Depakine syrup 57.64 mg/ml 150 ml bottle No. 1 ➤ instructions for use

Pharmacological properties of the drug Depakin

An anticonvulsant, effective in various forms of epilepsy. It is believed that valproate increases the concentration of GABA in the central nervous system by inhibiting the enzyme GABA transferase. The main mechanism of its action is probably due to the enhancement of GABAergic synaptic transmission. In experimental and clinical studies, two mechanisms of the anticonvulsant action of valproate have been identified: • the first is a direct pharmacological effect associated with the concentration of valproate in the blood plasma and brain; • the second is apparently indirect, probably due to metabolites of valproate that remain in the brain, or to modifications of transmitters, or a direct effect on the membrane. The most likely hypothesis is that GABA levels increase after valproate administration. Valproate reduces the duration of the intermediate sleep phase and at the same time increases the slow-wave sleep phase. The bioavailability of sodium valproate when administered orally is about 100%. The volume of distribution is predominantly limited to blood and extracellular fluid. Valproate penetrates into the cerebrospinal fluid and brain. The concentration of valproic acid in the CSF approximately corresponds to the concentration in the blood plasma. The half-life is approximately 8–20 hours and is usually shorter in children. The drug crosses the placenta and is found in small quantities in breast milk (1–10% of the serum concentration). The minimum concentration of valproate in blood serum required for a therapeutic effect is 40–50 mg/l, this concentration ranges from 40–100 mg/l. When the concentration of valproate in the blood serum is above 200 mg/l, a reduction in the dose of the drug is necessary. When administered orally, a steady-state concentration in the blood plasma is achieved quickly - after 3-4 days. Binding to plasma proteins is strong and dose dependent. The valproate molecule can be dialyzed, but only its free form (approximately 10%) is excreted. Sodium valproate is primarily excreted in the urine, after metabolism by glucuroconjugation and beta-oxidation. Unlike other antiepileptic drugs, valproate does not accelerate either its own catabolism or the catabolism of other substances, such as estroprogestogens and oral anticoagulants. This is due to the lack of an inducing effect on enzymes, including cytochrome P450. Compared to the enteric-coated form, Depakine Chrono (sustained release form) in equivalent doses is characterized by the absence of a delay in absorption after administration; prolonged absorption; identical bioavailability; peak total plasma concentration and free substance concentration (Cmax) are lower (decrease in Cmax is about 25%, but with a relatively stable plateau phase from 4 to 14 hours after administration); as a result of using the same dose twice a day, the fluctuation in plasma concentration is reduced by half; more linear correlation between doses and blood concentrations (total and free substance).

Compound

Indications for use of the drug Depakin

Treatment of generalized or focal epilepsy, especially with the following types of seizures: absences, myoclonic, tonic-clonic, atonic, mixed; for focal epilepsy: simple or combined seizures, secondary generalized seizures, specific syndromes (Vest, Lennox-Gastaut); prevention of seizures during fever in children or in the presence of risk factors for seizure recurrence. Depakine Chrono is also used for the treatment and prevention of manic syndrome in bipolar affective disorders in adults.

Nosological classification (ICD-10)

• F31 Bipolar affective disorder
• G25.3 Myoclonus
• G40 Epilepsy
• G40.0 Localized (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures with focal onset
• G40.1 Localized (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures
• G40.2 Localized (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures
• G40.3 Generalized idiopathic epilepsy and epileptic syndromes
• G40.4 Other types of generalized epilepsy and epileptic syndromes
• G40.6 Grand mal seizures, unspecified [with or without petit mal seizures]
• G40.8 Other specified forms of epilepsy
• G40.9 Epilepsy, unspecified
• R56.0 Convulsions during fever

Use of the drug Depakine

The dose is set taking into account the patient’s age, body weight and individual sensitivity to the drug. The optimal dose is determined depending on the clinical effect. Determination of the concentration of valproic acid in the blood plasma is carried out in addition to clinical observation in cases where it is not possible to achieve adequate control of seizures, or in cases of threat of side effects. The effective concentration of the drug in the blood is usually 40-100 mg/l (300-700 µmol/l). The drug is taken orally, preferably during meals, without chewing the tablets. The daily dose is recommended to be taken in one or two doses. One-time use is possible for well-controlled epilepsy. When replacing the enteric immediate-release form of valproate, which provided disease control, with a sustained-release form, the daily dose should be maintained. At the beginning of treatment for patients not taking other antiepileptic drugs, the dose is increased after 2-3 days to reach the optimal dose within approximately 1 week. The optimal dose in patients who are already taking antiepileptic drugs replaced by Depakine is achieved gradually, over about 2 weeks. In this case, the dose of the previous drug is gradually reduced, and then its use is stopped. If it is necessary to use other antiepileptic drugs, they are added gradually. The initial daily dose is usually 10–15 mg/kg, then it is gradually increased to the optimal dose, which is usually 20–30 mg/kg. However, if the seizures do not stop, the dose can be increased. Careful monitoring of patients receiving the drug in doses above 50 mg/kg is necessary. For children weighing over 6 kg, the average daily dose is approximately 30 mg/kg (it is better to use the syrup form). For children under 1 year of age, it is recommended to divide the daily dose into 2 doses, for children over 1 year - into 3 doses. For adolescents and adults, the average daily dose is 20–30 mg/kg. In elderly patients, the dose is set taking into account the clinical situation.

Depakine-Chrono extended-release tablets 500 mg No. 30

A country

France
The country of production may vary depending on the batch of goods. Please check with the operator for detailed information when confirming your order.

Active substance

Valproic acid

Compound

1 tablet contains: sodium valproate** 333 mg, valproic acid** 145 mg. Excipients: colloidal anhydrous silicon dioxide - 4 mg, methylhydroxypropylcellulose 4000 mPa.s (hypromellose) - 176 mg, ethylcellulose (20 mPa.s) - 12 mg, sodium saccharin - 10 mg, hydrated colloidal silicon dioxide - 50 mg, methylhydroxypropyl cellulose 6 mPa.s (hypromellose) - 7.2 mg, 30% polyacrylate dispersion - 24 mg, macrogol 6000 - 7.2 mg, talc - 7.2 mg, titanium dioxide - 1.2 mg.* corresponds to 300 mg of valproic acid in 1 tablet.** corresponds to 500 mg of valproic acid in 1 tablet. Long-acting, film-coated tablets of almost white color, oblong, scored on both sides. sodium valproate* 199.8 mg valproic acid* 87 mgExcipients: methylhydroxypropylcellulose 4000 mPa.s (hypromellose) - 105.6 mg, ethylcellulose (20 mPa.s) - 7.2 mg, sodium saccharin - 6 mg, hydrated colloidal silicon dioxide - 32.4 mg, methylhydroxypropylcellulose 6 mPa.s (hypromellose) - 4.8 mg, 30% polyacrylate dispersion - 16 mg, macrogol 6000 - 4.8 mg, talc - 4.8 mg, titanium dioxide - 0.8 mg. 50 pcs. — polypropylene bottles (2) — cardboard packs.

pharmachologic effect

An anticonvulsant drug that has a central muscle relaxant and sedative effect. Shows antiepileptic activity in various types of epilepsy. The main mechanism of action appears to be related to the effect of valproic acid on GABA-ergic

Indications for use

Adults As monotherapy or in combination with other antiepileptic drugs: - treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic); - Lennox-Gastaut syndrome; - treatment of partial epileptic seizures (partial seizures with secondary generalization or without it). 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).

Mode of application

Depakine Chrono is intended only for adults and children over 6 years of age weighing more than 17 kg. This dosage form is not recommended for children under 6 years of age (risk of the tablet getting into the respiratory tract when swallowed). Depakine chrono is a slow-release dosage form, this avoids sudden increases in the concentration of valproic acid in the blood after taking the drug and maintains a constant for a longer period of time concentration of valproic acid in the blood during the day. Long-acting tablets Depakine Chrono 300 mg or 500 mg can be divided to facilitate taking an individually selected dose. Tablets are taken without crushing or chewing them. Epilepsy The doctor selects the daily dose individually. To prevent the development of epilepsy attacks, the drug should be used in the minimum effective dose (especially during pregnancy). The daily dose is set in accordance with the age and body weight of the patient. A stepwise (gradual) increase in dose is recommended until the minimum effective dose is reached. A clear relationship between the daily dose, plasma concentration and therapeutic effect has not been established. Therefore, the optimal dose should be determined primarily by clinical response. Determination of plasma valproic acid levels can serve as an addition to clinical monitoring if epilepsy is uncontrolled or if side effects are suspected. The therapeutic blood concentration range is usually 40-100 mg/L (300-700 µmol/L). For monotherapy, the initial dose is usually 5-10 mg valproic acid per kg body weight, then this dose is gradually increased every 4-7 days from calculating 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 aged 6-14 years (body weight 20-30 kg) - 30 mg of valproic acid acid/kg body weight (600-1200 mg); - for adolescents (body weight 40-60 kg) - 25 mg valproic acid/kg body weight (1000-1500 mg); - for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg valproic acid / kg body weight (1200-2100 mg). Although the daily dose is determined depending on the age and body weight of the patient, the wide range of individual sensitivity to valproate should be taken into account. If epilepsy is not controllable at such doses, they can be increased under the control of the patient’s condition and the concentration of valproic acid in the blood. In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, you should not increase the daily dose above the recommended average daily dose before this period. The daily dose can be divided into 1-2 doses, preferably with meals. Use in one dose is possible with well-controlled epilepsy. Most patients who are already taking Depakine in medicinal form of non-prolonged action, can be switched to Depakine Chrono immediately or over several days, while patients should continue to take the previously selected daily dose. For patients who have previously taken antiepileptic drugs, the transfer to Depakine Chrono should be carried out gradually, reaching the optimal dose the drug for 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. Cancellation of an antiepileptic drug that the patient had previously taken should be carried out gradually. other antiepileptic drugs can reversibly induce microsomal liver enzymes, you should monitor the concentration of valproic acid in plasma for 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), reduce the daily dose of valproic acid. If the need 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 an initial dose of 20 mg of sodium valproate per kg of body weight. Depakine chrono can be taken 1 or 2 times a day. The dose should be increased as quickly as possible to achieve the minimum effective therapeutic dose that produces the desired clinical effect. 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 care observation. When continuing treatment of manic episodes in bipolar disorders, the drug is used in an individually selected minimum effective dose. Children and adolescents The effectiveness and safety of the drug in the treatment of manic episodes in bipolar disorders in patients under 18 years of age have not been assessed. Special groups of patientsChildren and adolescents, women, women with 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 there are changes in the pharmacokinetics of valproic acid in elderly patients, they are of limited clinical significance, and the dose of valproic acid in elderly patients should be adjusted in accordance with achieving control of seizures of epilepsy. 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 of valproic acid in the blood serum (free fraction and fraction bound to plasma proteins) in order to avoid possible errors in dose selection.

Interaction

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 the serum concentration of lithium. Valproic acid increases the concentration of 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 the concentration of primidone in plasma, which leads to an increase in its side effects ( such as sedative effects); 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 the total concentration of 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 simultaneous use of valproic acid and carbamazepine, an increase in the plasma concentration of the active metabolite of carbamazepine is possible with signs of overdose. 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 down 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 increased toxicity of zidovudine, especially hematological effects, by slowing 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 reduce plasma concentrations of olanzapine. Valproic acid may lead to an increase in 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 simultaneously with valproic acid. Increased hypotensive effect of nimodipine (for oral administration and, by extrapolation, for parenteral administration) due to an increase in its plasma concentration by 50% (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 microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine) reduce the plasma concentration of valproic acid. In the case of combination therapy, the dose of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood. The concentration of valproic acid metabolites in the blood serum may be increased if it is co-administered 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 drug during treatment with aztreonam and after its cessation are necessary. When felbamate and valproic acid are combined, the clearance of valproic acid decreases by 22-50% and the plasma concentration of valproic acid increases accordingly. Plasma concentrations of valproic acid should be monitored. Clinical observation and monitoring of laboratory parameters are necessary; dose adjustment of valproate is possible during treatment and after discontinuation of felbamate. When used simultaneously with carbamazepine, the plasma concentration of valproic acid may decrease due to acceleration of its metabolism in the liver. Clinical observation, determination of plasma concentrations and, if necessary, dose adjustment of both anticonvulsants are necessary. An increase in the concentration of lamotrigine in plasma is possible (due to valproate slowing down the metabolism of lamotrigine in the liver). If the simultaneous use of these drugs is necessary, clinical monitoring is required. Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing seizures, 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, a decrease in the anticonvulsant effectiveness of valproic acid is possible. B 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 level is required index. The concentration of valproic acid in the blood plasma may increase with simultaneous use of cimetidine or erythromycin (as a result of a slowdown in its hepatic metabolism). Decrease in the concentration of valproic acid in the blood with its simultaneous use with carbapenems (panipenem, meropenem, imipenem): for 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, valproic acid blood concentrations should be carefully monitored during carbapenem treatment and after its discontinuation. Rifampicin may decrease valproic acid blood concentrations, resulting in loss of the therapeutic effect of valproic acid. Therefore, it may be necessary to increase the dose of valproic acid while using rifampicin and after its withdrawal. Protease inhibitors, such as lopinavir, ritonavir, reduce the plasma concentration of valproic acid when used simultaneously with it. Cholestyramine can lead to a decrease in plasma concentrations of valproic acid when used simultaneously with it. Other interactions Concomitant use of valproic acid and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia. Patients receiving these combinations require careful medical monitoring 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, the hepatotoxic effect of valproic acid may be enhanced. The simultaneous 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 effect, with valproic acid the risk of inhibition of bone marrow hematopoiesis increases.

Side effect

To determine the frequency of adverse reactions, the WHO classification is used: very often (? 10%), often (? 1% and 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 history and his close blood relatives;— severe liver damage with a fatal outcome when using valproic acid in the patient’s close blood relatives;— severe liver dysfunction;— severe pancreatic dysfunction; - hepatic porphyria; - established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme ?-polymerase (POLG), for example, Alpers-Huttenlocher syndrome, and suspected diseases caused by ?-polymerase defects in children in under 2 years of age (applies to the use of dosage 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 tablets entering the respiratory tract when swallowed). With caution - 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, ritonavir), cholestyramine (due to pharmacokinetic interactions at the level of metabolism or binding with blood plasma proteins, it is possible to change the plasma concentrations of either these drugs and/or valproic acid); - simultaneous use with carbamazepine (risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid); - simultaneous use with topiramate or acetazolamide (risk of developing encephalopathy); - in patients with existing carnitine palmitoyltransferase (CPT) type II deficiency (higher risk of developing rhabdomyolysis when taking valproic acid).

Overdose

Symptoms: clinical manifestations of acute massive overdose usually occur in the form of coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive decrease in blood pressure and 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. With a massive overdose, death is possible, but usually the prognosis for an overdose is favorable. Symptoms of overdose may vary, the development of convulsive seizures has been reported at very high plasma concentrations of valproic acid. 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.

special instructions

Before starting the use of the drug Depakine chrono 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 indicators, including the prothrombin index, may be required, and dose adjustment of the drug may be required, and, if necessary, repeated clinical and laboratory examinations. Before starting therapy or surgery, as well as in the event of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determination of bleeding time, the number of formed elements in the peripheral blood, including the number of platelets. Severe liver damage Predisposing factors: there are isolated reports of the development of severe liver damage, sometimes fatal. Clinical experience shows that patients at risk include patients receiving multiple antiepileptic drugs at the same time, children under 3 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). In children over 3 years of age, the risk of liver damage is significantly reduced and decreases progressively as the patient's age increases. In most cases, liver damage occurs within the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually when valproic acid is used as part of combination antiepileptic therapy. Symptoms suspicious for liver damage: clinical monitoring of patients is mandatory for early diagnosis of liver damage . In particular, you should pay attention to the appearance of the following symptoms that may precede the onset of jaundice, especially in patients at risk: - non-specific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain ;- resumption of seizures in patients with epilepsy. Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of these symptoms to their doctor. If these symptoms occur, 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 prothrombin index. Confirmation of an 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, requires discontinuation of use drug Depakine Chrono. As a precaution, if patients were taking salicylates concomitantly, their use should also be discontinued. Pancreatitis There have been reported rare 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. Children are at increased risk of developing pancreatitis; 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. 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. Female children and adolescents, women of childbearing potential and pregnant women Depakine Chrono should not be used in children and adolescents females, women of childbearing potential, and pregnant women, unless alternative treatments are ineffective or intolerable. This limitation is associated with a high risk of teratogenicity and mental and physical development disorders in children who are 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 is planning 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 Chrono during pregnancy. 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 Chrono during pregnancy. In particular, the physician prescribing valproic acid should ensure that the patient understands: - the nature and degree of risk when using valproic acid during pregnancy, in particular, the risk of teratogenic effects, as well as the risk of disturbances in 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 your doctor , if she suspects that pregnancy has occurred, or when she anticipates this possibility. A woman planning a pregnancy should definitely try, if possible, to switch to an alternative treatment before she attempts to conceive. Treatment with valproic acid should be continued only after , as a physician experienced in the treatment of epilepsy and bipolar disorders, will re-evaluate the benefit-risk balance of treatment for her. Suicidal thoughts and attempts Suicidal thoughts or 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 small increase in the risk of suicidal thoughts and attempts of 0.19% 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 receiving Depakine Chrono should be constantly monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be provided. Patients and caregivers are advised to seek immediate medical attention if the patient experiences suicidal thoughts or attempts to seek medical attention immediately. Carbapenems Concomitant use of carbapenems is not recommended. Patients with known or suspected mitochondrial diseases Valproic acid may initiate or aggravate the manifestations of the patient's existing mitochondrial diseases caused by mutations in the mitochondrial DNA, as well as the nuclear gene encoding the mitochondrial enzyme β-polymerase (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding β-polymerase (POLG); for example, in patients with Alpers-Huttenlocher syndrome, valproic acid use was associated with a higher incidence of acute liver failure and liver-related deaths. Diseases caused by β-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 β gene (POLG) should be carried out to diagnose such diseases. Increased seizures As with the use of other antiepileptic drugs, when taking valproic acid, some patients experienced, instead of improvement, a reversible increase in the frequency and severity of seizures seizures (including the development of status epilepticus) or the appearance of new types of seizures. In case of worsening seizures, patients should immediately consult with their doctor. Children (information refers 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 it is necessary to use the drug, it is recommended to use it in monotherapy and in 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 development...

Dispensing conditions in pharmacies

On prescription

Side effects of the drug Depakin

Allergic reactions (exanthematous rash), in extremely rare cases - toxic epidermal necrosis, Stevens-Johnson syndrome, erythema multiforme, confusion, very rarely - stupor or lethargy, sometimes leading to transient coma (may be isolated or associated with an increased frequency of seizures during duration of therapy; their severity decreases after discontinuation or when the dose of the drug is reduced; most often, such effects occur during complex treatment, especially with phenobarbital, or after a sharp increase in the dose of valproate); very rarely - reversible dementia associated with reversible cerebral atrophy, which disappears several weeks or months after discontinuation of the drug, rarely - reversible parkinsonism; nausea, vomiting, stomach pain, diarrhea (often appear at the beginning of treatment in some patients, they usually go away on their own within a few days without stopping the drug); moderate hyperammonemia, which does not cause changes in liver function and does not require discontinuation of the drug (in case of hyperammonemia associated with neurological symptoms, further examination of the patient is necessary; the risk of hyperammonemia increases when using the drug in patients with a deficiency of carbamide cycle enzymes; cases of hyperammonemia accompanied by stupor and coma in such patients); decreased fibrinogen levels or increased bleeding time, usually without associated clinical symptoms; often - thrombocytopenia, rarely - anemia, macrocytosis and leukopenia, extremely rarely - pancytopenia; hair loss, mild hand tremors and drowsiness (transient in nature and/or dependent on the dose of the drug) ; vasculitis; headache; weight gain; rarely - hearing loss (both reversible and irreversible); reversible Fanconi syndrome; rarely - impaired renal function, peripheral edema, amenorrhea and irregular menstrual cycle; liver dysfunction (rare reports). Conditions for the occurrence of liver dysfunction With complex anticonvulsant therapy, a group at increased risk of developing hepatitis includes infants and children under 3 years of age with severe epilepsy, especially associated with brain damage, mental retardation and/or metabolic or degenerative diseases of genetic origin. In children over 3 years of age, the incidence of such complications is significantly reduced. In the vast majority of cases, severe reactions from the liver are observed during the first 6 months of treatment, usually between the 2nd and 12th weeks, and more often with complex antiepileptic treatment. Pancreatitis. In extremely rare cases, when taking valproate, severe forms of pancreatitis were noted, which in some cases led to death. Children under 3 years of age are at particular risk. This risk decreases with age. Risk factors may include severe epileptic seizures, neurological impairment, or anticonvulsant therapy. Liver disorders associated with pancreatitis increase the risk of death. Possible signs of liver dysfunction Early diagnosis is based primarily on clinical examination. First of all, the symptoms that may precede jaundice should be taken into account, especially in patients at risk: • nonspecific symptoms, usually appearing suddenly: asthenia, anorexia, fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain; • recurrence of epileptic seizures. It is recommended to inform the patient (or the child’s parents) that if such clinical symptoms appear, it is necessary to urgently consult a doctor for advice and immediately conduct a clinical examination, including a liver function test. Detection of liver dysfunction It is necessary to check liver function before starting treatment and periodically during the first 6 months of treatment, especially in patients at risk . The most important are tests reflecting the protein-synthetic function of the liver and especially the prothrombin index. If an abnormally low level of prothrombin is detected, especially accompanied by a significant decrease in the level of fibrinogen and blood clotting factors, an increase in the level of bilirubin and transaminases, treatment with valproate should be suspended. If salicylates were included in the treatment regimen, then, as a precaution, their use should also be stopped (since salicylates use the same metabolic pathways as valproate).

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.

Special instructions for the use of the drug Depakin

The active substance Depakine in the human body is converted into valproic acid, so other drugs that undergo the same transformation should not be used simultaneously in order to avoid an overdose of valproic acid (for example, divalproate, valpromide). Early diagnosis of liver damage when using the drug is based primarily on clinical examination. Great attention should be paid to symptoms that may precede jaundice, especially in patients at risk: nonspecific symptoms, usually appearing suddenly - asthenia, anorexia, fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain; increased frequency of epileptic seizures. It is recommended to inform the patient (or the child's parents) that if such clinical symptoms appear, it is necessary to urgently consult a doctor for advice and immediately conduct a clinical examination, including a liver function test. When treated with Depakine, as with other antiepileptic drugs, especially at the beginning of treatment, a slight isolated and temporary increase in the level of liver enzymes may be observed, without any clinical symptoms. In this case, it is recommended to conduct a more complete laboratory examination (including, in particular, determination of the prothrombin index) in order to revise the dose, if necessary, and repeat the tests in accordance with changes in parameters. For children under 3 years of age, the use of valproate as monotherapy is recommended, after establishing the effectiveness of its therapeutic action, since these patients represent a risk group for developing liver disease or pancreatitis . Concomitant use of valproate with salicylates should be avoided in children under 3 years of age due to the risk of developing liver disease. Before starting therapy or surgery, in case of spontaneous hematomas or bleeding, it is recommended to conduct a blood test (determine the blood count, including platelet count, bleeding time and coagulation tests) . In patients with renal failure, it may be necessary to reduce the dose. Since monitoring plasma concentrations of the drug may lead to erroneous conclusions, the dose should be adjusted according to clinical response . Acute abdominal pain and gastrointestinal symptoms such as nausea, vomiting and/or anorexia require immediate medical attention. In case of pancreatitis, Depakin should be discontinued. If a deficiency of carbamide cycle enzymes is suspected, metabolic studies should be performed before starting treatment with Depakin, due to the risk of hyperammonemia. In children with unexplained hepatodigestive symptoms (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, with mental retardation, cases of death of a newborn or child in the family history, before starting treatment with Depakine, it is necessary to conduct a metabolic study, especially ammonemia during fasting and after administration food. Although dysfunction of the immune system rarely occurs during treatment with Depakine, the possible benefits of its use must be compared with the potential risks when prescribing the drug to patients with systemic lupus erythematosus. Patients should be warned about the possibility of weight gain at the beginning of treatment, and, to avoid this, the need to follow a diet. Children under the age of 6 years are not recommended to use Depakine Chrono due to the risk of it entering the respiratory tract when swallowed. The use of an antiepileptic drug may sometimes be accompanied by the resumption or development of new types of seizures in the patient, regardless of the spontaneous fluctuations observed in some epileptic conditions. In relation to Depakine Chrono, this primarily concerns modification of concurrent antiepileptic treatment or pharmacokinetic interactions, toxicity (hepato- or encephalopathy) and overdose. Pregnancy period . When using any antiepileptic drugs in women with epilepsy, the overall incidence of congenital defects in children born to them is 2–3 times higher than among the general population (about 3%). Although an increase in the number of children with congenital defects has been observed with the use of combination therapy, the respective role of the disease itself and the drugs taken by the mother has not yet been established. The most common malformations are cleft lip and malformations of the cardiovascular system. Sudden interruption of antiepileptic treatment may worsen the course of the mother's illness and lead to detrimental consequences for the fetus. Experimental studies on mice, rats and rabbits showed the teratogenic effect of the drug. Cases of facial dysmorphia have been described. Multiple malformations, especially of the limbs, were rarely noted. The frequency of such effects has not yet been precisely established. Along with this, Depakine predominantly causes a disorder in the development of the neural tube: myelomeningocele, vertebral bifida. The incidence of such complications is 1–2%. In some cases, facial dysmorphia and malformations of the limbs (especially shortening of the limbs) were observed. The frequency of such complications has not yet been precisely established. If a woman taking Depakine is planning a pregnancy, the indications for antiepileptic treatment should be reconsidered. During pregnancy, effective antiepileptic treatment with Depakin should not be interrupted; monotherapy is recommended in the minimum effective dose, which is divided into several doses per day. The validity of preventing developmental disorders of the neural tube using folic acid has not yet been confirmed. Therefore, regardless of whether the patient takes foliates or not, a special prenatal examination of the patient is necessary in order to identify disorders of the neural tube or other abnormalities of fetal development during the first months of pregnancy. In newborns whose mothers took Depakine during pregnancy, hemorrhagic syndrome may occur, probably associated with hypofibrinogenemia, which may be caused by a decrease in coagulation factors. Afibrinogenemia, which can be fatal, has been observed. However, this syndrome must be distinguished from a decrease in vitamin K-dependent factors caused by the use of phenobarbital and other enzyme inducers. Therefore, in pregnant women before childbirth, as well as in newborns, it is necessary to analyze the platelet count, the level of fibrinogen in the serum, and coagulation tests to determine coagulation factors. Birth trauma may increase the risk of bleeding. Breastfeeding period . Excretion of valproate into breast milk is low. To date, only one case of thrombocytopenia in a three-month-old child is known, which manifested itself after stopping breastfeeding. There is no evidence of any significant adverse clinical symptoms in children who were breastfed while their mother was using Depakine. Therefore, you can consider the possibility of breastfeeding while taking the drug as monotherapy, taking into account the possibility of its side effects, especially hematological and liver dysfunction. Impact on the ability to drive a car and perform work that requires increased attention . The patient should be warned about the possibility of drowsiness, especially in the case of combined anticonvulsant therapy or a combination of Depakine with benzodiazepines.

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).

Interactions of the drug Depakine

The simultaneous use of Depakine with drugs that can cause seizures or reduce the seizure threshold, depending on the possible risk, is not recommended or contraindicated. These drugs include most antidepressants (tricyclics, selective serotonin uptake inhibitors), antipsychotics (phenothiazines and butyrophenones), mefloquine, bupropion and tramadol. Contraindicated combinations Mefloquine - risk of epileptic seizures in patients with epilepsy with increased metabolism of valproic acid and the convulsant effect of mefloquine. St. John's wort is a risk of reducing the concentration of valproic acid in the blood plasma and the effectiveness of the drug. Combinations not recommended Lamotrigine - increased risk of severe skin reactions (toxic epidermal necrolysis syndrome). An increase in the concentration of lamotrigine in the blood plasma due to a slowdown in its metabolism in the liver under the influence of valproate. If such a combination is necessary, careful monitoring of the patient is required. Combinations that require special caution when using Carbamazepine - the concentration of the active metabolite of carbamazepine in the blood plasma increases, signs of its overdose appear. The concentration of valproic acid in the blood plasma decreases due to increased metabolism in the liver under the influence of carbamazepine. With simultaneous use, it is necessary to clinically monitor the patient, determine the concentration of valproic acid and carbamazepine in the blood plasma, and review the dosage of the drugs. Carbapenems, monobactams (meropenem, panipenem, aztreonam, imipenem) - the risk of seizures due to a decrease in the concentration of valproic acid in the blood serum. It is recommended to clinically monitor the patient, determine the concentration of drugs in the blood plasma and, possibly, review the dosage of Depakine during treatment with an antibacterial drug and after its discontinuation. Felbamate - increased concentration of valproic acid in blood serum and risk of overdose. Clinical and laboratory monitoring is necessary; it is possible to review the dosage of Depakine during treatment with felbamate and after its discontinuation. Phenobarbital, primidone - an increase in the concentration of phenobarbital or primidone in the blood plasma with the appearance of signs of overdose, especially in children; a decrease in the concentration of valproic acid in the blood plasma due to an increase in its metabolism in the liver under the influence of phenobarbital or primidone. Clinical monitoring of the patient is necessary during the first 15 days of combined treatment and immediate reduction of the dose of phenobarbital or primidone if signs of sedation appear; determination of drug levels in blood plasma. Phenytoin - there is a danger of reducing the concentration of valproic acid in the blood plasma due to increased metabolism in the liver under the influence of phenytoin. It is recommended to clinically monitor the patient's condition, determine the level of drugs in the blood plasma and, possibly, change their doses. Topiramate - there is a risk of hyperammonemia or encephalopathy under the influence of valproic acid taken in combination with topiramate. Strict clinical monitoring of the patient's condition is necessary to detect ammonemia during the first month of treatment and when symptoms appear that indicate its occurrence. Combinations that should be taken into account Nimodipine (oral and parenteral) - increased hypotensive effect of nimodipine due to an increase in its concentration in the blood plasma (weakening of metabolism by valproic acid). Other forms of interactions Oral contraceptives - valproate does not have an enzyme-reducing effect, and therefore does not reduce the effectiveness of gestoprogestogens in women taking hormonal contraceptives.

Use during pregnancy and breastfeeding

Risk associated with developing epileptic seizures during pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia may pose a particular risk for both the mother and the fetus, due to the possibility of death.

Risk associated with the use of Depakine® Chronosphere™ during pregnancy

Experimental reproductive toxicity studies conducted in mice, rats and rabbits have demonstrated that valproic acid is teratogenic.

Congenital malformations

Available clinical data have demonstrated a higher incidence of minor and severe malformations, in particular, congenital neural tube defects, craniofacial deformities, malformations of the limbs and CVS, hypospadias, and multiple malformations affecting different organ systems in children born to mothers who took valproic acid during pregnancy, compared with their frequency when taking a number of other antiepileptic drugs during pregnancy. Thus, the risk of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was approximately 1.5, 2.3, 2.3 and 3.7 times higher compared with phenytoin monotherapy , carbamazepine, phenobarbital and lamotrigine, respectively.

Data from a meta-analysis that included registry and cohort studies showed that the incidence of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was 10.73% (95% CI 8.16– 13.29%). This risk is greater than the 2–3% risk of major congenital malformations in the general population. This risk is dose-dependent, but it is not possible to establish a threshold dose below which such a risk does not exist.

Mental and physical development disorders

It has been shown that prenatal exposure to valproic acid may have adverse effects on the mental and physical development of exposed children. This risk appears to be dose-dependent, but it is not possible to establish a threshold dose below which such a risk does not exist. The exact gestational period for the risk of developing these effects has not been established, and risk is possible throughout pregnancy.

Studies of preschool children exposed in utero to valproic acid have shown that up to 30–40% of these children had early developmental delays (such as delayed gait and speech delays), as well as lower intellectual abilities, poor language skills (intrinsic speech and speech understanding) and memory problems.

Intelligence quotient (IQ) scores measured in children aged 6 years with a history of prenatal exposure to valproic acid were on average 7 to 10 points lower than in children exposed prenatally to other antiepileptic drugs. Although the role of other factors that could adversely affect the intellectual development of children exposed to valproic acid in utero cannot be ruled out, it is clear that in such children the risk of intellectual impairment may be independent of maternal IQ. Data on long-term outcomes are limited.

There is evidence that children exposed to valproic acid in utero have an increased risk of developing autistic spectrum disorders (approximately 3- to 5-fold increased risk), including childhood autism. Limited evidence suggests that children exposed to valproic acid in utero are more likely to develop attention-deficit/hyperactivity disorder (ADHD).

Both valproic acid monotherapy and combination therapy containing valproic acid are associated with adverse pregnancy outcomes, but combination antiepileptic therapy containing valproic acid has been reported to be associated with a higher risk of adverse pregnancy outcome compared with valproic acid monotherapy (i.e. e. the risk of developing disorders in the fetus is less when using valproic acid in monotherapy).

Risk factors for fetal malformations are: a dose of more than 1000 mg/day (however, a lower dose does not eliminate this risk) and the combination of valproic acid with other anticonvulsants.

In connection with the above, the drug Depakine® Chronosphere™ should not be used during pregnancy and in women of childbearing potential unless absolutely necessary, i.e. its use is possible in situations where other antiepileptic drugs are ineffective or the patient cannot tolerate them.

The question of the need to use the drug Depakine® Chronosphere™ or the possibility of refusing its use should be resolved before starting use or reviewed if a woman taking Depakine® Chronosphere™ is planning a pregnancy.

Women of childbearing potential should use effective methods of contraception during treatment with Depakine® Chronosphere™.

Women of childbearing potential should be informed of the risks and benefits of using valproic acid during pregnancy.

If a woman is planning or has been diagnosed with pregnancy, the need for treatment with valproic acid should be re-evaluated depending on the indication:

- if bipolar disorder is indicated, discontinuation of treatment with valproic acid should be considered (see below);

- if epilepsy is indicated, the question of continuing treatment with valproic acid or its discontinuation is decided after reassessing the benefit-risk ratio. If, after reassessing the balance of benefit and risk, treatment with valproic acid must still be continued during pregnancy, it is recommended to use it in the lowest effective daily dose, divided into several doses. It should be noted that during pregnancy, the use of extended-release dosage forms of the drug is more preferable than other dosage forms.

If possible, even before pregnancy, you should additionally start taking folic acid (at a dose of 5 mg/day), because Folic acid may reduce the risk of neural tube defects. However, currently available data do not support its preventive effect against congenital malformations caused by valproic acid.

Special prenatal diagnostics, including detailed ultrasound, should be carried out on an ongoing basis (including in the third trimester of pregnancy) to identify possible defects in the formation of the neural tube or other malformations of the fetus.

Risk to newborns

Isolated cases of hemorrhagic syndrome have been reported in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with hypofibrinogenemia and/or decreased levels of other coagulation factors. The development of afibrinogenemia, which could be fatal, has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

Therefore, in newborns whose mothers were treated with valproic acid during pregnancy, coagulation tests should be performed (determining the number of platelets in peripheral blood, plasma concentration of fibrinogen, coagulation factors and coagulogram).

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

Cases of hypothyroidism have been reported in newborns whose mothers took valproic acid during pregnancy.

Newborns whose mothers took valproic acid in the last trimester of pregnancy may experience withdrawal symptoms (including agitation, irritability, hyperreflexia, tremors, hyperkinesia, muscle tone disorders, tremor, seizures and feeding difficulties).

Breastfeeding period

Excretion of valproic acid into breast milk is low, its concentration in milk is 1–10% of the concentration in serum.

There are limited clinical data on the use of valproic acid during breastfeeding, and therefore the use of the drug during this period is not recommended.

Based on the literature data and limited clinical experience, the issue of breastfeeding can be considered during monotherapy with Depakin® Chronosphere™, but the side effect profile of the drug, especially the hematological disorders it causes, should be taken into account.

Fertility. Due to the possibility of developing dysmenorrhea, amenorrhea, polycystic ovaries, an increase in the concentration of testosterone in the blood, a decrease in fertility in women is possible (see “Side effects”). In men, valproic acid can reduce sperm motility and impair fertility (see “Side Effects”). These fertility problems have been found to be reversible after cessation of treatment.

Overdose of the drug Depakine, symptoms and treatment

Clinical manifestations of a significant overdose usually occur in the form of coma of varying severity with muscle hypotonia, hyporeflexia, miosis and respiratory depression. Possible intracranial hypertension due to cerebral edema. Emergency care in a hospital should include gastric lavage (effectively within 10–12 hours after taking the tablets), osmotic diuresis, and constant monitoring of the functions of the cardiovascular and respiratory systems. In severe cases, dialysis or exchange transfusion is indicated. There are reports of the successful use of naloxone as an antidote for acute drug poisoning. With a significant overdose, death is possible, but the prognosis is usually favorable.