cases occur without seizures at all and are clinically manifested only by severe speech impairment (in the first case) and progressive mental degradation (in the second), caused, according to modern concepts, by constant discharges of epileptiform activity in the brain, detected by electroencephalography (EEG) or magnetoencephalography [6, 8, 9, 23, 28, 42]. In addition, in recent decades, dozens of observations have been published in which the main or only problem is not rare or absent seizures in the patient, but mental, communicative, cognitive, behavioral and social disorders associated with the picture of prolonged nonconvulsive status epilepticus or constant discharges of local or generalized epileptic activity in the EEG [2–8, 14, 16, 23, 25, 27, 32]. The coincidence of the localization of epileptic discharges in structures associated with impaired higher mental functions, the temporal connection between the appearance and disappearance of clinical disorders with epileptic activity, and the success of anticonvulsant therapy confirm the epileptic nature of these long-term nonconvulsive psychoneurological disorders [2–8, 10, 20, 24, 32–34 , 38]. By analogy with Landau–Kleffner acquired epileptic aphasia, cases of acquired epileptic frontal syndrome, an autistic, neuropsychological and behavioral disorder have been described [30, 31]. Based on the detection of epileptic discharges in the structures of the limbic-reticular complex in cases of schizophrenic, depressive and anxiety disorders resistant to psychotropic drugs, the concept of “psychotic epilepsy” was proposed [41]. These disorders constitute, according to the literature and our own estimates, depending on the form, from 5 to 40% of behavioral, mental and neuropsychological disorders [12, 28] and up to 3–10% of all epileptic disorders [7]. In all such cases, the reason for the patient or his parents to see a doctor is discommunicative, intellectual, pedagogical, psychotic, behavioral, and emotional disorders. The difficulties of correct diagnosis of such patients lie in the fact that at the time of treatment there are no special complaints about seizures, although in some cases (up to 50%), a special survey allows them to be identified in a long-term history [3, 7]. Since the complaints are not of a specific neurological nature, these patients are monitored and managed by psychiatrists (in cases of behavioral, mental, educational, social disorders) or defectologists (in cases of speech communication disorders). In the absence of seizures, the presence of epileptiform activity in the EEG in patients (if it is examined at all) is considered as an epiphenomenon that does not give rise to the prescription of antiepileptic drugs; patients are treated syndromologically without taking into account the pathogenetic mechanisms of the disorders and are often treated with psychostimulants, nootropics, psychotropic drugs, which causes failure treatment, and often worsening symptoms, since all these drugs reduce the threshold for convulsive readiness. Meanwhile, correct diagnosis and treatment of these disorders as epileptic allows 80% of such patients resistant to the mentioned therapy to obtain good improvement with the use of valproic acid (Depakine Chrono) and other antiepileptic drugs that suppress epileptic activity in the EEG [2, 3, 6– 8, 10, 17, 24, 26, 28, 32–34, 38].

1. Main clinical manifestations of non-convulsive epileptic encephalopathies with behavioral and mental disorders

As already indicated, the disorders observed in epileptic encephalopathies represent almost the entire spectrum of symptoms of mental and behavioral disorders of ICD-10, as well as a wide range of syndromes of neuropsychological disorders, usually described within the framework of organic brain damage in neurological diseases. Accurate data determining the population representation of the discussed forms of psychoneurological disorders are currently not available. This is partly due to the novelty of the problem, but mainly due to the fact that publications devoted to it, and, accordingly, the clinical forms identified by the authors, as well as their rubrication, depend on the specialist’s profession. Thus, publications by neurologists and epileptologists mainly discuss neuropsychological disorders, classifying them as primary neurological pathologies, such as acquired epileptic aphasia, acquired epileptic visual agnosia, acquired epileptic frontal lobe syndrome [3, 6, 8, 14, 16, 18]. In publications by pediatricians and psychiatrists, the same disorders are interpreted as autism, pervasive developmental disorders, school skills disorders, etc. [7, 10, 12, 24, 25, 28, 37]. On the other hand, hyperkinetic disorders such as tics (Tourette's syndrome), being a primary psychiatric diagnostic entity, are in most cases treated by neurologists. Thus, it should be recognized that this entire group of disorders is a general psychoneurological one, but the largest number of such patients is found in pediatric institutions providing assistance to children with behavioral and mental disorders. The difficulties in assessing the relative frequency of various manifestations of nonconvulsive encephalopathies are also determined by the fact that, as a rule, they occur in complex combinations and the diagnosis is made according to the main disorder corresponding to the profile of the specialist to whom the patient is seen. According to our observations, in child psychiatry departments, the most common forms of disorders are socialized and unsocialized behavior disorders and disorders of school skills, causing oppositional disorder (about 30%), hyperkinetic disorders (about 30%), attention deficit, general developmental delay (about 20). %); Less common (about 3–5%) are the diagnoses of “autism,” “Asperger’s syndrome,” and “selective mutism” [7, 10]. At the same time, in the same populations, there are numerous cases of neuropsychological speech disorders, interpreted as a general delay in speech development with various forms of speech disorders in the form of dysphasia, expressive aphasia, speech dyspraxia, often interpreted as stuttering, agrammatism, dyslexia, verbal memory disorders, dysarthria , dyslalia. These disorders are sometimes combined with orolingual incoordination, drooling and, as a rule, are combined with each other [5]. In neurological publications, diagnoses of neuropsychological disorders account for up to 60% and include Landau-Kleffner epileptic acquired aphasia syndrome (about 20%), epileptic encephalopathy with persistent spike-wave complexes in slow-wave sleep, acquired frontal lobe syndrome, acquired visual agnosia, speech dyspraxia [ 2, 3, 9, 8]. Particular manifestations of the listed syndromes include dyslexia, disorders of processing sequential information, deficits in visuospatial skills, and acoustic agnosia [39]. Although epileptic encephalopathies are described mainly as disorders of childhood, they can also occur in adulthood, according to some data - after 17-20 years, in some cases - older. Developing for the first time in adulthood, disorders associated with epileptic encephalopathy manifest themselves as schizophrenic, affective and anxiety disorders, sometimes complicated by addiction disorders [2, 3, 35, 40, 41, 45]. Complaints about neurological disorders proper (in addition to neuropsychological disorders) in the sensorimotor sphere caused by epileptic dysfunction are usually absent in non-convulsive epileptic encephalopathies with behavioral and mental symptoms. The most typical general asthenic complaints are fatigue, decreased performance and perseverance, increased nervousness, episodic tension headaches, and parasomnias are also noted. Anamnestic data and hereditary factors include pregnancy pathology, impaired gestation, perinatal pathology, parental alcoholism, parental mental illness, epilepsy in relatives, a history of febrile convulsions, and mild traumatic brain injury. An objective examination usually reveals subclinical signs of reflex hemisyndrome without pathological signs, weak signs of oral automatism, Chvostek’s symptom, increased deep reflexes, and muscle hypotonia.

2. Electroencephalographic and other paraclinical manifestations of non-convulsive epileptic encephalopathies with behavioral and mental disorders

Certain patterns have been identified in the manifestation of different types of epileptiform activity in the EEG.
Generalized bilateral synchronous discharges
of spike-wave activity caused by the involvement of the nuclei of the nonspecific activating reticular formation and the mediobasal structures of the frontal lobes, patterns of typical and atypical absences or their statuses are manifested by dysfunction of tracking, directed attention, short-term memory, consciousness, goal-directed behavior, attention, function conscious contact, learning ability.
In a milder form, these epileptic disturbances in the EEG are manifested by moderate confusion, disorientation, some slowness of reaction, a feeling of strangeness, sometimes lasting up to several days [29]. Such mild disorders associated with episodic discharges of generalized bilaterally synchronous discharges in the EEG, usually regarded as “subclinical,” are called “transient cognitive impairment.” It has been shown that they may underlie serious disorders of learning, development and behavior in children with epilepsy, and the degree of these permanent disorders correlates with the frequency and intensity of epileptic electrogenesis in the EEG [9, 11, 13, 33, 37]. Bilaterally synchronous epileptiform discharges in the frontal leads are caused by epileptic activity in the cingulate gyrus and orbitofrontal cortex and are accordingly accompanied by severe frontal dysfunction with disorders of socially motivated behavior, aggression, autism, and mutism [7, 25, 31]. If EEG data is underreported, such clinical disorders are regarded in children and adolescents as general learning and behavioral disorders, oligophrenia [37]. In older patients, patterns of absence status involving nonspecific midline structures are manifested by disturbances in holistic thinking with psychiatric symptoms. So, back in 1949 H. Wycis et al. using long-term stereotactic recordings showed that in some patients diagnosed with schizophrenia who have never had epileptic seizures, paranoid symptoms are directly related to epileptic discharges recorded in the mediobasal structures of the brain with normal convexital EEG [45]. The presence of patterns of generalized epileptiform activity, indicating dysfunction of the midline and mediobasal structures of the brain in disorders interpreted as schizophrenia or depression, was also shown in later studies [2, 35, 40, 41]. Focal epileptiform changes in the EEG
are manifested by dysfunctions associated with the corresponding localization. In Landau–Kleffner epileptic aphasia, epileptiform discharges are recorded in the temporal leads. With left-sided localization of discharges, amnestic, sensory and motor aphasia is noted. In right-sided cases, auditory agnosia, disarticulation, and speech dyspraxia may be observed [3, 7, 8, 16, 36, 39]. In extreme severity, these disorders create a picture of mutism, which, if misdiagnosed, is interpreted as deaf-muteness, which leads to attempts to teach patients sign language and, in the absence of treatment for epileptic dysfunction, to lifelong loss of speech [2, 6, 20]. Centrotemporal spikes are accompanied by speech dyspraxia, up to mutism, dyslexia, agrammatism, and disorders of serial information processing. If centrotemporal spikes are combined with a pattern of constant spike-wave complexes in slow-wave sleep, severe general mental retardation is associated with this [3, 5, 7, 8, 16, 18, 23, 31, 34, 36, 39]. Occipitolobar epileptic discharges manifest themselves along with other disorders in visuospatial agnosia [7, 18]. Frontal-lobar discharges of epileptiform activity are manifested by schizoaffective disorders, dysfunction of socialization, the ability to plan behavior, and aggression [2–6, 25, 31]. In addition to this gross epileptiform activity, epileptic encephalopathies can be accompanied by a general slowdown in electrical activity, disturbances in topical differentiation, excessive synchronization in the theta and delta range, bilaterally synchronous bursts of delta, theta and alpha activity, which, due to the extremely high amplitude ( up to 1000 μV or more) acquire an acute form and, accordingly, an epileptiform character [10, 19]. Considering the critical role of identifying epileptiform activity for the correct therapeutic approach in the group of pathologies under discussion, if it is suspected, a thorough EEG examination is necessary using all the necessary functional tests, and in the absence of obvious data in the daytime recording, a sleep EEG study, since in Landau-Kleffner epileptic aphasia epileptiform activity can be detected during the transition from the first to the second stage of sleep and beyond. It should be noted that the clinical phenomena of epileptic encephalopathy can occur with epileptic foci in the mediobasal regions of the temporal and frontal lobes, which are not manifested in the scalp EEG. Magnetoencephalography is used to diagnose such disorders.

3. Pharmacotherapy of non-convulsive epileptic encephalopathies

Thus, over the past two decades, independent research in related fields of medicine - neurology, epileptology, psychiatry and pediatrics - has led to the identification of almost the same group of pathologies, characterized by the presence of severe permanent brain dysfunction, manifested by behavioral, mental and neuropsychological disorders without actual epileptic seizures, combined with persistent epileptiform activity in the EEG. It is the abnormal “epileptic” hypersynchronous activity of neurons in functionally significant parts of the brain that leads to disruption of the corresponding mental function. The relative rarity of their descriptions is explained by the fact that these cases fall on the divide between psychiatry and neurology. A patient with dominant mental complaints is immediately referred to a psychiatrist, who, as a rule, begins symptomatic treatment with psychotropic drugs and nootropics, without paying due attention to EEG data, to which in most cases the patient is not even referred, and in the absence of seizures, even in the presence of epileptiform activity the patient is not prescribed antiepileptic drugs, and the disorder is not considered a form of epileptic disease. It is interesting to note that, working in neurological institutions, we collected a little more than a dozen of the analyzed observations over a period of about 20 years. Work in pediatric psychiatric institutions for only 4 years yielded about a hundred additional cases [2–8, 10]. It is obvious that such patients end up in neurological institutions only by chance, and in the absence of a neurologist with in-depth specialization in EEG and epileptology in a psychiatric institution, these cases are not diagnosed and, accordingly, are treated incorrectly: such patients receive antipsychotics, antidepressants, nootropics, psychostimulants. These drugs lower the seizure threshold and often lead to worsening symptoms. Carbamazepine, prescribed in some cases as a behavior corrector, can also worsen the condition of these patients, in particular, leading to the appearance of “electrical status epilepticus in slow-wave sleep” [2, 9, 22]. As follows from the above, treatment of mental, behavioral and cognitive, neuropsychological disorders caused by epileptic encephalopathy should be aimed at suppressing epileptiform activity in the EEG, since it is epileptic discharges in the brain that cause disruption of higher functions, manifested by corresponding psychopathology. Therefore, the choice of drug should be focused specifically on its effectiveness in suppressing epileptiform activity, and, in addition, it is desirable that it itself has a positive psychocognitive effect and does not give negative side effects in this regard. It should be said that some anticonvulsants in a certain percentage of cases enhance epileptiform activity, and sometimes lead to the appearance or worsening of epileptic seizures. This is characteristic of carbamazepine, phenobarbital, phenytoin, and of the newest drugs – lamotrigine, topiramate, vigabatrin [21, 22]. In addition, these drugs in some cases aggravate mental and behavioral symptoms [6, 21, 22]. The only drug that has been proven to effectively suppress epileptiform activity in the EEG is valproic acid [1–3]. Its second important property is that it almost never causes the appearance, frequency or severity of epileptic seizures [2, 3, 22]. That is why in the overwhelming majority of publications devoted to the treatment of epileptic nonconvulsive encephalopathies, valproic acid is used and recommended for use as the drug of first choice [1–8, 10, 12, 17, 24, 32, 33]. In our studies, which to date have included more than 50 patients who were observed for at least a year, improvement to one degree or another was obtained in all, and in 70% of cases practical recovery was achieved [3, 7, 10]. Particularly indicative is the study by S.I. Shevelchinsky et al. (2004), who compared two groups of patients with behavioral disorders, similar in all respects, one of which was treated with antipsychotics, and the other with Depakine Chrono. The results were assessed quantitatively based on the results of pathopsychological and neuropsychological testing and the dynamics of pathological activity in the EEG during treatment. For most indicators, patients treated with Depakine Chrono showed a statistically significant improvement, while treatment with neuroleptics was either ineffective or caused deterioration in the same indicators [10]. It is as a drug with the best combination of effectiveness and safety that valproate is recommended in special works devoted to the treatment of epileptic encephalopathies, including non-convulsive ones [17]. The use of the Depakine Chrono form is also motivated by the fact that in maintaining normal cognitive processes, the most important role belongs to the continuity of the psyche, as well as the normal flow of information processes in slow-wave sleep. Both of these aspects are disrupted by epileptiform discharges, which are activated when the concentration of the drug in the blood decreases. It is the property of depakine chrono to maintain a stable concentration throughout the day that is a factor in its particular effectiveness in the treatment of epileptic encephalopathies [1, 2]. Next, we summarize the main properties of Depakine Chrono, which determine its primary choice for epileptic encephalopathies.

Rationale for the use of depakine chrono as a first-choice drug for epileptic encephalopathies

1. The absence of contraindications and the risk of worsening symptoms and the addition of other disorders, due to the following clinical and pharmacological features of Depakine compared to alternative drugs: a) Depakine Chrono does not cause sedation, motor stiffness, agitation, dyskinesias and other psychomotor phenomena inherent in antipsychotics, tranquilizers, psychostimulants, antidepressants and other psychotropic drugs; b) depakine chrono effectively suppresses epileptiform activity, in contrast to neuroleptics, which lower the threshold of convulsive readiness, and carbamazepine, which often increases epileptiform activity in the EEG with aggravation of psychiatric symptoms and possible provocation of seizures [2, 6]; c) depakine chrono eliminates the risk of developing iatrogenic late dystonia, dyskinesia, parkinsonian syndrome, possible with the use of neuroleptics and, accordingly, does not require the use of correctors; e) depakine does not cause dependence and tolerance of symptoms to the drug due to a decrease in the sensitivity of neuronal receptors. 2. In addition to the antiepileptic effect, valproic acid has its own antipsychotic effect, independent of the anticonvulsant effect, and is used regardless of epilepsy as an antipsychotic drug, behavior corrector, anxiolytic for mood disorders, addiction diseases, emotional disorders, making up, for example, 35% of all drugs used in psychiatric clinics in the USA [15]. 3. Valproic acid is a neuroprotector and protects neurons from excitotoxic death, characteristic of a number of neurological, epileptic and psychiatric diseases and thereby prevents the progression of the disease, and in some cases contributes to its interruption and practical recovery [2, 6]. 4. Valproic acid promotes the differentiation of neuroblasts and the proliferation of dendrites, thereby promoting the maturation of the functional systems of the brain [6]. 5. Effective suppression of epileptic activity in the EEG by valproic acid makes it possible, already on the 3rd–5th day of a stabilized therapeutic dose, to verify, using EEG control, the correct choice of the drug, predict success in a given patient, and subsequently monitor the success of treatment using the dynamics of EEG changes [1 –6]. 6. Treatment with valproic acid in most cases does not produce adverse side effects from the central nervous system, and if they occur, they are not long-term and are completely reversible when the drug is discontinued or its dose is reduced [2, 3, 12, 15]. It should be noted that, in contrast to epileptic seizures, which require treatment for at least 2 years, and sometimes for life, treatment with depakine for chronic non-convulsive epileptic cognitive disorders under EEG and clinical control is carried out only for the time necessary to stabilize the achieved clinical effect. Our experience suggests that, provided that epileptiform activity in the EEG is successfully completely suppressed under the influence of depakine chrono, the required duration of treatment in most cases ranges from 6 months to 2-3 years. If unsuccessful, other antiepileptic drugs are used that suppress epileptiform activity in the EEG (topiramate, lamotrigine) [26]. If ineffective in cases of severe speech disorders associated with Landau-Kleffner syndromes and “electrical status in slow-wave sleep,” steroids are used, and if pharmacotherapy is ineffective, surgical treatment is used [20, 38]. This aggressiveness of therapy emphasizes the critical role of epileptic activity in the EEG in the development of behavioral, mental and cognitive disorders.

Drug interactions

Effect of valproic acid on other drugs

Valproic acid may potentiate the effect of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines

(with simultaneous use, careful medical monitoring and, if necessary, dose adjustment are recommended).

Valproic acid does not affect serum lithium

.

Valproic acid increases phenobarbital

in plasma (due to a decrease in its hepatic metabolism), and therefore the development of the sedative effect of the latter is possible, 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 the plasma concentration of phenobarbital.

Valproic acid increases primidone

in plasma, which leads to 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.

Valproic acid reduces total phenytoin

in plasma. In addition, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of overdose (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 concentration of phenytoin and its free fraction in the blood is recommended.

With the simultaneous use of valproic acid and carbamazepine

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

Valproic acid slows the metabolism of lamotrigine

in the liver and increases T1/2 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.

Valproic acid may increase plasma concentrations of zidovudine,

which leads to an increase in the toxicity of zidovudine, especially hematological effects, by slowing down its metabolism by valproic acid. Continuous clinical observation and monitoring of laboratory parameters is necessary. A blood test should be done to rule out the development of anemia during the first two months of combination therapy.

Valproic acid may reduce the mean clearance of felbamate.

by 16%.

Valproic acid may decrease plasma concentrations of olanzapine.

Valproic acid may lead to increased plasma concentrations of rufinamide

. This increase depends on the concentration of valproic acid in the blood. Caution should be exercised, especially in children, because this effect is more pronounced in this population.

Valproic acid may lead to increased plasma concentrations of propofol.

Consideration should be given to reducing the dose of propofol when used concomitantly with valproic acid.

Strengthening the hypotensive effect of nimodipine

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

Co-administration of temozolomide

with valproic acid leads to a mild, but statistically significant, decrease in the clearance of temozolomide.

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 case of combination therapy, the dose of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

Serum concentrations of valproic acid metabolites may be increased when administered concomitantly with phenytoin or phenobarbital.

. Therefore, patients receiving these combinations should be carefully monitored for signs and symptoms of hyperammonemia, as some metabolites of valproic acid can inhibit enzymes of the carbamide cycle (urea cycle).

When used simultaneously with aztreonam

there is a risk of developing seizures due to a decrease in the concentration of valproic acid in the blood plasma. Clinical observation, determination of plasma concentrations of valproic acid and possible dose adjustment of the anticonvulsant during treatment with aztreonam and after its cessation are necessary.

When combining felbamate

and valproic acid, the clearance of valproic acid decreases by 22-50% and, accordingly, the plasma concentration of valproic acid increases. Plasma concentrations of valproic acid should be monitored.

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.

With the simultaneous use of valproic acid and St. John's wort preparations

the anticonvulsant effectiveness of valproic acid may be reduced.

In 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.

With the simultaneous use of valproic acid and indirect anticoagulants (warfarin and other coumarin derivatives)

careful monitoring of INR and prothrombin index is required.

Plasma concentrations of valproic acid may increase with concomitant use of cimetidine or erythromycin

(as a result of a slowdown in its hepatic metabolism).

Reduced concentrations of valproic acid in the blood when used simultaneously with carbapenems (panipenem, meropenem, imipenem):

within 2 days of joint therapy, a 60-100% decrease in the concentration of valproic acid in the blood plasma was observed, 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 plasma concentrations of valproic acid. If treatment with carbapenems cannot be avoided, close monitoring of valproic acid blood concentrations should be performed during carbapenem treatment and after its discontinuation.

Rifampicin

may reduce the concentration of valproic acid in the blood, which leads to loss of the therapeutic effect of valproic acid. Therefore, it may be necessary to increase the dose of valproic acid during simultaneous use of rifampicin and after its discontinuation.

Protease inhibitors such as lopinavir, ritonavir

, reduce the plasma concentration of valproic acid when used simultaneously with it.

Cholestyramine

may lead to a decrease in plasma concentrations of valproic acid when used simultaneously.

Other interaction

Concomitant use of valproic acid and topiramate

or
acetazolamide
was accompanied by encephalopathy and/or hyperammonemia. Patients receiving these combinations should be closely monitored for the development of symptoms of hyperammonemic encephalopathy.

Concomitant use of valproic acid and quetiapine

may increase the risk of developing neutropenia/leukopenia.

Valproic acid does not have the ability to induce liver enzymes and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen

drugs in women using hormonal contraception.

When taking ethanol and other potentially hepatotoxic drugs

simultaneously with valproic acid, it is possible to enhance the hepatotoxic effect of valproic acid.

Concomitant use of clonazepam

with valproic acid can lead in isolated cases to increased severity of absence status.

With the simultaneous use of drugs that have myelotoxic effects

, with valproic acid the risk of suppression of bone marrow hematopoiesis increases.

Depakine in the treatment of epilepsy in children

• a wide range of therapeutic activity (impact on a variety of types of attacks); • possibility of use in various age groups; • linear and predictable pharmacokinetics; • lack of autoinduction of liver enzymes; • the ability to quickly and easily increase the dose; • absence of life-threatening side effects; minimal number of serious side effects; • absence of negative impact on cognitive functions; • absence of the phenomenon of tolerance (“habituation”) and low risk of aggravation of epileptic seizures; • a wide selection of dosage forms (syrup, tablets, extended-release tablets, solution for intravenous administration); • affordable price. Unfortunately, there is not yet an “ideal” antiepileptic drug for all forms of epilepsy and for all patients with epilepsy. It is possible that each form of epilepsy requires its own special AED, since epilepsies are heterogeneous conditions, presumably with different mechanisms of epileptogenesis. Therefore, the number of drugs used to treat epilepsy has increased significantly over the past 10 years and continues to increase at a rapid pace. Currently, there is a fairly wide selection of AEDs with a variety of mechanisms of action. The World Health Organization (WHO) considers the following 6 antiepileptic drugs to be “essential”: carbamazepine, sodium valproate, phenytoin, phenobarbital, diazepam and ethosuximide. According to WHO, drugs that meet the requirements for improving health in the majority of patients in a particular population (in this case, the population of patients with epilepsy) are necessary. Despite the large number of AEDs, a neurologist usually uses 3–4 drugs in daily practice. The first two belong to traditional AEDs and are called the “gold standard” for the treatment of epilepsy. These are carbamazepine and valproate (valproic acid salt). In the European literature on epileptology, these drugs are called “first-line antiepileptic drugs.” In the American tradition, phenytoin is added to carbamazepine and valproate. Of course, the definition of the term “first-line AED” depends on national preferences and the availability of the drug in a particular country. In addition, the choice of priority drugs may change due to the introduction of new AEDs into practice. Sodium valproate (original drug - Depakine, pharmaceutical, France) has been used in the treatment of epilepsy for 37 years. During this time, various aspects of its pharmacokinetics, efficacy and tolerability have been carefully studied. Next, we consider how Depakine corresponds to the “ideal” drug that we would like to have at our disposal for the treatment of epilepsy. Efficacy in different types of seizures and different epileptic syndromes It is possible that sodium valproate demonstrates the widest spectrum of antiepileptic activity of all known AEDs, since it is essentially effective in all types of seizures, regardless of the form of epilepsy. Its effectiveness has been proven for a variety of types of generalized epileptic seizures - tonic-clonic, myoclonus, absence seizures, epileptic spasms, generalized tonic and atonic seizures. It is the first-line drug of choice in the treatment of most idiopathic and symptomatic generalized epilepsies [1]. The effectiveness of valproate is considered unsurpassed in the treatment of idiopathic generalized epilepsies [2]. The drug allows you to get rid of different types of seizures observed in juvenile myoclonic epilepsy (myoclonus, generalized tonic-clonic seizures and absence seizures) for the vast majority of patients. A recently published study by Nikolson A. et al. (2004), which included a large population of patients with idiopathic generalized epilepsy, showed the superior effectiveness of valproate compared to topiramate and lamotrigine [3]. In patients with childhood absence epilepsy, the use of valproate can achieve remission in 80% of all cases [4]. Valproate is widely used in the treatment of atypical absence seizures, tonic, atonic and myoclonic seizures associated with cryptogenic and symptomatic generalized epilepsies. It is used for Lennox-Gastaut syndrome and in the treatment of West syndrome, progressive myoclonus-epilepsy [1]. Sodium valproate is effective in the treatment of focal seizures of various localizations, perhaps slightly inferior in effectiveness to carbamazepine [2]. It is known that in the treatment of partial epilepsy, as a rule, carbamazepine is the first-line drug of choice. At the same time, there are a number of randomized studies showing that sodium valproate is also effective in partial epilepsy, its effectiveness is comparable to that of carbamazepine [5]. For example, a study on the comparative effectiveness and tolerability of various AEDs in the treatment of partial epilepsy demonstrated similar effectiveness of valproate and carbamazepine and slightly better tolerability of valproate [6]. Similar results were obtained by M. de Silva et al. (1996) in a pediatric population with partial epilepsy [7]. A recent study conducted by Kuncikova M. and the VIPe Study Group, as close as possible to daily clinical practice, showed that sodium valproate is effective and well tolerated in the treatment of partial epilepsy in children and adults [8]. The remission rate reached 84% in children and 73% in adults and was similar for different types of epileptic seizures, different etiologies of epilepsy and localization of the epileptic focus. In addition, there was a high level of retention on the drug (% of patients continuing treatment after some time); it reached 90% after 6 months of treatment. Only 2% of patients discontinued participation in the study due to side effects. Based on the results obtained, the researchers conclude that sodium valproate may be the first-line drug of choice in the treatment of partial epilepsy in children and adults. It should be mentioned that there is no clear boundary between focal and generalized epilepsies. Facts such as the presence of focal seizures in the structure of generalized epilepsies, the detection of focal EEG changes in generalized epilepsies in 30–35% of all cases, the presence of focal structural abnormalities in idiopathic generalized epilepsies, as well as the leading role of the frontal lobes in the pathogenesis of this form of epilepsy are well known. like juvenile myoclonic. On the other hand, focal epileptic seizures can be accompanied by secondary generalized epileptic discharges on the EEG. This phenomenon is called secondary bilateral synchronization. Secondary bilateral synchronization is an encephalographic pattern consisting of a sequence of focal spikes, polyspikes or spike-wave complexes (less commonly slow waves), followed by a burst of bilateral, synchronous and symmetrical spike-wave activity, distributed over both hemispheres. The development of secondary bilateral synchronization leads to aggravation of the course of epilepsy with an increase in the total number of attacks and the appearance of new, previously uncharacteristic for the patient, types of attack. Seizures associated with secondary bilateral synchrony are potentially disabling, as many of them result in patients falling. E. Perrucca et al. and other researchers advise not to prescribe or prescribe with great caution carbamazepine in the presence of secondary bilateral synchronization on the EEG, despite the fact that the exact mechanisms of aggravation of epilepsy in this case are not known [9]. If secondary bilateral synchronization occurs during the administration of carbamazepine and leads to aggravation of the course of epilepsy, carbamazepine should be discontinued. In a patient with focal epilepsy with secondary bilateral synchronization, the drugs of choice are valproate, ethosuximide, lamotrigine, topiramate in monotherapy or in various combinations. Relatively speaking, we treat these focal epilepsies in the same way as generalized ones (with the same drugs). In children of the first three years of life, without video-EEG monitoring, it is difficult to distinguish focal seizures from generalized ones (clinically they are very similar). In a significant number of children, accurate diagnosis of the form of epilepsy is impossible in the early stages of examination, and sometimes later, even despite the use of the most complex diagnostic methods. In addition, childhood is characterized by an extraordinary variety of epileptic syndromes; the boundaries between them are sometimes blurred, some syndromes can evolve into others, etc. In such clinical situations, it is recommended to prescribe AEDs that are effective in a wide range of conditions and have a low potential risk of attack aggravation, that is, valproate. A separate indication for the use of valproate is the presence of status epilepticus in a child. Our country does not have most of the drugs that are used throughout the world to relieve status epilepticus (there are no dosage forms for intravenous administration of drugs such as phenobarbital and phenytoin). In fact, the only drug that domestic neurologists and resuscitators have at their disposal is a benzodiazepine for intravenous injection. The appearance and distribution of the injectable form of Depakine in our country has significantly facilitated the fight against status epilepticus, including in children. Injectable Depakine is believed to be effective in approximately 70–80% of all cases of status epilepticus not sensitive to benzodiazepine [1]. It is possible that the breadth of the therapeutic spectrum of sodium valproate is due to the multiple mechanisms of action of valproic acid. According to E. Perucca, “evaproic acid should be considered not only a GABAergic drug, but a substance with different and complex mechanisms of action” [1]. E. Perucca lists the following mechanisms of action of valproic acid: • increases the synthesis and release of GABA, thereby potentiating GABAergic transmission in certain areas of the brain; • reduces the release of excitatory amino acids, b-hydroxybutyric acid and weakens the excitation of neurons caused by the activation of N-methylD-aspartate (NMDA) glutamate receptors; • has a direct effect on membrane excitation, including blockade of voltage-dependent sodium channels; • modulates dopaminergic and serotonergic transmission (this mechanism is used to ensure the effectiveness of the drug in psychiatric disorders and other neurological disorders in addition to epilepsy). Use of the drug in various age groups Valproate is effective in all age groups: from young children to elderly patients with epilepsy. Children have their own peculiarities in the metabolism of drugs, including AEDs. The metabolic rate in young children is higher than in adults due to higher activity of liver enzymes. Therefore, in childhood, it is possible to use higher dosages of AEDs (in particular, it is possible to use valproate dosages of more than 30–40 mg per kg of body weight per day). Features of the pharmacokinetics and pharmacodynamics of sodium valproate The drug has linear and predictable pharmacokinetics (therapeutic concentration in the blood increases in direct proportion to increasing doses of the drug). Well and quickly absorbed after oral administration. The maximum concentration of the drug in the blood when using capsules, tablets without a special coating and syrup is achieved after 1–3 hours. If the tablets are surrounded by a special coating that dissolves in the intestines, then the maximum concentration is reached after 3–5 hours. Sodium valproate is an AED widely used in the polytherapy of epilepsy. Based on data from experimental and clinical studies, it is assumed that valproate has a synergistic effect with lamotrigine [10]. The combination of valproate and lamotrigine is often used in the treatment of both generalized and focal epilepsies in children. The predominant effectiveness of the combination of sodium valproate with ethosuximide in the treatment of absence epilepsy has been proven [10]. In general, sodium valproate does not accelerate its own metabolism and the metabolism of other antiepileptic drugs, thereby not leading to the development of toxic effects or a decrease in the therapeutic effect. However, when using combinations of drugs, you should always be aware of their interactions. Although valproate does not induce liver enzymes, it may affect the concentrations of other drugs in the blood of patients. In general, valproate slightly increases the concentrations of carbamazepine, ethosuximide, lamotrigine, topiramate, phenytoin and phenobarbital. In turn, enzyme-inducing drugs (phenytoin, carbamazepine, phenobarbital) reduce the concentration of valproate when used together. The ability to quickly achieve a therapeutic dose is a significant advantage of sodium valproate compared to a number of other AEDs. The starting dose of valproate (10 mg per kg of body weight per day), in fact, is the minimum effective dose at which it is already possible to reduce the number of epileptic seizures. The maintenance daily dose can be achieved after 5–10 days. As a rule, it will be equal to 20–30 mg per kg of body weight per day; in some children, higher doses are used, but this already requires monitoring the concentration of the drug in the patient’s blood serum. Tolerability of the drug. Valproate is considered to have a favorable tolerability profile [1,9,11]. Its side effects are well studied and documented. The two most important idiosyncrasies associated with valproate have been described: pancreatitis and liver failure. Acute pancreatitis rarely leads to death, and a severe clinical situation can be avoided if the drug is discontinued if symptoms of pancreatitis develop (acute abdominal pain, vomiting, increased activity of urinary diastase and blood amylase). As for liver failure, it develops in one in 20,000 patients taking valproate. Fatal outcomes when hepatotoxicity occurs can be avoided if the risk factors for its development are known and the drug is promptly discontinued if symptoms occur. Parents of a patient being prescribed valproate for the first time should consult a doctor immediately if the child experiences apathy, drowsiness, anorexia, vomiting, and an increase in the number of seizures. In addition to prompt drug withdrawal, intravenous administration of L-carnitine is recommended. The risk group includes children under two years of age, especially those receiving AED polytherapy, suffering from mental retardation and the presence of certain inborn errors of metabolism (mitochondrial encephalomyopathies, in which carnitine metabolism is impaired). This same risk group includes children who already have liver disease or have elevated liver enzymes. The most common chronic side effects are gastrointestinal (nausea, vomiting, dyspepsia). The use of tablets with a special enteric coating or with controlled release of the active substance can significantly reduce the frequency of these side effects. Side effects such as weight gain, tremor, dysmenorrhea and transient hair loss are relatively common. The incidence of weight gain is about 15% [1]. As a rule, dietary restrictions do not lead to weight normalization. Since the effect of weight gain is dose-dependent, it is advisable to use the minimum effective dose to prevent its development. Alopecia may occur in up to 12% of all patients receiving the drug, is dose-dependent (disappears with dose reduction) or may resolve spontaneously despite continued treatment. Data on the possibility of developing polycystic ovary syndrome while taking valproate and the incidence of this complication are extremely contradictory, since there are studies demonstrating a high frequency of this pathology in the population of girls and women with epilepsy, regardless of the AEDs used [1]. Thrombocytopenia is a dose-dependent side effect, often reversible by reducing the dose of the drug, and rarely serves as a reason for discontinuation of the drug. As a rule, it does not lead to any clinical manifestations if the platelet count is not lower than 100,000/μl. Careful monitoring of the platelet count is indicated when the platelet count is less than 80,000/µL. According to expert epileptologists, the question of discontinuing the drug arises if thrombocytopenia leads to the appearance of other symptoms - disorders of the coagulation system or the formation of hemorrhages on the skin and mucous membranes [10]. A separate problem in studying the side effects of AEP is their influence on cognitive functions (the speed of psychomotor reactions, memory and attention). This problem is especially relevant in the treatment of epilepsy in children. It is believed that if the negative impact of AEP on cognitive functions is observed in a child, then this can significantly violate his learning, that is, reduce the quality of life. It is possible that the prolonged existence of the negative impact of AEP in children can lead to summation and increase in cognitive violations. Most researchers admit that in children the least negative effects on cognitive functions have valproate and lamotridine (recently, levetiracetes are added to these two drugs). The risk of aggravation of epileptic attacks. Recently, it has become obvious that the AEP could potentially aggravate (worsen) the course of epilepsy (Table 1). It is well known that sodium valproate is an Aer with a low risk of aggravation of epileptic attacks. Given the importance of the safe use of AEP, E. Hirsh and P. Genton studied all the affordable literature on the aggravation of attacks by Walproat [12]. They analyzed 20 publications dedicated to 99 clinical cases. The authors conclude that, given the total number of patients in the world receiving valproates, the aggravating potential of this drug can be considered low. All conditions and conditions under which Walproat can cause a deterioration in the course of epilepsy are well known and can be avoided (for example, the situation of an overdose of the drug). Long -term clinical experience in the use of valproates confirms the conclusions based on the study of publications. The low risk of aggravation emphasizes the feasibility of using valproat in a wide range of children with epilepsy. Another problem that occurs with prolonged use of AEP is the development of addiction to the drug (tolerance), as a result of which the initially high effectiveness of the drug decreases. In clinical practice, the phenomenon of tolerance leads to the fact that a patient in remission, at some time, against the background of an unchanged dose of the drug, a relapse of epileptic attacks arise. Relapse inevitably entails an increase in the dose of the drug, and after some time as a result of addictive the effect of increasing the dose disappears again. But an endless increase in the dose of AEP is impossible, so patients are often transferred to another drug. The most pronounced phenomenon of addiction for such an AEP group as benzodiazepines. Partly for this reason, benzodiazepines are rarely used in chronic treatment of epilepsy. Admission to varying degrees is also characteristic of other AEP. In the experimental models of epilepsy, it is shown that of all AEP the smallest addiction develops precisely to Valproata [13]. The high level of retention of patients with epilepsy on the valproat is also associated with this (see above). The variety of dosage forms in Russia precisely Valproat is the Aer with the widest selection of dosage forms. It is produced in the form of a syrup, tablets with an intestinal shell (Depakin Enterik), prolonged tablets (chrono depakin), a solution for iv administration. Children of an early age, as well as to those children who have disorders of swallowing, may be prescribed anticonvulsants in the form of syrup. However, prolonged use of liquid forms implies multiple intake of the drug during the day. It should be taken into account that multiple methods of the drug complicate the process of therapy for the patient. This should be avoided if our patient can swallow pills without much difficulty. One of the most rational and effective approaches is the use of prolonged drugs or so -called drugs with controlled release. In trading names, these drugs are designated as “retard” or “chrono” (depakin chrono). The use of prolonged drugs allows: • Avoid pronounced fluctuations in blood concentrations; • reduce the number of techniques per day; • reduce the likelihood of dose -dependent side effects; • Apply higher doses of the drug. The higher therapeutic efficiency of the sodium of sodium prolonged action in comparison with conventional forms of release was demonstrated in a number of studies [11]. Sometimes the transfer of the patient from the usual form of the drug to a prolonged form and without increasing the dose gives a distinct positive clinical effect. While the usual drug should be taken 3 times a day, the drug of prolonged action can be used once or twice a day. Of course, a decrease in the frequency of taking the drug simplifies the drug for the patient and improves the quality of his life. Therefore, from the very beginning of therapy, preference should be given to dosage forms with controlled release. The above has already been said about how important it was to provide emergency assistance to the appearance of the injection form of the valproat. In the near future, another dosage form of sodium valproata - chronosphere (Chronosphere®) will become available in Russia. This is a smell powder and with a neutral taste (unlike syrup), consisting of microparticles (microspheres), which, like Depakin Chrono, guarantees the controlled release of the drug, that is, it can be used 1-2 times a day. The chronicle is intended for children under 6 years of age. The powder can be dissolved in cold drinks and non -combustible food, while dividing the powder can provide a more thorough selection of dose of the drug. Thus, the sodium valproate is one of the main AEPs used in children with epilepsy. Walproat can help a child of any age and with any epileptic syndrome if the doctor knows the side effects of the drug well and can avoid their occurrence. The key to the successful use of Walproat is its low price compared to the price of newer AEPs (especially taking into account the fact that price increase does not always guarantee an increase in efficiency). Thus, despite many years of experience in using the drug, and most likely, thanks to this experience, Valproat continues to be a “gold standard” in the treatment of epilepsy in children.

References 1. Perucca E. Pharmacological and Therapeutical Properties of Valproate. A Summary After 35 years of Clinical Experience. CNS Drugs; 2002; V.16 (10); P.695–714. 2. Panayiotopoulos CP The Epilepsies. Seizures, Syndromes and Management; 2005; Blandon Medical Publishing; P. 515–517. 3. Nikolson A., Appleton RE, Chadwick DW, Smith DF The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalized epilepsies. J. Neurol. Neurosurg. Psychiatry; 2004; V.75; P.75 – 79. 4. Burgeois B., Beaumanoir A., ​​Blajev B. et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsy; 1987; V.28 (2) P. 8 –11. 5. Beydoun A. Monotherapy trials of new antiepileptic drugs. Epilepsy; 1997; V.38 (9); P. 21–31. 6. Heller AJ, Chesterman P, Elwes RD et al. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomized comparative monotherapy trial. J. Neurol. Neurosurg. Psychiatry. 1995; V. 58(1); P.44–50. 7. De Sylva M., MacArdle B., McGowan M. et al. Randomized comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet; 1996; V.16 (347); P.709–713. 8. Kuncikova M. and the VIPe Study Group. A Multinational observational study of the effectiveness and tolerability of first–line therapy with sodium valproate (Depakine?) in partial epilepsy; 2006 (in press) 9. Perucca E., Gram L., Avanzini G., Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsy; 1998; V.39(1); P.5–17. 10. Role of Valproate Across the Ages. Acta Neurologia Scandinavica; 2006; V.114 (suppl.184); P.15 11. Guerrini R. Valproate as a Mainstay of Therapy for Pediatric Epilepsy. Pediatric Drugs; 2006; V.8(2); P.113–129. 12. Hirsh E., Genton P. Antiepileptic Drug–Induced Pharmacodynamic Aggravation of Seizures. Does Valproate Have a Lower Potential? CNS Drugs; 2003; V.17 (9); P.633–640. 13. Loscher W., Shmitd D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsy; 2006; V.47 (8); P. 1253–84.

Depakine Chronosphere, 30 pcs., 100 mg, extended-release granules

Before starting the use of Depakine® Chronosphere™ and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed.

As with the use of most antiepileptic drugs, when using valproic acid, a slight increase in the activity of liver enzymes is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In these patients, a more detailed study of biological parameters, including the prothrombin index, may be necessary, and the dose of the drug may need to be adjusted, and, if necessary, repeated clinical and laboratory examinations.

Before starting therapy or before surgery, as well as in the event of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine the bleeding time and the number of formed elements in the peripheral blood, including platelets.

Severe liver damage

Predisposing factors.

Clinical experience shows that the risk group includes patients receiving multiple 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; patients simultaneously taking salicylates (since salicylates are metabolized through the same metabolic pathway as valproic acid).

After 3 years of age, the risk of liver damage decreases significantly and decreases progressively as the patient ages. In most cases, such liver damage occurred during the first 6 months of treatment, most often between the 2nd and 12th weeks of treatment, and usually when valproic acid was used as part of combination antiepileptic therapy.

Symptoms indicating possible 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, which may precede the onset of jaundice, especially in patients at risk (see above):

- nonspecific symptoms, especially those that began suddenly, 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 of these symptoms to their doctor. 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 determination of the prothrombin index. Confirmation of abnormal prothrombin index, especially in combination with abnormalities in other laboratory parameters (significant decrease in fibrinogen and coagulation factors, increased bilirubin concentration and increased transaminase activity), as well as the appearance of other symptoms indicating liver damage (see above ), requires discontinuation of the use of the drug Depakine® Chronosphere™. As a precaution, if patients were concomitantly receiving salicylates, their use should also be discontinued.

Pancreatitis.

There are rare reported cases of severe forms of pancreatitis in children and adults, developing regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis have been observed with rapid progression of the disease from the first symptoms to death. Young children are at increased risk of developing pancreatitis; 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 should be evaluated immediately. If pancreatitis is confirmed, in particular with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment should be initiated.

Suicidal thoughts and attempts.

Suicidal thoughts and attempts have been reported in patients receiving antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a 0.19% increase in the risk of suicidal thoughts and attempts in all patients taking antiepileptic drugs (including a 0.24% increase in this risk in patients taking antiepileptic drugs ), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown. Therefore, patients taking Depakine® Chronosphere™ should be constantly monitored for suicidal thoughts and attempts, and if they occur, appropriate treatment should be provided. Patients and caregivers are advised to seek immediate medical attention if a patient experiences suicidal thoughts or attempts.

Carbapenems.

Concomitant use of carbapenems is not recommended (see “Interactions”).

Patients with established or suspected mitochondrial diseases.

Valproic acid can initiate or aggravate the manifestations of the patient's mitochondrial diseases caused by mutations in mitochondrial DNA, as well as in the nuclear gene encoding the mitochondrial enzyme γ-polymerase
(POLG)
.
In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding polymerase γ (POLG)
, such as patients with Alpers-Huttenlocher syndrome, a higher incidence of acute liver failure and liver-related deaths was associated with the use of valproic acid .
Diseases due to γ-polymerase defects may be suspected in patients with a family history of such diseases or symptoms suggestive of their presence, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura and others. In accordance with current clinical practice, testing for mutations in the polymerase γ gene (POLG)
(see “Contraindications”).

Women of childbearing potential, pregnant women.

Depakine® Chronosphere™ should not be used in female children and adolescents, women of childbearing potential and pregnant women, unless alternative treatments are ineffective or not tolerated. This limitation is associated with a high risk of teratogenicity and mental and physical development disorders in children who were exposed to valproic acid in utero. The benefit/risk ratio should be carefully re-evaluated in the following cases: during regular review of treatment, when a girl reaches puberty and, urgently, if a woman taking valproic acid plans or becomes pregnant.

During treatment with valproic acid, women of childbearing potential should use reliable methods of contraception, and they should be informed of the risks associated with taking Depakine® Chronosphere™ during pregnancy (see "Use during pregnancy and lactation"). To help the patient understand these risks, the physician prescribing valproic acid should provide the patient with comprehensive information about the risks associated with taking Depakine® Chronosphere™ during pregnancy.

In particular, the physician prescribing valproic acid should ensure that the patient understands:

- the nature and magnitude of the risks when using valproic acid during pregnancy, in particular, the risks of teratogenic effects, as well as the risks of disorders of the mental and physical development of the child;

— the need to use effective contraception;

- the need for regular review of treatment;

- the need for urgent consultation with her doctor if she suspects that she is pregnant, or when she suspects the possibility of pregnancy.

A woman planning a pregnancy should definitely try, if possible, to switch to an alternative treatment before she attempts to conceive (see “Use during pregnancy and lactation”).

Treatment with valproic acid should be continued only after a physician experienced in the treatment of epilepsy and bipolar disorders has re-evaluated the benefits and risks of treatment.

Children. The information applies to dosage forms of the drug Depakine®, which can be taken by children under 3 years of age.

In children under 3 years of age, if the drug is necessary, it is recommended to use it in monotherapy. However, before starting treatment, you should weigh the ratio of the potential benefits of using valproic acid and the risk of liver damage and the development of pancreatitis when using it.

In children under 3 years of age, concomitant use of valproic acid and salicylates should be avoided due to the risk of hepatotoxicity.

Kidney failure.

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free form in the blood serum. If it is impossible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Enzyme deficiency of the carbamide cycle (urea cycle).

If an enzymatic deficiency of the carbamide cycle is suspected, the use of valproic acid is contraindicated. Several cases of hyperammonemia with stupor or coma have been described in such patients. In these cases, metabolic studies should be performed before starting treatment with valproic acid (see "Contraindications").

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, with mental retardation, or a family history of death of a newborn or infant, metabolic studies should be carried out before starting treatment with valproic acid, in particular the determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after meals (see “Contraindications”).

Patients with systemic lupus erythematosus.

Although it has been shown that during treatment with Depakine® Chronosphere™, dysfunction of the immune system is extremely rare, the potential benefits of its use must be compared with the potential risks when using the drug in patients with systemic lupus erythematosus.

Increase in body weight.

Patients should be warned about the risk of weight gain at the beginning of treatment, and measures, mainly dietary, should be taken to minimize this phenomenon.

Patients with diabetes.

Given the possibility of adverse effects of valproic acid on the pancreas, when using the drug in patients with diabetes mellitus, blood glucose concentrations should be carefully monitored. When testing urine for the presence of ketone bodies in patients with diabetes, it is possible to obtain false positive results, because valproic acid is excreted by the kidneys, partly in the form of ketone bodies.

Patients infected with HIV.
In vitro
, valproic acid has been shown to stimulate HIV replication under certain experimental conditions.
The clinical significance of this fact, if any, is unknown. Additionally, the significance of these in vitro
for patients receiving maximally suppressive antiretroviral therapy has not been established. However, these data should be taken into account when interpreting the results of continuous viral load monitoring in HIV-infected patients taking valproic acid.

Patients with existing carnitine palmitoyltransferase (CPT) type II deficiency.

Patients with existing CPT type II deficiency should be warned of the increased risk of rhabdomyolysis when taking valproic acid.

Ethanol.

During treatment with valproic acid, ethanol consumption is not recommended.

Other special instructions.

The inert matrix of the drug Depakine® Chronosphere™ (extended release drug) due to the nature of its excipients is not absorbed in the gastrointestinal tract; after the release of the active substances, the inert matrix is ​​excreted in the feces.

Impact on the ability to drive vehicles and operate machinery.

Patients should be warned about the risk of developing drowsiness, especially in the case of combined anticonvulsant therapy or when combining Depakine® Chronosphere™ with benzodiazepines (see “Interactions”).

Pharmacokinetics

Absorption

The bioavailability of valproic acid when taken orally is close to 100%. Food intake does not affect the pharmacokinetic profile of the drug.

Cmax of valproic acid in the blood plasma after taking the drug Depakin® Chronosphere™ orally is achieved after approximately 7 hours. Compared with the enteric-coated dosage form, equivalent doses of the drug Depakin® Chronosphere™ are characterized by longer absorption, identical bioavailability, and a more linear correlation between doses and plasma concentrations of valproic acid (total concentration and concentration of the free fraction). In addition, Cmax and Cmax of the free fraction of valproic acid in plasma are lower (the decrease is about 25%), but there is a relatively more stable plateau phase of plasma concentrations from 4 to 14 hours after administration, the magnitude of fluctuations in plasma concentrations when taking the drug Depakine ® Chronosphere™, compared to an enteric-coated dosage form, is halved, resulting in valproic acid being more evenly distributed in tissues throughout the day.

With a course of taking the drug, Css of valproic acid in the blood serum is achieved within 3–14 days.

Serum concentrations of valproic acid of 40–100 mg/L (300–700 µmol/L) are usually effective (determined before taking the first dose of the drug during the day). At serum concentrations of valproic acid above 100 mg/l, an increase in side effects is expected, including the development of intoxication.

Distribution

Vd depends on age and is usually 0.13–0.23 l/kg or in young people – 0.13–0.19 l/kg. Due to a decrease in the magnitude of fluctuations in plasma concentrations when taking the drug Depakine® Chronosphere™, valproic acid is more evenly distributed in tissues throughout the day compared to the immediate-release dosage form of valproic acid.

The binding of valproic acid to plasma proteins (mainly albumin) is high (90–95%), dose-dependent and saturable. In elderly patients, people 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 may 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 into the cerebrospinal fluid and brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding concentration in the blood serum, i.e. close to the concentration of the free fraction of valproic acid in blood serum.

Valproic acid passes into the breast milk of nursing mothers. When the Css of valproic acid in the blood serum is reached, its concentration in breast milk is up to 10% of its concentration in the blood serum.

Metabolism

Valproic acid is metabolized in the liver by glucuronidation, as well as beta, omega and omega1 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 its own metabolism or the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants .

Removal

Valproic acid is primarily excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation.

When valproic acid is used in monotherapy, its T1/2 is 12–17 hours. When combined with antiepileptic drugs that induce microsomal liver enzymes (such as primidone, phenytoin, phenobarbital and carbamazepine), the plasma clearance of valproic acid increases, and T1/2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

T1/2 in children over 2 months of age is close to that in adults.

In patients with liver diseases, T1/2 of valproic acid increases. In case of overdose, an increase in T1/2 up to 30 hours was observed. Only the free fraction of valproic acid in the blood (5–10%) is subject to hemodialysis.

Features of pharmacokinetics during pregnancy

With an increase in Vd of valproic acid in the third trimester of pregnancy, its renal and hepatic 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 association of valproic acid with blood plasma proteins may change, which may lead to an increase in the content of the free therapeutically active fraction of valproic acid in the blood serum.