Instructions for use DEPAKINE

Nosological classification (ICD-10)

• F95 Tiki
• 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
• R25.2 Cramp and spasm
• R56.0 Convulsions during fever

Compound

Depakine 150 ml syrup

Depakine 150 ml syrup

Trade name Depakine® International nonproprietary name Valproic acid Dosage form Syrup 5 g/100 ml, 150 ml Composition 100 ml of syrup contain the active substance - valproic acid 5 g (in the form of sodium valproate 5.764 g). excipients: sodium hydroxide, methyl parahydroxybenzoate, propyl parahydroxybenzoate, 67% sucrose solution in terms of dry product, 70% sorbitol solution (crystallizing), glycerin, artificial flavor - cherry, concentrated hydrochloric acid or concentrated sodium hydroxide solution, purified water. Description Transparent syrupy liquid of pale yellow color with the smell of cherry. Pharmacotherapeutic group Antiepileptic drugs. Fatty acid derivatives. Valproic acid. ATC code N03A G01 Pharmacological properties Pharmacokinetics Various pharmacokinetic studies carried out with valproate have shown that: - bioavailability in the blood after oral administration is close to 100% - volume of distribution is limited mainly to the blood and rapidly exchanging extracellular fluid. Valproate penetrates into the cerebrospinal fluid and brain tissue - the half-life is 15-17 hours - a minimum serum concentration of 40-50 mg/l is sufficient to produce a therapeutic effect, with a wide range from 40 mg/l to 100 mg/l . If higher plasma concentrations are necessary, the expected benefit should be weighed against the risk of adverse reactions, in particular dose-related ones. However, levels above 150 mg/l require dose reduction - plasma concentrations of the saturation stage are reached after 3-4 days - valproate is very well bound to plasma proteins; binding to proteins is dose-dependent and saturable - valproate is excreted primarily in the urine after metabolism by glucuronic conjugation and beta-oxidation - valproate can be dialyzed, however, hemodialysis is effective only on the free fraction of valproate in the blood (approximately 10%). Valproate does not induce enzymes of the cytochrome P450 metabolic system; unlike most other antiepileptic drugs, it does not accelerate either its own degradation or that of other substances such as estrogens, progestogens and oral anticoagulants. Pharmacodynamics Valproate has a pharmacological effect mainly on the central nervous system. The anticonvulsant effect of the drug manifests itself in various types of convulsive seizures in animals and epilepsy in humans. Experimental and clinical studies of valproate indicate two types of anticonvulsant effects. The first type is a direct pharmacological effect associated with valproate concentrations in blood plasma and brain tissue. The second type of action is indirect and is likely associated with valproate metabolites located in brain tissue, or associated with changes in neurotransmitters or direct effects on the membrane. The most widely accepted hypothesis relates to gamma-aminobutyric acid (GABA) levels, which increase after valproate administration. Valproate reduces the duration of intermediate sleep phase while increasing the slow-wave sleep phase. Indications for use For adults and children As monotherapy or in combination with other antiepileptic treatment: - treatment of clonic, tonic, tonic-clonic seizures, absences, myoclonic and atonic seizures and Lennox-Gastaut syndrome - treatment of focal epilepsy: focal seizures with secondary generalization or without it. For children, prevention of seizure recurrence after one or more febrile seizures meeting the criteria for complicated febrile seizures when intermittent benzodiazepine prophylaxis is ineffective. Directions for use and dosage Dosage Average daily dose: - for infants and young children: 30 mg/kg (syrup, oral solution or extended-release granules should be preferred) - for adolescents and adults: 20-30 mg/kg (should be give preference to tablets, extended-release tablets or extended-release granules). The drug must be prescribed in milligrams. The bottle of syrup is equipped with an oral dosage syringe inserted into the adapter cap. Method of administration For oral administration. Administer the syrup using the oral syringe included in the box (with a white plunger). It is advisable to take the daily dose with meals: - divided into 2 doses for patients under 1 year old - divided into 3 doses for patients over 1 year old. Initiation of treatment - For patients undergoing treatment and taking other antiepileptic drugs, sodium valproate is started gradually to achieve the optimal dose after approximately 2 weeks, and then, if necessary, the combination treatment is reduced depending on the effectiveness of treatment. - For patients who are not taking other antiepileptic drugs, it is advisable to increase the dose in stages, every 2-3 days, so that in about one week the optimal dose is reached. - if necessary, combination treatment with other antiepileptic drugs should be started gradually (see section “Drug Interactions”). Side effects - liver disease (see "Special Instructions") - teratogenic risk (see "Pregnancy and Lactation") - confusion or convulsions: in some cases, stupor and lethargy were observed, sometimes leading to temporary coma (encephalopathy), as isolated , and associated with a paradoxical increase in seizures in the presence of valproate with a decrease in the frequency of seizures upon cessation of treatment or after a dose reduction. Such conditions occur most often during polytherapy (especially in combination with phenobarbital) or after a sharp increase in the dose of valproate - at the beginning of treatment, gastrointestinal complaints (nausea, vomiting, stomach pain, diarrhea) may appear, which, as a rule, resolve after a few days without discontinuation of treatment - temporary and/or dose-dependent undesirable effects: hair loss, slight postural tremor and drowsiness - headaches - dose-dependent thrombocytopenia, observed, as a rule, systematically and without clinical consequences. For asymptomatic thrombocytopenia, drug dosage reduction alone, based on platelet count, if possible, and epilepsy control, usually results in resolution of thrombocytopenia - decreased fibrinogen levels or increased bleeding time, usually without clinical consequences, have been reported in particularly at high doses. Valproate has an inhibitory effect on the second phase of platelet aggregation. Cases of anemia, macrocytosis, leukopenia and, in exceptional cases, pancytopenia were recorded less frequently - increased body weight; Since increased body weight is a risk factor for polycystic ovary syndrome, careful monitoring of patients' body weight is necessary (see "Special Instructions"). - amenorrhea and irregular menstrual cycle - skin reactions, such as exanthematous rash Often - isolated, moderate hyperammonemia, not accompanied by changes in liver function indicators, especially with polytherapy, does not lead to discontinuation of treatment. However, cases of hyperammonemia have been reported that occur with neurological symptoms (which can progress to coma) and require additional tests (see “Special Instructions”). Uncommon - ataxia - vasculitis - angioedema - syndrome of inappropriate secretion of antidiuretic hormone Rare - reversible parkinsonism syndrome - reversible Fanconi syndrome - bone marrow aplasia - agranulocytosis - DRESS syndrome (Drug Rash with Eosinophylia and Systemic Symptoms) Very rare - cognitive impairment with latent and progressive onset, which can progress to complete dementia, and are reversible within a few weeks or months after discontinuation of treatment - hyponatremia - enuresis and urinary incontinence - mild peripheral edema Exceptional cases - pancreatitis, requiring premature cessation of treatment. Sometimes fatal (see "Special Instructions") - kidney damage - hearing loss, reversible and irreversible - Lyell's syndrome, Stevens-Johnson syndrome and erythema multiforme Contraindications - hypersensitivity to valproate, divalproate, valpromide or any of the components history of medication - acute hepatitis - chronic hepatitis - personal or family history of severe hepatitis, especially associated with drugs - hepatic porphyria - combination with mefloquine or St. John's wort (see "Drug interactions") Drug interactions Concomitant use of drugs that provoke seizures or drugs that lower the seizure threshold should be taken into account, and not even recommended or contraindicated given the seriousness of the potential risk of adverse events. These drugs include most antidepressants (imipramines, selective serotonin reuptake inhibitors), antipsychotics (phenothiazines and butyrophenones), mefloquine (see below), bupropion and tramadol. Contraindicated combinations (see "Contraindications") - Mefloquine There is a risk of developing epileptic seizures in patients with epilepsy due to the increased metabolism of valproic acid and the seizure-provoking effect of mefloquine. — St. John's wort There is a risk of decreased plasma concentrations and decreased effectiveness of the anticonvulsant. Combinations not recommended (see "Special Instructions") - Lamotrigine There is an increased risk of developing serious skin reactions (Lyell's syndrome). Moreover, it is possible to increase the plasma concentration of lamotrigine, because Sodium valproate slows down the metabolism of the latter in the liver. If treatment with this combination is necessary, strict clinical monitoring is required. Combinations requiring precautions during use - Aztreonam, imipenem, meropenem There is a risk of developing convulsive seizures as a result of a decrease in plasma concentrations of valproic acid. Clinical observation and determination of plasma concentrations are recommended; dose adjustment of the anticonvulsant may be required during treatment with the anti-infective agent and after its discontinuation. — Carbamazepine There is an increase in plasma concentrations of the active metabolite of carbamazepine with signs of overdose and a decrease in plasma concentrations of valproic acid as a result of increased hepatic metabolism by carbamazepine. Clinical observation, determination of plasma concentrations and dose adjustment of both anticonvulsants are recommended. — Felbamate There is an increase in serum concentrations of valproic acid with a risk of overdose. Clinical and laboratory monitoring and possible dose adjustment of valproate are recommended during treatment with felbamate and after its discontinuation. — Phenobarbital, primidone Most often, children experience an increase in plasma concentrations of phenobarbital and primidone with overdose symptoms caused by suppression of hepatic metabolism. There is also a decrease in the plasma concentration of valproic acid, caused by an increase in its hepatic metabolism under the influence of phenobarbital or primidone. Clinical monitoring is required during the first 15 days of combination treatment, with immediate reduction of phenobarbital or primidone doses if sedation develops; and plasma concentrations of both anticonvulsants should be monitored. - Phenytoin (and - by extrapolation - fosphenytoin) There is a change in plasma concentrations of phenytoin. In addition, there is a risk of a decrease in plasma concentrations of valproic acid due to increased hepatic metabolism under the influence of phenytoin. Clinical monitoring, determination of plasma concentrations and, possibly, dose adjustment of both anticonvulsants are necessary. — Topiramate There is a risk of hyperammonemia or encephalopathy, usually associated with valproic acid, when administered concomitantly with topiramate. Increased clinical and laboratory monitoring is necessary at the start of treatment and in the event of symptoms indicating this effect. — Rifampicin Rifampicin may decrease blood levels of valproic acid, resulting in no therapeutic effect. Therefore, it may be necessary to adjust the dose of valproate when coadministered with rifampicin. — Zidovudine There is a risk of increased adverse reactions to zidovudine, in particular hematological effects, due to a decrease in metabolism under the influence of valproic acid. Regular clinical and laboratory monitoring is necessary. Blood counts should be checked for anemia in the first two months of use of the combination. Combinations to consider - Nimodipine (for oral and - by extrapolation - parenteral administration) There is a risk of increasing the hypotensive effect of nimodipine due to an increase in its plasma concentration (valproic acid suppresses its metabolism). Other interactions - Oral contraceptives Valproate does not have enzyme-inducing activity and therefore does not reduce the effectiveness of estrogen-progestogen hormonal contraception Special instructions Special warnings Since this drug is converted in the body to valproic acid, it should not be combined with other drugs that are subject to the same transformation, to avoid overdose of valproic acid (for example, divalproate, valpromide). Liver disease Conditions for its occurrence Exceptional cases of liver damage with severe and sometimes fatal outcomes have been recorded. The risk is greatest among infants and children under 3 years of age who have severe epilepsy, and especially epilepsy associated with brain damage, mental retardation, and/or a genetic metabolic disorder or degenerative disease. At the age of over 3 years, the frequency is much lower, and with age it gradually decreases. In the vast majority of cases, such liver damage is observed in the first 6 months of treatment, usually between 2 and 12 weeks, and, as a rule, during antiepileptic polytherapy. Early signs Early diagnosis is based mainly on the clinical picture of the disease. In particular, you should pay attention to two types of symptoms that may precede the development of jaundice, especially in patients at risk (see “Conditions for its occurrence”): - firstly, nonspecific systemic and in most cases sudden onset symptoms, such as asthenia, anorexia, loss of strength, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain - secondly, relapses of epileptic seizures, despite strict adherence to treatment. It is recommended to inform the patient or his family, if it is a child, that they should immediately consult a doctor if such a clinical picture develops. In addition to the physical examination, laboratory tests of liver function should be performed immediately. Detection During the first 6 months of treatment, liver function should be periodically monitored. Among the standard tests, the most important are those that reflect the state of protein synthesis, in particular, prothrombin time (PT). If a pathologically low level of PT is confirmed, especially if it is accompanied by other abnormalities in laboratory parameters (a significant decrease in the level of fibrinogen and blood coagulation factors, an increase in the level of bilirubin and transaminases - see "Special instructions"), it is necessary to stop treatment with valproate (and - as precautions - salicylate derivatives, if they are prescribed simultaneously, since their metabolism is carried out in the same way). Pancreatitis The drug should be taken with caution in patients with impaired pancreatic function. In exceptional cases, pancreatitis has been reported, sometimes fatal. It can occur regardless of the patient’s age and duration of treatment; young children are especially at risk. Pancreatitis with an unfavorable outcome is observed, as a rule, in young children and in patients with severe epilepsy with brain damage or against the background of anticonvulsant polytherapy. The risk of death is higher with pancreatitis occurring along with liver failure. Danger of suicide Suicidal thoughts and behavior have been reported in patients treated with antiepileptic drugs for various indications. The meta-analysis of data obtained in randomized, placebo controlled clinical studies of antiepileptic agents also showed a certain increase in the risk of suicidal thoughts and behavior. The reasons for this risk are unknown, and the available data does not allow excluding the presence of increased risk when taking sodium valproate. Therefore, it is necessary to strictly check patients for any signs of suicidal thoughts and behavior, they may require appropriate treatment. Patients (and persons caring for them) should be advised to seek medical help if suicidal thoughts or suicidal behavior take place. A warning regarding the indication of epilepsy. The introduction of an anti -epileptic drug may, in rare cases, be accompanied by an increase in seizures or the appearance of a new type of seizures in the same patient, regardless of spontaneous vibrations observed with some types of epilepsy. In the case of a valproat, this mainly happens when changes in the concomitant anti -epileptic treatment or drug interaction (see “drug interactions”), toxicity (liver or encephalopathy disease, see “special instructions” and “side effects”) or an overdose. Interaction with other drugs is not recommended for the simultaneous use of this drug with lamotridigin (see “Medicinal interactions”). Syrup, this drug contains sorbiti and maltile. Its use is not recommended for patients with fructose intolerance, glucose dysfunction syndrome and galactose, with a deficiency of sugarzya-amomaltase. The composition of the drug includes methyl parahydroxybenzoate and propyl parahydroxybenzoate, which can cause the development of allergic reactions of a slow type. Precautions of precautions when applying control of the liver function should be carried out before treatment (see “contraindications”), and then, during the first 6 months of treatment, it is periodically repeated, especially in patients with risk group (see “special instructions”). The drug should be taken with caution in patients with hemorrhagic diathesis. It should be emphasized that, as in the case of most anti-epileptic agents, an isolated, temporary, moderate increase in transaminases without any clinical symptoms, especially at the beginning of treatment, can be observed. In such cases, it is recommended to conduct a more complete laboratory examination (in particular, the determination of prothrombin time) in order to reconsider the dosage, and depending on the change in the indicators, the analyzes are repeated. For children under 3 years of age, the use of valproat is recommended only as monotherapy after comparing the benefits of treatment and risk of developing liver and pancreatitis in this age group (see “Special Instructions”). Before starting treatment, as well as before surgical operations and in cases of hematomas or spontaneous bleeding, it is recommended to make a preliminary blood test (a total blood picture, including the number of platelets, bleeding time and blood coagulation indicators) (see “side effects”). It should be avoided by the simultaneous appointment of salicylate derivatives due to possible hepatotoxicity (see “special instructions”) and the risk of bleeding. With renal failure, an increase in the concentration of valproic acid in the blood should be taken into account and in accordance with this to reduce the dose. In the case of acute abdominal pain or such gastrointestinal symptoms, such as nausea, vomiting and/or anorexia, the presence of pancreatitis should be excluded, and with an increase in the level of pancreatic enzymes, treatment should be stopped and alternative treatment measures should be taken. Patients with a deficiency of enzymes of the carbamide cycle are not recommended for this drug. In such patients, several cases were described by hyperonymia, which occurred with a stupor or coma. Before starting the treatment of children with a history of liver and gastrointestinal symptoms of unexplored etiology (anorexia, vomiting, cases of cytolysis), lethargia or coma delay or deaths of a newborn or young child in a family history, it is necessary to survey metabolism, in particular, on the presence of ammonium on an empty stomach and after eating. Despite the fact that this drug causes violations of the immune system only in exceptional cases, it should be carefully weighed by the benefits and risk when prescribing the drug to patients suffering from systemic red lupus. When starting treatment, the patient should be informed of a possible increase in weight and appropriate measures, mainly dietary, which he should be taken to minimize such a risk. Before you start the treatment of women of childbearing age, you should make sure that they have no pregnancy, as well as that effective contraception has begun in advance, before the start of treatment (see “Pregnancy and Lactation”). Pregnancy based on the available data, the intake of sodium valproate is not recommended throughout pregnancy and women of childbearing age, which does not use effective contraception. The sodium valproate is 3-4 times increases the risk of fetal development in women who use this drug compared to a general population in which the risk is 3%. The most commonly observed malformations of the fetus include defects in the closure of the nervous tube (≈ 2-3%), malformations of the face, facial splitting, craniostenosis, heart defects, malformations of the kidneys and genitourinary organs, and limb deformation. Doses exceeding 1000 mg/day, and combining with other anti -confulsants are important risk factors in the formation of such malformations of the fetus. Modern epidemiological data do not indicate a decrease in the coefficient of general mental development of children with the exposition of sodium in utero. Nevertheless, such children describe some decrease in verbal abilities and/or more frequent appeal to speech therapy or for medical help. Moreover, among children who exposed the sodium in Utero, several isolated cases of autism and related violations were recorded. To confirm or refute all these results, additional studies are necessary. When planning pregnancy, if a pregnancy is planned, you should certainly solve the issue of the use of other therapeutic drugs. If the use of sodium valproate is inevitable (i.e. there is no other alternative), it is recommended to prescribe the minimum effective daily dose and give preference to dosage forms of prolonged release or, if it is impossible, distribute the daily dose of several techniques to avoid the emergence of peaks of maximum concentrations of valproine acid in plasma. There is no data confirming the effectiveness of additional folic acid by women subject to sodium valproate during pregnancy. However, given the favorable effect, which is exerted by folic acid in other conditions, you can offer its reception at a dose of 5 mg/day one month before conception and within 2 months after it. Regardless of the intake of folic acid, an examination for the presence of malformations should be identical to everyone. During pregnancy , if the choice of another drug is absolutely impossible, and you need to continue treatment with a sodium valproat (that is, there is no other alternative), it is recommended to prescribe a minimum effective dose, avoiding doses, exceeding 1000 mg/day, if possible. Regardless of the intake of folic acid, screening for the presence of malformations should be identical. Before childbirth, the coagulogram of a pregnant woman should be examined before childbirth, including determining the number of platelets, a fibrinogen level and blood coagulation time (activated partial prothrombin time - APV). This drug can cause newborn Therefore, a newborn at birth should be carried out by a blood test, which consists, at least in determining the number of platelets, the level of fibrinogen and APV. In addition, in newborns, cases of hypoglycemia in the first week of life were registered. Lactation of sodium valproate is released into breast milk in small amounts. However, based on the data on reduced verbal abilities in young children who have exposed the drug in utero (see above), patients should be advised to abandon breastfeeding. Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms, you need to pay attention to patients, in particular those who drive a car or working mechanisms, to the risk of drowsiness, especially in cases of anticonvulsial political therapy or taking the drug simultaneously with other drugs, able to enhance drowsiness. An overdose of symptoms: the clinical picture of massive acute poisoning, usually includes a quiet one (which can be more or less deep) with muscle hypotension, hyporephlexia, myose, a decrease in respiratory function and metabolic acidosis. Small cases of intracranial hypertension associated with the edema of the brain are described. Treatment: measures taken in the hospital - gastric lavage, if necessary, maintaining effective diuresis, monitoring the condition of the cardiovascular and respiratory systems. In very severe cases, if necessary, extrarenal blood cleansing (dialysis) can be carried out. Usually, the prognosis of such poisoning is favorable. However, several cases of death have been registered. The form of release and packaging of 150 ml of the drug in dark glass bottles with a polypropylene lid, inaccessible to children and opened with turning the lid when pressed on it. The bottle, together with the oral syringe and (PENP) adapter - a white piston and instructions for medical use in the state and Russian languages ​​are placed in a pack of cardboard. Storage conditions are stored at a temperature of not higher than 25 ° C, in a place protected from direct sunlight. Keep out of the reach of children! Shelf life 3 years after opening the bottle is 1 month. Do not use after the expiration date. Conditions for dispensing from pharmacies By prescription

Directions for use and doses

Inside. The drug should be taken only with a double-sided dosing spoon located in a cardboard box, or with a dosage syringe located in a cardboard box. There is a large dosing spoon on one side of the spoon and a small dosing spoon on the other side. The large dosage spoon holds 200 mg of sodium valproate, the small one - 100 mg of sodium valproate.

This dosage form of the drug Depakine® (syrup) is primarily intended for use by children.

The dosage syringe is marked with graduations in milligrams of sodium valproate. After opening, the bottle can be stored at a temperature not exceeding 25 °C for 1 month.

Dosage regimen

The dose should be set taking into account the age and body weight of the patient.

It is recommended to divide the daily dose:

— for two doses for patients under 1 year of age;

— for three doses for patients over 1 year of age.

The initial daily dose for adults and children weighing more than 25 kg is usually 5-10 mg/kg, then it is increased by 5 mg/kg every 4-7 days until the optimal dose is reached to prevent the occurrence of epileptic attacks.

Average daily dose:

— for children (up to 14 years) — 30 mg/kg (it is preferable to take the drug in syrup form);

— for adolescents (14–18 years old) — 25 mg/kg (it is preferable to take solid dosage forms of the drug Depakine®);

- for adults and elderly patients (body weight from 60 kg and above) - 20 mg/kg (preferable to take solid dosage forms of the drug Depakine®).

Therefore, the average daily doses presented in the table are recommended.

Table

* Dose in terms of mg of sodium valproate.

The average daily dose can be increased under the control of 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 date.

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

A clear correlation between the daily dose, the concentration of valproic acid in the blood serum and the therapeutic effect has not been established. Therefore, the optimal dose of the drug should be selected primarily on the basis of clinical response. Determination of the concentration of valproic acid in the blood serum can serve as an addition to clinical monitoring if epilepsy is uncontrollable or the development of side effects is suspected. Doses that provide serum valproic acid concentrations of 40–100 mg/L (300–700 µmol/L) are usually effective. If there is a justified need to achieve higher concentrations in the blood serum, the ratio of the expected benefit and the risk of side effects, especially dose-dependent ones, should be carefully weighed. at serum concentrations of valproic acid above 100 mg/l, an increase in side effects is expected, including the development of intoxication. Therefore, the serum concentration determined before taking the first dose per day should not exceed 100 mg/l.

For patients who have previously taken antiepileptic drugs, the transition to taking the drug Depakine® syrup should be carried out gradually, reaching the optimal dose of the drug within approximately 2 weeks. In this case, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previously taken antiepileptic drug is discontinued, its withdrawal should be carried out gradually.

If it is necessary to use valproic acid with other antiepileptic drugs, they should be added gradually (see “Interaction”). Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, the concentrations of valproic acid in the blood should be monitored for 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), reduce the daily dose of Depakine ® syrup.

Special patient groups

Female children and adolescents, women of childbearing potential and pregnant women. Treatment with Depakine® syrup should be started under the supervision of a specialist experienced 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 in 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.

Elderly age. 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 such patients should be adjusted according to the achievement of control of epileptic seizures.

Renal failure and/or hypoproteinemia. 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 blood serum (free fraction and fraction bound to plasma proteins) to avoid possible errors in dose selection.

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

Valproic acid has been found to stimulate HIV replication under certain experimental conditions.
The clinical significance of this fact is unknown. In addition, the significance of data obtained from 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 (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.