From what appoint depakine chrono. Depakine chrono: what is prescribed, dosage, analogues. Application in childhood

INN: Valproic acid

Manufacturer: Sanofi Winthrop Industry

Anatomical-therapeutic-chemical classification: Valproic acid

Registration number in the Republic of Kazakhstan: No. RK-LS-5 No. 021135

Registration period: 12.01.2015 - 12.01.2020

ALO (Included in the Free Outpatient Drug Supply List)

ED (Included in the List of drugs in the framework of the guaranteed volume of medical care, subject to purchase from a single distributor)

Instruction

Tradename

Depakine Chrono

International non-proprietary name

Valproic acid

Dosage form

Film-coated tablets, extended release, divided into 300 mg

Compound

One tablet contains

active substances: sodium valproate 199.8 mg,

valproic acid 87.0 mg,

(corresponding to 300 mg sodium valproate)

Excipients: hypromellose 4000, ethylcellulose, sodium saccharin, colloidal silicon dioxide,

shell composition: hypromellose, macrogol 6000, talc, titanium dioxide (E171), polyacrylate dispersion 30%.

Description

Tablets oblong, with hemispherical edges, almost white, with a biconvex surface, scored on both sides, film-coated.

Pharmacotherapeutic group

Antiepileptic drugs. Derivatives of fatty acids. Valproic acid.

ATX code N03AG01

Pharmacological properties

Pharmacokinetics

Suction

The bioavailability of the drug Depakin Chrono in plasma when taken orally is close to 100%.

Depakin Chrono circulates in plasma in the form of valproic acid. Absorption of Depakine® Timed Release Chrono Tablets in the digestive tract begins immediately, is regular and prolonged. This results in the absence of peaks of valproic acid in plasma and contributes to the maintenance of therapeutic concentrations of valproic acid for a long time.

Distribution

Valproic acid is distributed mainly into the blood and into the extracellular fluid.

Protein binding is limited mainly to albumins, is dose-dependent and saturable. With a total plasma concentration of valproic acid of 40-100 mg / l, the unbound fraction, as a rule, is 6-15%.

The concentration of valproic acid in cerebrospinal fluid is similar to the concentration of the unbound fraction in blood plasma (about 10%).

Valproic acid undergoes dialysis, but the content of the dialyzed fraction is significantly reduced due to binding to albumin (about 10%).

Sodium valproate crosses the placenta. Valproic acid has been found in milk (1-10% of total serum concentration) during lactation in women treated with Depakine® Chrono.

At the beginning of long-term therapy with the intake (oral form) of the drug Depakine® Chrono, the achievement of an equilibrium serum concentration of valproic acid takes approximately 3-4 days, and in some cases longer.

The therapeutic plasma concentration is usually considered to be a concentration of 40-100 mg / l of valproic acid (278-694 mmol / l). If the total concentration of valproic acid in the blood plasma remains above 150 mg / l (1040 mmol / l), the daily dose should be reduced.

Metabolism

Depakine Chrono is mainly metabolized in the liver. Major metabolic pathways include glucuronidation and beta-oxidation. Unlike most other antiepileptic drugs, sodium valproate does not accelerate its own degradation, nor that of other substances such as estrogen and progesterone. This property is reflected in the absence of an inducing effect on enzymes, including enzymes of the cytochrome P450 system.

breeding

With long-term use of the drug, the average half-life of valproic acid in adults is 10.6 hours (although it can vary from 5 to 20 hours), which requires taking the drug twice a day. The half-life in term infants is 20-30 hours and gradually approaches the values ​​in adults, depending on the development of the child.

Excretion of valproic acid occurs mainly by the kidneys, while a small part is excreted unchanged, and most is excreted as metabolites.

Kinetics in selected groups of patients

Patients with renal insufficiency: albumin binding is reduced. An increase in the serum concentration of the unbound fraction of valproic acid should be borne in mind, and the dose of the drug should be reduced accordingly.

Elderly patients: changes in pharmacokinetic values ​​were noted, however, they were not particularly significant; therefore, the dose should be determined according to the clinical response (achievement of seizure control).

Pharmacodynamics

Preclinical pharmacological studies have shown that Depakine® exhibits anticonvulsant properties in various experimental models of epilepsy (generalized and focal seizures).

Similarly, in clinical studies, Depakine® showed antiepileptic activity in various forms of epilepsy. The mechanism of action appears to involve increased GABAergic activity, preventing or limiting discharge propagation.

In several studies in vitro sodium valproate has been shown to stimulate HIV-1 replication, but this effect is small and could not be replicated in most studies. The clinical significance of these observations for patients infected with HIV-1 is unknown. When prescribing sodium valproate to patients infected with HIV-1, these data should be taken into account when interpreting the results of viral load monitoring.

Indications for use

As monotherapy:

Primary generalized epilepsy: petit mal seizure/absence, massive bilateral myoclonus, grand mal seizure with or without myoclonus, photosensitive forms.

As monotherapy or in combination with other antiepileptic drugs:

Secondary generalized epilepsy, particularly West syndrome (infantile spasms) and Lennox-Gastaut syndrome

Partial epilepsy with elementary or complex symptoms (psychosensory forms, psychomotor forms)

Mixed forms (generalized and partial epilepsy)

Treatment of manic episodes associated with bipolar disorder

Prevention of relapse of episodes of mood disorder in adult patients with bipolar disorder who have experienced a therapeutic response to manic episodes when treated with valproate.

Dosage and administration

Epilepsy

Usual dose

The daily dose should be prescribed depending on the age and weight of the patient. However, it should be remembered that individual sensitivity to valproate varies greatly.

The optimal dose should be determined depending on the clinical response obtained; in cases where satisfactory seizure control is not achieved or when the development of side effects from taking the drug is suspected, in addition to clinical observations, it may be necessary to determine the concentration of the active substance of the drug in the blood plasma.

ATas first-line monotherapy, when taken orally

The formula of prolonged action (Chrono) allows you to take the drug in the form of a single daily dose. It is advisable to take the drug at the beginning of a meal. The standard daily dose is: 25 mg/kg for newborns and children; 20-25 mg/kg for adolescents; 20 mg/kg for adults, and 15-20 mg/kg for the elderly.

If possible, Depakine® Chrono should be administered gradually, starting with a daily dose of 10-15 mg/kg, and gradually increase the dose every 2-3 days, reaching the optimal dose within about a week. In the case of taking the drug as monotherapy when a certain dose is reached, i.e. 15 mg/kg/day for the elderly, 20 mg/kg/day for adults and adolescents, 25 mg/kg/day for children and infants, may be monitored. If satisfactory clinical efficacy is observed at this stage, the drug should be continued at this dose.

The need to exceed the daily dose of 25 mg / kg for the elderly, 30 mg / kg for adults and adolescents, or 35 mg / kg for children and infants occurs only in rare cases, especially with monotherapy with the drug.

However, if taking the drug at such doses does not achieve seizure control, you can continue to increase the dose; if the dose exceeds 50 mg/kg, it is recommended to divide the daily dose into 3 doses, as well as to strengthen clinical and biochemical control (see "Special Instructions").

The combination of the drug Depakinewith other antiepileptic drugs

Sodium valproate should be taken in the same manner as first-line monotherapy. The average daily dose is usually similar to the dose used in monotherapy. However, in some cases this dose may be increased by 5-10 mg/kg.

It should also be borne in mind the effect of the drug Depakine® on other antiepileptic drugs. (see "Drug Interactions").

Replacement of an antiepileptic drug with Depakine

If the appointment of Depakine involves the gradual and complete replacement of the previous drug, it should be administered in the same way as with first-line monotherapy. The dosage of some previous drugs, in particular barbiturates, should be immediately reduced, followed by a gradual phased withdrawal of the drug. Cancellation of the drug should be 2-8 weeks.

Manic episodes in patients with bipolar disorder

The desired clinical effect is usually achieved at a plasma concentration of valproate in the range between 45 and 125 μg / ml.

The recommended maintenance dose for the treatment of bipolar disorder is 1000-2000 mg/day. In rare cases, the dose may be increased to a maximum of 3000 mg / day. Dose adjustment should be based on individual clinical response.

Prevention of relapse of manic episodes associated with bipolar disorder

The dose used for the prevention of relapse corresponds to the minimum effective dose that provides adequate control of the symptoms of acute manic syndrome in this patient. Do not exceed the maximum daily dose of 3000 mg.

Special Dosage Instructions

Depakine® Chrono in the form of scored tablets should be taken with half a glass of pure water, milk or other soft drink.

Side effects

Congenital, familial and genetic disorders ( see "Pregnancy")

Inhibition of bone marrow hematopoiesis, including true erythrocyte aplasia

Agranulocytosis. Coagulation disorders consistent with type I von Willebrand disease have been reported in the literature. If the patient is scheduled for surgery or in the event of spontaneous bleeding or hematoma, a blood test (CBC, including platelets, bleeding time, and coagulation tests, including determination of factor VIII).

Quincke's edema, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), allergic reactions

Syndrome of inappropriate secretion of antidiuretic hormone (SNASAG)

Confusion

Digestive disturbances (nausea, upper abdominal pain, diarrhea) may occur in some subjects at the start of treatment, but usually disappear after a few days without interruption of treatment. The frequency of occurrence of such disorders can be significantly reduced if Depakine® is administered very gradually, with the intake of coated tablets (Chrono), and taken at the beginning of a meal. In these cases, symptomatic treatment may be prescribed.

There were several cases of hyperactivity or irritability that occurred at the beginning of treatment, especially in children. In some cases (≥0.1%-<1%) наблюдался мелкоамплитудный постуральный тремор, преимущественно на руках; такое явление могло быть временным. Может потребоваться снижение дозы.

Several cases of stupor and lethargy, sometimes leading to transient coma/encephalopathy, have been reported, either alone or associated with an increased incidence of seizures during therapy. Events were reduced with discontinuation of therapy or dose reduction. These cases occurred mainly when taking combination therapy (in particular, a combination with phenobarbital or topiramate) or after a sharp increase in the dose of valproate.

Transient and/or dose related alopecia

Amenorrhea and dysmenorrhea were observed

The phenomena of hypothermia

Often

Thrombocytopenia (≥ 1-<10%). Прием препарата Депакин Хроно может привести к падению числа тромбоцитов от 10000 до 30 000/мм³, часто это падение зависит от дозы и является временным. Оценка числа тромбоцитов рекомендуется перед началом приема препарата, а затем через 3-6 месяцев лечения, а также перед любой хирургической операцией, особенно если принимаемая доза препарата превышает 30 мг/кг/сут.

Increased appetite and weight gain (in 10.5% of cases), especially in adolescents and young women. Because weight gain can exacerbate the clinical symptoms of PCOS, weight should be carefully monitored (see section 4.4). "Precautionary measures").

Transient and / or dose-dependent drowsiness (≥ 1% -<10%)

Sometimes

Vasculitis

Ataxia

Rarely

Anemia, hematological adverse effects of leukopenia and pancytopenia

Deafness, both reversible and irreversible

Very rarely

Hyponatremia

Isolated hyperammonemia, without significant liver damage, as assessed using conventional tests. In the absence of clinical manifestations, there is no mandatory need to stop treatment. However, if hyperammonemia is accompanied by neurologic symptoms, further investigations are warranted ( see Precautions).

Neurological effects, such as clouding of consciousness, as a rule, are easily reversible, were observed in patients who took sodium valproate in combination with other antiepileptic drugs, in particular phenobarbital, and in whom the introduction of the drug into the therapy regimen did not occur gradually

Reversible dementia associated with reversible cerebral atrophy (<0,01%)

Pancreatitis (<0,01%), иногда с летальным исходом (see Precautions). All patients who experience acute pain in the abdomen while taking sodium valproate / valproic acid require an immediate medical examination (determination of the activity of pancreatic enzymes, other appropriate tests).

Severe liver damage<0,01%), иногда со смертельным исходом.

Infants and young children under 3 years of age with severe epilepsy, in particular epilepsy associated with brain damage, mental retardation and/or a metabolic or degenerative disease of genetic origin, are at particularly high risk. The incidence of liver dysfunction is significantly reduced after the age of 3 years and gradually decreases with age.

In most cases reported, liver damage occurred during the first 6 months of therapy, most often between the second and twelfth weeks, and usually when taking several antiepileptic drugs.

Warning signs and detection

Early diagnosis is mainly based on clinical signs.

In particular, two types of clinical manifestations that may precede the development of jaundice deserve close attention, especially in patients at risk (see "Development Conditions"):

General, non-specific signs, usually with sudden onset, such as weakness, anorexia, depression, and drowsiness, sometimes accompanied by repeated vomiting and abdominal pain

Loss of control of epileptic seizures

Patients (or their family members, if children are concerned) should be warned that if symptoms occur, they should immediately consult a doctor. In addition to clinical examination in such cases, an immediate liver function test should be performed.

The most important standard tests include the study of protein synthesis, especially the determination of the prothrombin index. If the prothrombin index turns out to be abnormally low, especially if this is accompanied by other abnormal laboratory values ​​​​(a significant decrease in the concentration of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin, an increase in the level of transaminases - see. "Precautionary measures"), taking the drug Depakin Chrono should be discontinued.

Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme.

Non-severe peripheral edema

Urinary incontinence

isolated cases

reversible parkinsonism

Reversible Fanconi syndrome, but the pathophysiological mechanism of this phenomenon is still unclear.

A decrease in the level of fibrinogen in the blood and an increase in the prothrombin index, especially when taking high doses of the drug, however, as a rule, without any clinical consequences. Sodium valproate inhibits the second stage of platelet aggregation.

Contraindications

Acute and chronic hepatitis

Having a family history of severe hepatitis, especially drug-induced hepatitis

Known hypersensitivity to sodium valproate

Hepatic porphyria

Combined reception with mefloquine and St. John's wort

Children's age up to 6 years

Drug Interactions

Effects of valproate on other drugs

Valproic acid is an inhibitor of cytochrome P450 isoenzymes CYP2C9 and CYP3A. The conclusion about the expected metabolic effects can be made on the basis of the corresponding scheme. The following interactions are especially important:

- Antipsychotics, monoamine oxidase inhibitors (MAOIs), antidepressants, and benzodiazepines

Depakine Chrono may enhance the effect of other neuropsychotropic drugs such as neuroleptics, monoamine oxidase inhibitors, antidepressants and benzodiazepines; Based on this, it is necessary to conduct clinical monitoring and possible correction of therapy.

-Phenobarbital

Depakin Chrono increases the plasma concentration of phenobarbital due to its inhibitory effect on hepatic metabolism, which leads to drowsiness, especially in children. Therefore, patients should be clinically monitored during the first 15 days of taking combination therapy with an immediate reduction in the dose of phenobarbital in case of drowsiness, and, if necessary, determination of the plasma concentration of phenobarbital is also recommended.

- Primidon

Depakine® Chrono increases the plasma concentration of primidone and enhances its side effects (such as drowsiness). This interaction stops with long-term treatment. It is recommended to conduct clinical monitoring, especially at the beginning of combination therapy, and, if necessary, to adjust the dose of primidone.

-Phenytoin

Depakin Chrono reduces the total concentration of phenytoin in plasma. In particular, it leads to an increase in the free fraction of phenytoin, with possible signs of overdose (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended. When determining the concentration of phenytoin in plasma, it is necessary to measure the concentration of the unbound form.

- Carbamazepine

In patients taking sodium valproate / valproic acid with carbamazepine, clinical toxicity was observed, which is associated with a possible increase in the toxicity of carbamazepine under the influence of sodium valproate / valproic acid. Therefore, clinical monitoring is recommended, especially at the beginning of combination therapy, as well as dose adjustment, if necessary.

- Lamotrigine

The risk of rash may be increased when lamotrigine is co-administered with valproic acid if lamotrigine is added to valproic acid.

Sodium valproate may decrease the metabolism of lamotrigine and increase its mean half-life. If necessary, the dose of lamotrigine should be reduced.

- Zidovudine

Sodium valproate/valproic acid may cause a significant increase in plasma concentrations of zidovudine, with an increased risk of zidovudine toxicity.

Effect of other drugs on valproic acid

Antiepileptic drugs with enzyme-inducing action (especially phenytoin, phenobarbital and carbamazepine) reduce the serum concentrations of valproic acid. In the case of combination therapy, doses of drugs should be adjusted according to the clinical response and the concentration of valproic acid in the blood.

When felbamate is combined with sodium valproate, an increase in the concentration of valproic acid in serum may be observed. Monitoring of plasma concentrations is necessary.

Mefloquine enhances the metabolism of valproic acid; in addition, it has a convulsive effect, which leads to the risk of epileptic seizures when taking two drugs at the same time.

Simultaneous use of the drug Depakine® Chrono with drugs that have a high ability to bind to proteins (for example, acetylsalicylic acid) can lead to an increase in the concentration of the unbound form of valproic acid in plasma.

The simultaneous use of cimetidine or erythromycin is likely to lead to an increase in the concentration of valproic acid (due to a decrease in the metabolism of valproic acid in the liver).

A decrease in the concentration of valproic acid in the blood, in combination with convulsions, was sometimes observed in patients taking valproate simultaneously with antibiotics of the carbapenem group (panipenem / meropenem / imipenem, etc.). If these antibiotics are needed, plasma concentrations of valproic acid should be monitored more closely.

Rifampicin can reduce blood levels of valproate, resulting in no therapeutic effect. With the simultaneous use of valproate with rifampicin, dose adjustment of valproate may be necessary.

Other interactions

Since valproic acid does not normally have an enzyme-inducing effect, it does not reduce total plasma concentrations of estrogen and progesterone in women using hormonal contraception. For the same reason, valproate does not reduce total plasma concentrations of vitamin K antagonists.

However, Depakine® Chrono may increase the level of the free fraction of warfarin due to competitive binding to albumin. For this reason, careful monitoring of the prothrombin index is necessary in patients receiving vitamin K antagonists.

The simultaneous use of valproate and topiramate has been associated with encephalopathy and/or hyperammonemia. Patients receiving these two drugs should be closely monitored for signs and symptoms of hyperammonaemic encephalopathy.

special instructions

Although sodium valproate rarely causes immune system symptoms, the benefit/risk ratio must be carefully weighed before prescribing the drug to patients with systemic lupus erythematosus.

Before starting treatment, it is necessary to conduct an examination of liver function ( see "Side effects"), after which periodic monitoring should be carried out for 6 months, especially for patients at risk (see. "Side effects"). It should be emphasized that there is often an isolated and transient increase in transaminase activity, without clinical manifestations, especially at the beginning of treatment. In this case, it is necessary to conduct a more complete set of laboratory tests (in particular, the determination of the prothrombin index). It may be necessary to change the dose, and depending on the change in values, it will be necessary to re-monitor liver function.

Very rare cases of severe pancreatitis, sometimes fatal, have been reported. The risk is especially high for young children and decreases with age. Risk factors include severe seizures, neurological deficits, and multidrug anticonvulsant therapy. The risk of death increases if, simultaneously with the development of pancreatitis, a patient has a decrease in liver function.

Patients experiencing acute abdominal pain should be seen by a doctor as soon as possible. In the presence of pancreatitis, sodium valproate should be discontinued.

For children under 3 years of age, Depakin® should only be prescribed as monotherapy, and therapy should not be started until the clinical benefit of taking the drug is compared with the risk of developing liver disease or pancreatitis in patients of this age group.

As a precautionary measure due to the risk of hepatotoxicity, patients should not take salicylic acid derivatives concomitantly with Depakine®.

In patients with impaired renal function, serum concentrations of unbound valproic acid may increase; in this case, the dose should be reduced.

Before a patient undergoes surgery or if spontaneous bleeding or hematoma occurs, a blood test (complete blood count, including platelet count, bleeding time, and clotting time) should be performed before starting treatment ( see "Side effects").

If there is a suspicion of a deficiency of enzymes involved in the urea cycle, before starting treatment, it is necessary to analyze metabolic functions due to the risk of hyperammonemia under the action of valproate.

The patient should be informed of the risk of weight gain at the start of treatment and appropriate measures should be taken to reduce this risk (see "Side Effects").

Women of childbearing age

The decision to use the drug Depakine® Chrono in women of childbearing age should be made only after a very careful analysis, if the benefits of taking this drug outweigh the risk of congenital anomalies in the fetus. Such a decision should be made before the first appointment of the drug Depakine® Chrono, as well as if a woman already taking the drug is planning a pregnancy.

Suicidal thoughts and behavior

Suicidal thoughts and behavior have been reported in patients receiving antiepileptic drugs for several indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a slight increase in the risk of suicidal thoughts and behavior. The mechanism of this effect is not known.

Thus, it is necessary to monitor patients for the presence of suicidal thoughts and behavior, and it is necessary to prescribe appropriate treatment. Patients (and their caregivers) should be informed that they are advised to seek immediate medical attention if suicidal thoughts or behavior occur.

Pregnancy

During pregnancy, tonic-clonic seizures and maternal status epilepticus with hypoxia carry an extremely high risk of death for the mother and unborn child.

The risk associated with the use of valproate

The teratogenic effect of the drug has been demonstrated in preclinical studies.

In humans: Available evidence suggests a higher incidence of minor or major malformations, particularly neural tube defects, craniofacial defects, limb malformations, cardiovascular malformations, and multiple anomalies involving various body systems in children born to mothers with epilepsy who took valproate, compared with the frequency of developmental defects that occur after the mother took some other antiepileptic drugs.

These data suggest that the use of polytherapy with antiepileptic drugs, including valproate, causes a higher risk of teratogenicity than the use of monotherapy with valproate alone.

There is some evidence of an association between intrauterine exposure to valproate and the risk of developmental delay, especially with regard to verbal abilities. Developmental delay is often associated with malformations and/or signs of dysmorphism. However, establishing a causal relationship is difficult due to the presence of possible confounding factors, such as low maternal or paternal intelligence, genetic, social and environmental factors, and poor control of maternal seizures during pregnancy.

Autism spectrum disorders have also been reported in children exposed to valproate in utero.

Given the above data

Women of childbearing age should be informed about the risks and benefits of using valproate during pregnancy.

Before prescribing Depakin® Chrono for the first time, and also, if a woman already taking Depakin® Chrono is planning a pregnancy, a specialist consultation is required. However, physicians are strongly encouraged to discuss reproductive issues with their patients.

If a woman is planning a pregnancy, a re-evaluation of the need for therapy with Depakin® Chrono is required, regardless of the indications for use. When taking the drug for the treatment of bipolar disorders, it is necessary to consider the possibility of discontinuing the prophylactic administration of the drug Depakine® Chrono. If, after a thorough assessment of the risks and benefits of prescribing the drug for any of the indications for use, Depakin® Chrono continues to be taken during pregnancy, it is recommended to take Depakin® Chrono at the minimum effective dose in several doses during the day. The use of a sustained release formula may be preferred over any other form of treatment.

In addition, it is recommended that appropriate doses of folic acid (eg, 5 mg per day) be started prior to pregnancy, if necessary, to minimize the risk of developing neural tube defects.

Specialized prenatal monitoring is recommended to detect the possible occurrence of neural tube defects or other malformations.

Risk in newborns

Exceptional cases of hemorrhagic syndrome have been reported in newborns whose mothers took sodium valproate/valproic acid during pregnancy. These cases of hemorrhagic syndrome are associated with hypofibrinogenemia. There have also been cases of afibrinogenemia, sometimes fatal. However, this syndrome must be distinguished from a decrease in the level of vitamin K-dependent factors that occurs under the influence of phenobarbital and enzyme inducers.

Therefore, newborns need to conduct a study of the number of platelets, the level of fibrinogen in the blood plasma, as well as tests for coagulation and clotting factors.

Lactation

The excretion of sodium valproate into breast milk is about 1-10% of the serum concentration. The drug may exhibit pharmacological effects in neonates. Breastfeeding should be stopped.

Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms Depakine® Chrono affects the ability to drive a car and operate machinery due to possible undesirable effects.

Patients should also be warned of the risk of drowsiness, especially if they are taking multiple anticonvulsants or concomitant benzodiazepines (see Drug Interactions).

Overdose

Symptoms: signs of acute massive overdose usually include mild to profound coma, muscle hypotension, hyporeflexia, miosis, respiratory failure, and metabolic acidosis.

Massive overdose can lead to death, however, usually the prognosis for overdose is favorable.

However, symptoms may vary, and convulsions have been reported in the presence of very high plasma concentrations of valproate.

Cases of intracranial hypertension associated with cerebral edema have been described.

Treatment: inpatient care for overdose should include gastric lavage, which is effective for 10-12 hours after taking the drug, as well as monitoring the state of the cardiovascular and respiratory systems.

Naloxone has been successfully used in isolated cases. In case of massive overdose, hemodialysis and hemoperfusion have been successfully used.

Release form and packaging

50 tablets in a polypropylene container with a polyethylene stopper with a desiccant. 2 containers, together with instructions for medical use in the state and Russian languages, are put into a cardboard box.

Storage conditions

Carefully. With diseases of the liver and pancreas in history. During pregnancy. With congenital fermentopathy. With oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia). With renal failure (dose adjustment required). With hypoproteinemia. In patients receiving multiple anticonvulsants due to an increased risk of liver damage. Concomitant use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, buterophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures). With the simultaneous use of antipsychotics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines (the possibility of potentiating their effects). With the simultaneous administration of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine (due to pharmacokinetic interactions at the level of metabolism or binding to plasma proteins, changes in plasma concentrations or these drugs and / or valproic acid, for more details see the section "Interaction with other drugs"). With the simultaneous use of carbamazepine, the risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid). With the simultaneous use of topiramate (risk of developing encephalopathy). Pregnancy and lactation period. Pregnancy. The risk associated with the development of epileptic seizures during pregnancy. During pregnancy, the development of generalized tonic-clonic seizures, status epilepticus with the development of hypoxia may pose a particular risk for both the mother and the fetus due to the possibility of death. The risk associated with the use of the drug during pregnancy. Experimental reproductive toxicity studies in mice, rats, and rabbits have demonstrated that valproic acid is teratogenic. Available clinical data confirm that children born to mothers with epilepsy treated with valproic acid have an increased incidence of intrauterine developmental disorders of varying severity (neural tube malformations; craniofacial deformities; malformations of the extremities, cardiovascular system; a also multiple intrauterine malformations affecting different organ systems) compared with the frequency of their occurrence when pregnant women take some other antiepileptic drugs. Available data suggest an association between intrauterine exposure to valproic acid and the risk of developmental delay (especially speech development) in children born to mothers with epilepsy who took valproic acid. Developmental delay is often combined with malformations and dysmorphic phenomena. However, in cases of developmental delay in such children, it is difficult to accurately establish a causal relationship with the use of valproic acid due to the possibility of simultaneous influence of other factors, such as the low level of intelligence of the mother or both parents; genetic, social factors, environmental factors; insufficient effectiveness of treatment aimed at preventing epileptic seizures in the mother during pregnancy. Various autistic disorders have also been reported in children exposed to valproic acid in utero. Both valproic acid monotherapy and combination therapy with valproic acid inclusion are associated with poor pregnancy outcomes, but combination antiepileptic therapy with valproic acid has been reported to be associated with a higher risk of adverse pregnancy outcomes compared with valproic acid monotherapy. In connection with the above, the drug should not be used during pregnancy and in women of childbearing age unless absolutely necessary. Its use is possible, for example, in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them. The question of the need to use the drug or the possibility of refusing to use it should be decided before starting the use of the drug or reconsidered if the woman receiving the drug is planning a pregnancy. Women of childbearing age should use effective contraception during treatment with the drug. Women of childbearing age should be informed about the risks and benefits of using valproic acid during pregnancy. If a woman is planning a pregnancy or she is diagnosed with pregnancy, then the need for treatment with valproic acid should be reassessed depending on the indications. When bipolar disorder is indicated, consideration should be given to discontinuing treatment with valproic acid. When epilepsy is indicated, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the benefit-risk ratio. If, after a reassessment of the benefit-risk ratio, treatment with the drug should still be continued during pregnancy, then it is recommended to use it in the minimum effective daily dose, divided into several doses. It should be noted that during pregnancy, the use of slow-release dosage forms of the drug is preferable. One month before conception and within 2 months after it, folic acid (at a dose of 5 mg per day) should be added to antiepileptic treatment, as this can minimize the risk of neural tube defects. Continuous special prenatal monitoring should be carried out to identify possible malformations of the neural tube or other malformations of the fetus. risk for newborns. It was reported about the development of isolated cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with hypofibrinogenemia and is possibly due to a decrease in the content of blood clotting factors. Fatal afibrinogenemia has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes. Therefore, in newborns born to mothers treated with valproic acid, it is imperative to determine the number of platelets in the blood, plasma fibrinogen concentration, blood clotting factors and a coagulogram. Cases of hypoglycemia have been reported in newborns whose mothers took valproic acid during the third trimester of pregnancy. breastfeeding period. Excretion of valproic acid into breast milk is low, its concentration in milk is 1-10% of its concentration in blood serum. Based on literature data and little clinical experience, mothers may plan to breastfeed when monotherapy with the drug, but the side effect profile of the drug, especially the hematological disorders caused by it, should be taken into account. Severe liver damage. predisposing factors. Clinical experience shows that patients at risk are patients receiving several antiepileptic drugs at the same time, children under three years of age with severe seizures, especially against the background of brain damage, mental retardation and / or congenital metabolic or degenerative diseases. After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the age of the patient increases. In most cases, liver damage occurred within the first 6 months of treatment. Symptoms suggestive of liver damage. For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, attention should be paid to the appearance of the following symptoms, which may precede the onset of jaundice, especially in patients at risk: non-specific symptoms, especially those of sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by recurrent vomiting and abdominal pain; recurrence of seizures in patients with epilepsy. Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of the symptoms to the attending physician. In the event of their occurrence, patients should immediately conduct a clinical examination and laboratory tests of liver function tests. Identification. Determination of liver function tests should be carried out before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative studies reflect the state of the protein-synthetic function of the liver, especially the prothrombin index. Confirmation of a deviation from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of transaminases) requires discontinuation of the drug. As a precaution, if patients received salicylates at the same time, their intake should also be discontinued, since they are metabolized along the same metabolic pathway as valproic acid. Pancreatitis. Children are at an increased risk of developing pancreatitis, with increasing age of the child the risk decreases. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for developing pancreatitis. Liver failure associated with pancreatitis increases the risk of death. Patients who develop severe abdominal pain, nausea, vomiting, and/or anorexia should be evaluated immediately. If the diagnosis of 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 initiated. 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. The mechanism of this effect is unknown. Therefore, patients receiving the drug should be constantly monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be carried out. Patients and their caregivers are advised if the patient has suicidal thoughts or attempts to seek immediate medical attention. Carbapenems. The simultaneous use of carbapenems is not recommended. Women of childbearing age. When using the drug in women of childbearing age, it is necessary to exclude pregnancy and make sure that the woman uses a reliable method of contraception. Methods for monitoring the safety of drug treatment. Before starting the use of the drug and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, a study of liver function should be performed. As with most antiepileptic drugs, a slight increase in the activity of "liver" enzymes is possible, especially at the beginning of treatment, which proceeds without clinical manifestations and is transient. In these patients, a more detailed study of laboratory parameters, including the prothrombin index, is necessary, and dose adjustment of the drug may be required, and, if necessary, repeated clinical and laboratory examinations. Before starting therapy or if a surgical operation is necessary, in case of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to conduct a hematological blood test (determine the leukocyte blood count, including platelet count; bleeding time and coagulogram). Children (information refers to dosage forms of the drug Depakine, which can be taken by children under the age of three). In children younger than three years of age, if necessary, the use of the drug is recommended for its use in monotherapy and in the dosage form recommended for children. At the same time, 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 should be weighed when using it. In children younger than 3 years, the simultaneous use of salicylates should be avoided due to the risk of hepatotoxicity and bleeding. Renal 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 not possible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient. Deficiency of carbamide cycle enzymes. If a deficiency of urea cycle enzymes is suspected, the use of valproic acid is not recommended. Several cases of hyperammonemia with stupor or coma have been described in these patients. In these cases, metabolic studies should be performed prior to treatment with valproic acid. In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of neonatal or infant death, metabolic studies should be performed prior to initiating treatment with valproic acid, in particular determination ammonemia (the presence of ammonia and its compounds in the blood) on an empty stomach and after eating. Patients with systemic lupus erythematosus. Although it has been shown that during treatment with the drug, violations of the immune system are extremely rare, the potential benefit of its use must be weighed against the potential risk when prescribing the drug to patients with systemic lupus erythematosus. Increase in body weight. Patients should be warned of the risk of weight gain at the start of treatment, and measures, mainly dietary, should be taken to minimize this phenomenon. Ethanol. During treatment with valproic acid, the use of ethanol is not recommended. Influence on the ability to drive vehicles or engage in other potentially hazardous activities. Patients should be warned about the risk of drowsiness, especially in the case of combined anticonvulsant therapy or when valproic acid is combined with benzodiazepines. During the period of treatment, it is necessary to be careful and discuss with the attending physician the possibility of driving vehicles and engaging in other potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

Composition and form of release

Depakine® chrono, 300 mg

• active substances: sodium valproate - 199.8 mg; valproic acid - 87 mg;
• excipients: methylhydroxypropylcellulose 4000 mPa s (hypromellose) - 105.6 mg; ethyl cellulose (20 mPa s) - 7.2 mg; sodium saccharinate - 6 mg; silicon dioxide colloidal hydrated - 32.4 mg; methylhydroxypropylcellulose 6 mPa s (hypromellose) - 4.8 mg; 30% dispersion of polyacrylate - 16 mg; macrogol 6000 - 4.8 mg; talc - 4.8 mg; titanium dioxide - 0.8 mg.

Depakine® chrono, 500 mg

Coated tablets, prolonged action - 1 tab.:

• active substances: sodium valproate - 333 mg; valproic acid - 145 mg;
• excipients: silicon dioxide colloidal anhydrous - 4 mg; methylhydroxypropylcellulose 4000 mPa s (hypromellose) - 176 mg; ethyl cellulose (20 mPa s) - 12 mg; sodium saccharin - 10 mg; silicon dioxide colloidal hydrated - 50 mg; methylhydroxypropylcellulose 6 mPa s (hypromellose) - 7.2 mg; 30% dispersion of polyacrylate - 24 mg; macrogol 6000 - 7.2 mg; talc - 7.2 mg; titanium dioxide - 1.2 mg.

Long-acting film-coated tablets, 300 mg. 50 tab. in a polypropylene bottle, closed with a PE stopper, with a desiccant. 2 vials placed in a cardboard box.

Long-acting film-coated tablets, 500 mg. 30 tab. in a polypropylene bottle, closed with a PE stopper, with a desiccant. 1 vial placed in a cardboard box.

Description of the dosage form

Oblong film-coated tablets, almost white in color, scored on both sides.

pharmachologic effect

Antiepileptic, anticonvulsant, normothymic.

Pharmacokinetics

Absorption

The bioavailability of sodium valproate and valproic acid when taken orally is close to 100%.

When taking the drug Depakin® chrono 500 mg at a dose of 1000 mg / day, Cmin in plasma is (44.7 ± 9.8) μg / ml, and Cmax in plasma is (81.6 ± 15.8) μg / ml. Tmax is 6.58 ± 2.23 hours. Css is achieved within 3-4 days of regular administration of the drug.

The average therapeutic range of serum concentrations of valproic acid is 50–100 mg/L. With a reasonable need to achieve higher plasma concentrations, the ratio of the expected benefit and the risk of side effects, especially dose-dependent ones, should be carefully weighed. at concentrations above 100 mg/l, an increase in side effects is expected up to the development of intoxication. At plasma concentrations above 150 mg / l, a dose reduction is required.

Distribution

Vd depends on age and is usually 0.13-0.23 l / kg, or in young people - 0.13-0.19 l / kg.

Communication with blood plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, the relationship with blood plasma proteins decreases. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid may increase to 8.5–20%.

With hypoproteinemia, the total concentration of valproic acid (free + plasma protein-bound fraction) may not change, but may also decrease due to an increase in the metabolism of the free (non-plasma protein-bound) fraction of valproic acid.

Valproic acid penetrates into the cerebrospinal fluid and the brain. The concentration of valproic acid in the CSF is 10% of the corresponding concentration in the blood serum.

Valproic acid passes into the breast milk of nursing mothers. In the state of reaching Css of valproic acid in the blood serum, its concentration in breast milk is from 1 to 10% of its concentration in the blood serum.

Metabolism

Metabolism is carried out in the liver by glucuronidation, as well as beta, omega and omega1 oxidation. More than 20 metabolites have been identified, metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on enzymes that are part of the cytochrome P450 metabolic system: unlike most other antiepileptic drugs, valproic acid does not affect the degree of both its own metabolism and the metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

breeding

Valproic acid is predominantly excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted by the kidneys unchanged.

The plasma clearance of valproic acid in patients with epilepsy is 12.7 ml/min.

T1 / 2 is 15-17 hours. When combined with antiepileptic drugs that induce microsomal liver enzymes, the plasma clearance of valproic acid increases, and T1 / 2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs. The values ​​of T1 / 2 in children older than 2 months of age are close to those in adults.

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

Features of pharmacokinetics during pregnancy

With an increase in Vd of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. At the same time, despite taking the drug at a constant dose, a decrease in serum concentrations of valproic acid is possible. In addition, during pregnancy, the relationship of valproic acid with plasma proteins may change, which can lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum.

Compared to the enteric-coated form, the extended-release form at equivalent doses is characterized by the following:

• no absorption delay time after ingestion;
• prolonged absorption;
• identical bioavailability;
• lower Cmax (decrease in Cmax by about 25%), but with a more stable plateau phase from 4 to 14 hours after administration;
• more linear correlation between dose and plasma drug concentration.

Pharmacodynamics

An antiepileptic drug that has a central muscle relaxant and sedative effect.

Shows antiepileptic activity in various types of epilepsy. The main mechanism of its action seems to be associated with the effect of valproic acid on the GABAergic system: an increase in the content of GABA in the CNS and activation of GABAergic transmission.

Indications for use

adults

• treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs);
• treatment and prevention of bipolar affective disorders.

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

Contraindications for use

• hypersensitivity to sodium valproate, valproic acid, seminatrium valproate, valpromide or any of the components of the drug;
• acute hepatitis;
• chronic hepatitis;
• severe liver disease (especially drug-induced hepatitis) in the history of the patient and his close blood relatives;
• severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;
• severe violations of the liver or pancreas;
• hepatic porphyria;
• established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), such as Alpers-Huttenlocher syndrome and suspected defective diseases (POLG), in children under 2 years of age (refers to the use of dosage forms of the drug Depakine ® intended for use by children);
• combination with mefloquine;
• combination with St. John's wort;
• children under 6 years of age (risk of getting the tablet into the respiratory tract when swallowing).

With caution: a history of liver and pancreas diseases; pregnancy; congenital fermentopathy; oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia); renal failure (dose adjustment required); hypoproteinemia; patients taking multiple anticonvulsants (due to an increased risk of liver damage); concomitant use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, SSRIs, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures); simultaneous use of antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (the possibility of potentiating their effects); concomitant 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 (ritonavir, ritonavir) , cholestyramine (due to pharmacokinetic interactions at the level of metabolism or association with plasma proteins, plasma concentrations of these drugs and / or valproic acid may change); simultaneous use of carbamazepine (risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid), topiramate or acetazolamide (risk of developing encephalopathy); existing insufficiency of carnitine palmitoyltransferase (CPT) type II (higher risk of developing rhabdomyolysis when taking valproic acid).

Use in pregnancy and children

The drug Depakine® chrono should not be used in female children and adolescents, women of childbearing age and pregnant women, unless other methods of treatment are ineffective or not tolerated by the patient. Every effort should be made to transfer a patient planning a pregnancy prior to conception to an appropriate alternative treatment, if possible.

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

The risk associated with the use of the drug Depakine® chrono during pregnancy. Experimental reproductive toxicity studies 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 neural tube defects, craniofacial deformities, limb and CVS malformations, hypospadias, and multiple malformations affecting different organ systems, in children born to mothers who took valproic acid during pregnancy compared with their frequency when taken during pregnancy with a number of other antiepileptic drugs. 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 monotherapy with phenytoin, 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 risk of severe congenital malformations in the general population, which was 2–3%. This risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk.

Disorders of mental and physical development. It has been shown that intrauterine exposure to valproic acid may have undesirable effects on the mental and physical development of children exposed to such exposure. Apparently, this risk is dose-dependent, but it is not possible to establish a threshold dose below which there is no such risk. The exact gestational period for the risk of developing these effects has not been established, and the risk cannot be ruled out throughout pregnancy. Studies of preschool children exposed to intrauterine exposure to valproic acid have shown that up to 30-40% of these children had a delay in early development (including a delay in mastering the skills of walking and speech development), as well as lower intellectual abilities, poor speech skills (own speech and speech comprehension) and memory problems.

The intelligence quotient (IQ index), measured in children aged 6 years with a history of intrauterine exposure to valproate, was on average 7-10 points lower than in children exposed to intrauterine exposure to other antiepileptic drugs. Although the role of other factors that can 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 the mother's IQ index. Data on long-term outcomes are limited. There is evidence that children exposed to valproic acid in utero have an increased risk of developing a spectrum of autistic disorders (approximately 3-fold increased risk), including childhood autism (approximately 5-fold increased risk). Limited evidence suggests that children exposed to valproic acid in utero are more likely to develop attention deficit/hyperactivity disorder.

Valproic acid monotherapy and valproic acid combination therapy are associated with poor pregnancy outcomes, but combination antiepileptic therapy that includes valproic acid has been reported to be associated with a higher risk of adverse pregnancy outcome compared to valproic acid monotherapy (i.e. risk the development of disorders in the fetus is less with the use of 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 foregoing, the drug Depakine® chrono should not be used during pregnancy and in women of childbearing potential unless absolutely necessary, i.e. its use is possible only in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

The question of the need to use the drug Depakin® chrono or the possibility of refusing to use it should be decided before the start of the use of the drug or reconsidered if a woman taking Depakin® chrono is planning a pregnancy.

Women should be informed about the need for pregnancy planning and monitoring.

Women of childbearing potential should use effective contraceptive methods during treatment with Depakine Chrono.

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

If a woman is planning a pregnancy or is diagnosed with pregnancy, then the need for treatment with valproic acid should be reassessed depending on the indication (see below):

• if bipolar disorder is indicated, consideration should be given to discontinuing treatment with valproic acid;
• when epilepsy is indicated, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the benefit-risk ratio. If, after reassessing the balance of benefits and risks, treatment with Depakine® chrono should still be continued during pregnancy, then it is recommended to use it at the minimum effective daily dose, divided into several doses. It should be noted that during pregnancy, the use of sustained-release dosage forms is more preferable.

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 on congenital malformations that occur under the influence of valproic acid. It is necessary to carry out a permanent (including in the III trimester of pregnancy) special prenatal diagnostics to identify possible malformations of the neural tube or other fetal malformations, including detailed ultrasound.

Before childbirth. Prior to delivery, the mother should undergo coagulation tests, in particular the determination of platelet count, fibrinogen concentration and clotting time (APTT).

risk for newborns. It was reported about the development of isolated cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia, and/or a decrease in other blood clotting factors. Afibrinogenemia has also been reported, which could be fatal. 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 received treatment with valproic acid during pregnancy, coagulation tests should be performed (determine the number of platelets in peripheral blood, plasma fibrinogen concentration, blood clotting factors and a coagulogram).

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

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

Neonates whose mothers took valproic acid in the last trimester of pregnancy may experience withdrawal syndrome (in particular, the appearance of agitation, irritability, hyperreflexia, trembling, hyperkinesia, muscle tone disorders, tremors, convulsions and difficulty feeding).

Fertility

In connection with 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. In men, valproic acid can decrease sperm motility and impair fertility.

These fertility disorders have been found to be reversible after discontinuation of treatment.

breastfeeding period. Excretion of valproic acid into breast milk is low, the concentration in milk is 1-10% of its concentration in blood 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 literature data and little clinical experience, breastfeeding with monotherapy with Depakine chrono can be considered, but the side effect profile of the drug, especially the hematological disorders it causes, should be taken into account.

Side effects

To indicate the frequency of development of adverse reactions (HP), the WHO classification is used: very often ≥10%; often ≥1 and

Congenital, hereditary and genetic disorders: teratogenic risk.

From the blood and lymphatic system: often - anemia, thrombocytopenia; infrequently - pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can be with or without bone marrow depression. After discontinuation of the drug, the blood picture returns to normal; rarely - disorders of bone marrow hematopoiesis, including isolated aplasia / hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis; a decrease in the content of blood coagulation factors (at least one), deviations from the norm of blood coagulability indicators (such as an increase in PT, APTT, thrombin time, INR). The appearance of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct an examination.

Laboratory and instrumental data: rarely - biotin deficiency / biotinidase deficiency.

From the nervous system: very often - tremor; often - extrapyramidal disorders, stupor *, drowsiness, convulsions *, memory impairment, headache, nystagmus; dizziness (with intravenous administration, dizziness may occur within a few minutes and disappear spontaneously within a few minutes); infrequently - coma *, encephalopathy *, lethargy *, reversible parkinsonism, ataxia, paresthesia, worsening of seizures; rarely - reversible dementia, combined with reversible brain atrophy, cognitive disorders; frequency unknown - sedation.

On the part of the organ of hearing and labyrinth disorders: often - reversible and irreversible deafness.

On the part of the organ of vision: the frequency is unknown - diplopia.

On the part of the respiratory system, chest and mediastinum: infrequently - pleural effusion.

From the digestive system: very often - nausea; often - vomiting, changes in the gums (mainly gingival hyperplasia), stomatitis, epigastric pain, diarrhea, which often occur in some patients at the beginning of treatment, but usually disappear after a few days and do not require discontinuation of therapy (frequent reactions from the digestive systems can be lowered by taking the drug during or after a meal); infrequently - pancreatitis, sometimes with a fatal outcome (the development of pancreatitis is possible during the first 6 months of treatment; in case of acute abdominal pain, it is necessary to control the activity of serum amylase; the frequency is unknown - abdominal cramps, anorexia, increased appetite.

From the side of the kidneys and urinary tract: infrequently - renal failure; rarely - enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of damage to the proximal renal tubules with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the development mechanism of which is still unclear.

From the skin and subcutaneous tissues: often - hypersensitivity reactions, such as urticaria, itching; transient (reversible) and / or dose-dependent pathological hair loss (alopecia), including androgenetic alopecia against the background of developed hyperandrogenism, polycystic ovaries (see below From the genital organs and mammary glands and From the endocrine system), as well as alopecia against the background of developed hypothyroidism (see below From the side of the endocrine system, From the side of the nails and the nail bed); infrequently - angioedema, rash, disorders of the hair (such as a violation of the normal structure of the hair, a change in hair color, abnormal hair growth (the disappearance of waviness and curly hair, or vice versa - the appearance of curly hair in individuals with initially straight hair); rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

On the part of the musculoskeletal and connective tissue: infrequently - a decrease in BMD, osteopenia, osteoporosis and fractures in patients taking Depakine for a long time. The mechanism of influence of Depakin® preparations on bone tissue metabolism has not been established; rarely - systemic lupus erythematosus, rhabdomyolysis.

From the endocrine system: infrequently - a syndrome of inadequate secretion of ADH, hyperandrogenism (hirsutism, virilization, acne, male pattern alopecia and / or an increase in the concentration of androgens in the blood); rarely - hypothyroidism.

On the part of metabolism and nutrition: often - hyponatremia, weight gain (weight gain should be carefully monitored, since weight gain is a factor contributing to the development of polycystic ovary syndrome); rarely - hyperammonemia (there may be cases of isolated and moderate hyperammonemia without changes in liver function indicators that do not require discontinuation of treatment. Hyperammonemia has also been reported, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and other neurological symptoms), which required discontinuation taking valproic acid and conducting an additional examination, obesity.

Benign, malignant and indeterminate tumors (including cysts and polyps): rarely - myelodysplastic syndromes.

From the side of the vessels: often - bleeding and hemorrhage; infrequently - vasculitis.

General disorders and changes at the injection site: infrequently - hypothermia, mild peripheral edema.

On the part of the liver and biliary tract: often - liver damage: abnormal 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 coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of hepatic transaminases in the blood; liver failure, in exceptional cases - fatal; monitoring of patients for possible violations of liver function is necessary.

From the genital organs and mammary glands: often - dysmenorrhea; infrequently - amenorrhea; rarely - male infertility, polycystic ovaries; frequency unknown - irregular menstruation, breast enlargement, galactorrhea.

Mental disorders: often - a state of confusion, hallucinations, aggressiveness **, agitation **, impaired attention **; depression (when combining valproic acid with other anticonvulsants); rarely - behavioral disorders**, psychomotor hyperactivity**, learning disabilities**; depression (with monotherapy with valproic acid).

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

** Adverse reactions, mainly observed in pediatric patients.

drug interaction

Effect of valproic acid on other drugs

Antipsychotics, MAO inhibitors, antidepressants, benzodiazepines. Valproic acid may potentiate the action of other psychotropic drugs such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, when they are used simultaneously with valproic acid, careful medical supervision is recommended and, if necessary, dose adjustment.

lithium preparations. Valproic acid does not affect serum lithium concentrations.

Phenobarbital. Valproic acid increases plasma concentrations of phenobarbital (by reducing its hepatic metabolism), and therefore the development of a sedative effect of the latter is possible, especially in children. Therefore, careful medical monitoring of the patient is recommended during the first 15 days of combination therapy with an immediate reduction in the dose of phenobarbital in the event of a sedative effect and, if necessary, the determination of plasma concentrations of phenobarbital.

Primidon. Valproic acid increases plasma concentrations of primidone with an increase in its side effects (including sedation); with prolonged treatment, these symptoms disappear. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy with dose adjustment of primidone if necessary.

Phenytoin. Valproic acid reduces total plasma concentrations of phenytoin. In addition, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing overdose symptoms (valproic acid displaces phenytoin from its association with plasma proteins and slows down its hepatic metabolism). Therefore, careful clinical monitoring of the patient and determination of the concentrations of phenytoin and its free fraction in the blood is recommended.

Carbamazepine. With the simultaneous use of valproic acid and carbamazepine, an increase in the plasma concentration of the active metabolite of carbamazepine with signs of overdose is possible. It was reported about the occurrence of clinical manifestations of toxicity of carbamazepine, tk. 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 appropriate dose adjustment of carbamazepine if necessary.

Lamotrigine. Valproic acid slows down the metabolism of lamotrigine in the liver and increases T1 / 2 of lamotrigine by almost 2 times. This interaction can lead to increased toxicity of lamotrigine, in particular to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical observation is recommended and, if necessary, a correction (reduction) in the dose of lamotrigine.

Zidovudine. Valproic acid can increase the plasma concentrations of zidovudine, which leads to an increase in the toxicity of zidovudine, especially hematological effects, by slowing down its metabolism by valproic acid. Constant clinical observation and monitoring of laboratory parameters is necessary. A blood test should be done to exclude the development of anemia during the first 2 months of combination therapy.

Felbamat. Valproic acid can reduce the mean clearance of felbamate by 16%.

Olanzapine. Valproic acid may decrease plasma concentrations of olanzapine.

Rufinamide. Valproic acid can lead to an increase in the plasma concentration of rufinamide. This increase depends on the concentration of valproic acid in the blood. Caution should be exercised, especially in children, as this effect is more pronounced in this population.

Propofol. Valproic acid can lead to an increase in plasma concentrations of propofol. Consideration should be given to reducing the dose of propofol when co-administered with valproic acid.

Nimodipine (for oral administration and (by extrapolation) solution for parenteral administration). Strengthening the hypotensive effect of nimodipine due to the fact that the simultaneous use of nimodipine with valproic acid can increase plasma concentrations of nimodipine by 50% (due to inhibition of the metabolism of nimodipine by valproic acid).

Temozolomide. Co-administration of temozolomide with valproic acid results in a slight 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, primidone, phenobarbital, carbamazepine) reduce plasma concentrations of valproic acid. In the case of combination therapy, the doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

The concentration of metabolites of valproic acid in the blood serum may be increased if it is used simultaneously with phenytoin or phenobarbital. Therefore, patients treated with these two drugs should be closely monitored for signs and symptoms of hyperammonemia, as some metabolites of valproic acid can inhibit the enzymes of the urea cycle (urea cycle).

Aztreonam. The 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 this antibacterial drug and after its termination is necessary.

Felbamat. With the combination of felbamate and valproic acid, the clearance of valproic acid is reduced by 22–50% and, accordingly, plasma concentrations of valproic acid increase. Plasma concentrations of valproic acid should be monitored. Clinical monitoring and monitoring of laboratory parameters are necessary, and dose adjustment of valproate is possible during treatment and after discontinuation of felbamate.

Carbamazepine. It is possible to reduce the plasma concentration of valproic acid due to the acceleration of its metabolism in the liver by carbamazepine. Clinical observation, determination of plasma concentrations is necessary, and dose adjustment of both anticonvulsants is possible.

Lamotrigine. It is possible to increase the concentration of lamotrigine in plasma (due to the slowing down of lamotrigine metabolism in the liver by valproate). If the simultaneous use of these drugs is necessary, clinical monitoring is required.

Mefloquine. Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing convulsions, therefore, with their simultaneous use, the development of an epileptic seizure is possible.

St. John's wort preparations. With the simultaneous use of valproic acid and preparations of St. John's wort, a decrease in the anticonvulsant effectiveness of valproic acid is possible.

Drugs that have a high and strong connection with plasma proteins (acetylsalicylic acid). In the case of simultaneous use of valproic acid and drugs that have a high and strong connection with plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free fraction of valproic acid.

Indirect anticoagulants, including warfarin and other coumarin derivatives. With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of INR and prothrombin index is required.

Cimetidine, erythromycin. Serum concentrations of valproic acid may increase in the case of simultaneous use of cimetidine or erythromycin (as a result of slowing down its hepatic metabolism).

Carbapenems (panipenem, meropenem, imipenem). Decrease in the concentration of valproic acid in the blood with its simultaneous use with carbapenems: for 2 days of co-therapy, a 60-100% decrease in the concentration of valproic acid in the blood was observed, which was sometimes combined with the occurrence of seizures. The simultaneous use of carbapenems in patients with a selected dose of valproic acid should be avoided due to their ability to quickly and intensively reduce the concentration of valproic acid in the blood. If treatment with carbapenems cannot be avoided, blood levels of valproic acid should be closely monitored during and after treatment with carbapenems.

Rifampicin. Rifampicin can reduce the concentration of valproic acid in the blood, which leads to the 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. Protease inhibitors, such as lopinavir, ritonavir, reduce the plasma concentration of valproic acid while using it.

Colestyramine. Colestyramine can lead to a decrease in plasma concentrations of valproic acid when used simultaneously with it.

Other interactions

With topiramate or acetazolamide. The simultaneous use of valproic acid and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia. Patients taking these drugs concomitantly with valproic acid should be under close medical supervision for the development of symptoms of hyperammoniemic encephalopathy.

with quetiapine. The simultaneous use of valproic acid and quetiapine may increase the risk of developing neutropenia / leukopenia.

With estrogen-progestogenic drugs. Valproic acid does not have the ability to induce liver enzymes and, as a result, does not reduce the effectiveness of estrogen-progestogenic drugs in women using hormonal methods of contraception.

With ethanol and other potentially hepatotoxic drugs. When they are used simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid.

with clonazepam. The simultaneous use of clonazepam with valproic acid can lead in isolated cases to an increase in the severity of the absence status.

With myelotoxic drugs. With their simultaneous use with valproic acid, the risk of inhibition of bone marrow hematopoiesis increases.

Dosage

This medicine is for use only in adults and children over 6 years of age weighing more than 17 kg.

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

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

Tablets are taken without crushing or chewing them.

Dosing regimen for epilepsy

The daily dose is selected by the attending physician individually.

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

With monotherapy, the initial dose is usually 5-10 mg / kg, which is then gradually increased every 4-7 days at a rate of 5 mg valproic acid / kg to the dose necessary to achieve control of epileptic seizures.

Average daily doses (with prolonged use):

• for children 6–14 years old (body weight 20–30 kg) - 30 mg valproic acid / kg (600–1200 mg);
• for adolescents (body weight 40-60 kg) - 25 mg valproic acid / kg (1000-1500 mg);
• for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg valproic acid / kg (1200-2100 mg).

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

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

In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, you should not increase the daily dose above the recommended average daily dose before this time.

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

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

Most patients who are already taking a non-prolonged-release dosage form of Depakine can be transferred to the dosage form of this drug of prolonged action immediately or within a few days, while patients should continue to take the previously selected daily dose.

For patients who have previously taken antiepileptic drugs, the transfer to the drug Depakine® chrono should be carried out gradually, reaching the optimal dose within about 2 weeks. At the same time, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If such a drug is canceled, then its cancellation should be carried out gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, it is necessary to monitor the concentration of valproic acid in the blood within 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), reduce the daily dose of valproic acid . If necessary, the combination of valproic acid with other antiepileptic drugs should be added to the treatment gradually.

Dosing regimen for manic episodes in bipolar disorders

Adults. The daily dose is selected by the attending physician individually.

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

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

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

The use of the drug in special groups of patients

Female children and adolescents, women of childbearing potential and pregnant women. Treatment with Depakine chrono should be initiated 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 benefit-risk ratio should be carefully reassessed when treatment is regularly reviewed. It is preferable to use Depakine® preparations in monotherapy and in the lowest effective doses and, if possible, in sustained release dosage forms. During pregnancy, the daily dose should be divided into at least 2 single doses.

Elderly patients. 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 selected in accordance with the achievement of control over epileptic seizures.

Renal failure, and / or hypoproteinemia. In patients with renal insufficiency and / or hypoproteinemia, the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be considered and, if necessary, reduce the dose of valproic acid, focusing on dose selection mainly on the clinical picture, and not on the total content of valproic acid in serum (free fraction and plasma protein-bound fraction together) to avoid possible errors in dose selection.

Overdose

Symptoms: Clinical manifestations of acute massive overdose usually occur in the form of a coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis, excessive reduction in blood pressure and vascular collapse / shock.

Cases of intracranial hypertension associated with cerebral edema have been described.

The presence of sodium in the composition of valproic acid preparations in case of their overdose can lead to the development of hypernatremia.

With a massive overdose, a fatal outcome is possible, but the prognosis for an overdose is usually favorable.

Symptoms of overdose may vary; seizures have been reported at very high plasma concentrations of valproic acid.

Treatment: emergency care for overdose in a hospital should be the following: gastric lavage, which is effective within 10-12 hours after taking the drug. To reduce the absorption of valproic acid, it may be effective to take activated charcoal, incl. its introduction through a nasogastric tube. It is required to monitor the state of the cardiovascular system and the respiratory system and maintain effective diuresis. It is necessary to control the functions of the liver and pancreas. Respiratory depression may require mechanical ventilation. Naloxone has been used successfully in some cases. In very severe cases of massive overdose, hemodialysis and hemoperfusion have been effective.

Precautionary measures

Before starting the use of the drug Depakin® chrono and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, a study of liver function should be performed.

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

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

Severe liver damage

predisposing factors. There have been isolated reports of the development of severe liver damage, sometimes fatal. Clinical experience shows that the risk group includes patients taking several antiepileptic drugs at the same time; infants and children under three years of age with severe seizures, especially against the background of brain damage, mental retardation and / or congenital metabolic or degenerative diseases; patients simultaneously taking salicylates (because salicylates are metabolized along the same metabolic pathway as valproic acid).

After 3 years of age, the risk of liver damage is significantly reduced and decreases progressively as the age of the patient increases. In most cases, such liver damage occurred during the first 6 months of treatment, most often between the 2nd and 12th week of treatment and usually with the use of valproic acid as part of combination antiepileptic therapy.

Symptoms suggestive of liver damage. For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, attention should be paid to the following symptoms, which may precede the onset of jaundice, especially in patients at risk (see above):

• non-specific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;
• recurrence of seizures in patients with epilepsy.

Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of these symptoms to the attending physician. Patients should immediately undergo a clinical examination and laboratory testing of liver function tests.

Identification. Determination of liver function tests should be carried out before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative studies reflect the state of the protein-synthetic function of the liver, especially the determination of the prothrombin index. Confirmation of a 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 coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of hepatic transaminases), as well as the appearance of other symptoms indicating a lesion liver (see above), requires discontinuation of the drug Depakine chrono. As a precaution, if patients were taking salicylates at the same time, their intake 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 an increased risk of developing pancreatitis, with increasing age of the child, this risk decreases. Risk factors for developing pancreatitis may include severe seizures, neurological disorders, or anticonvulsant therapy. Liver failure associated with pancreatitis increases the risk of death.

Patients who develop severe abdominal pain, nausea, vomiting, and/or anorexia should be evaluated immediately. If the diagnosis of 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 initiated.

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

Notice to female patients. If pregnancy occurs, valproic acid preparations can cause serious harm to the unborn baby. It is always necessary to use effective methods of contraception during treatment. If a woman is planning a pregnancy or becomes pregnant, she should immediately inform her doctor.

Depakine Chrono should not be used in female children and adolescents, women of childbearing potential and pregnant women, unless alternative treatments are ineffective or not tolerated. This limitation is associated with a high risk of teratogenicity and impaired mental and physical development in children who have been exposed to valproic acid in utero. The benefit/risk ratio should be carefully reassessed in the following cases: during regular review of treatment, when the girl reaches puberty and urgently in case of planning or pregnancy in a woman taking valproic acid.

During treatment with valproic acid, women of childbearing potential should use reliable methods of contraception and be informed about the risks associated with taking Depakine chrono during pregnancy. To help the patient understand these risks, the doctor prescribing valproic acid to her should provide the patient with comprehensive information about the risks associated with taking Depakine chrono during pregnancy. In particular, the physician prescribing valproic acid must ensure that the patient understands:

• the nature and magnitude of the risks when using valproic acid during pregnancy, in particular teratogenic effects, as well as disorders of the mental and physical development of the child;
• the need to use effective contraception;
• the need for regular review of treatment;
• the need for urgent consultation with her doctor if she suspects that she is pregnant or suspects the possibility of pregnancy. A woman planning a pregnancy should definitely try, if possible, to transfer to an alternative treatment before she attempts to conceive. Treatment with valproic acid should only be continued after a physician experienced in the treatment of epilepsy and bipolar disorder has reassessed the benefit/risk balance of treatment for it.

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 an increase in the risk of suicidal thoughts and attempts by 0.19% in all patients taking antiepileptic drugs (including a 0.24% increase in this risk in patients taking antiepileptic drugs according to about epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown. Therefore, patients taking Depakine chrono should be constantly monitored for suicidal thoughts and attempts, and if they occur, appropriate treatment should be carried out. Patients and their caregivers are advised if the patient has suicidal thoughts or attempts to seek immediate medical attention.

Carbapenems

The simultaneous use of carbapenems is not recommended.

Patients with established or suspected mitochondrial diseases. Valproic acid can initiate or exacerbate the manifestations of the patient's mitochondrial diseases caused by mutations in mitochondrial DNA, as well as in the nuclear gene encoding the mitochondrial enzyme POLG. In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding POLG; for example, in patients with Alpers-Huttenlocher syndrome, valproic acid has been associated with a higher incidence of acute liver failure and liver-related deaths. Diseases due to POLG 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. In accordance with current clinical practice, testing for mutations in the POLG gene should be performed to diagnose such diseases.

A paradoxical increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures

As with other antiepileptic drugs, when taking valproic acid in some patients, instead of improving, a reversible increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures was observed. 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, monotherapy is recommended in the dosage form recommended for children. At the same time, 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 should be weighed when using it. In children under 3 years of age, the simultaneous use of valproic acid and salicylates should be avoided due to the risk of toxic effects on the liver.

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 not possible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Enzyme deficiency of the urea cycle (urea cycle)

If an enzyme 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 these patients. In these cases, metabolic studies should be performed prior to treatment with valproic acid. 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, in particular the determination of ammonemia, should be performed before treatment with valproic acid ( the presence of ammonia and its compounds in the blood) on an empty stomach and after meals.

Patients with systemic lupus erythematosus

Although it has been shown that during treatment with Depakine® chrono, violations of the immune system are extremely rare, the potential benefit of its use must be compared with the potential risk when using the drug in patients with systemic lupus erythematosus.

Weight gain

Patients should be warned about the risk of weight gain at the beginning of treatment, and the need to take measures, mainly the appointment of a diet to minimize this phenomenon.

Patients with diabetes

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

Patients infected with human immunodeficiency virus (HIV)

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

Patients with existing type II CBT deficiency

Patients with existing type II CBT deficiency should be warned about the higher risk of developing rhabdomyolysis while taking valproic acid.

During treatment with valproic acid, the use of ethanol is not recommended.

Other special instructions

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

In 1 tab. the drug Depakine® chrono 300 mg contains 1.2 mmol (27.6 mg) sodium; drug Depakine® chrono 500 mg - 2 mmol (46.1 mg) sodium. This should be taken into account in patients on a strict low sodium diet.

Influence on the ability to drive vehicles or engage in other potentially hazardous activities. Patients should be warned about the risk of drowsiness, especially in the case of combined anticonvulsant therapy or when Depakine® chrono is combined with benzodiazepines.

INN: Valproic acid

Manufacturer: Sanofi Winthrop Industry

Anatomical-therapeutic-chemical classification: Valproic acid

Registration number in the Republic of Kazakhstan: No. RK-LS-3 No. 021192

Registration period: 19.02.2015 - 19.02.2018

ALO (Included in the Free Outpatient Drug Supply List)

Instruction

Tradename

Depakine Chrono

International non-proprietary name

Valproic acid

Dosage form

Tablets, film-coated, prolonged release, divided, 500 mg

Compound

One tablet contains

active substances: sodium valproate 333 mg

valproic acid 145 mg,

Excipients: hypromellose 4000, ethylcellulose, sodium saccharin, colloidal silicon dioxide.

shell composition: hypromellose, macrogol 6000, talc, titanium dioxide (E171), polyacrylate dispersion 30%.

Description

Oblong, almost white film-coated tablets with a break line.

Pharmacotherapeutic group

Antiepileptic drugs. Fatty acid derivatives. Valproic acid.

ATX code N03AG01

Pharmacological properties

Pharmacokinetics

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

When compared to the gastro-resistant formulation of valproate, the sustained release formulation at the same doses is characterized by the disappearance of the absorption lag period, prolonged absorption, identical bioavailability, lower total maximum concentration and plasma free substance concentration (Cmax lower by about 25% with a relatively stable plateau 4-14 hours after injection); this “flattening effect” provides a more constant and more evenly distributed concentration of valproic acid over a 24-hour period: after administration of the same dose twice a day, the amplitude of fluctuations in plasma concentrations is halved, a linear relationship between dose and plasma concentration (total and free substance) is more pronounced.

Pharmacodynamics

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

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

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

Indications for use

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

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

Dosage and administration

Depakine® Chrono is a Depakine extended-release dosage form that results in a decrease in peak plasma concentrations of the active substance and provides more uniform concentrations throughout the day.

Given the dosage of this drug, it is only for adults and children weighing over 17 kg.

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

For children under the age of 11, oral dosage forms are suitable syrup, oral solution and extended release granules.

Dosage

The initial daily dose is usually 10-15 mg / kg, then it is increased to the optimal dose (see below "Initiation of treatment").

The average daily dose is 20 - 30 mg/kg. However, if seizures are not controlled at such doses, they can be increased, while patients should be carefully monitored.

For infants and children, the usual dose is 30 mg/kg per day. For adults, the usual dose is 20-30 mg/kg per day. For elderly patients, the dose should be adjusted taking into account the control of epileptic seizures.

The daily dose is determined depending on the age and body weight of the patient; however, significant interindividual sensitivity to valproate should be taken into account.

A clear relationship between the daily dose, serum concentrations of the drug and the therapeutic effect has not been established: the dosage is determined mainly on the basis of the patient's response to treatment.

Determination of plasma levels of valproic acid may serve as an adjunct to clinical observation if epileptic seizures are not controlled or side effects are suspected. The effective therapeutic range is usually 40-100 mg/L (300-700 µmol/L).

Mode of application

For oral administration.

This drug is taken as 1 or 2 divided doses every day, preferably with meals.

With well-controlled epilepsy, it can be used as a single daily dose.

Tablets should be swallowed whole, without crushing or chewing.

Start of treatment

Patients in whom appropriate control is achieved with Depakine® fast-release dosage forms are recommended to maintain the daily dose when switching to Depakine® Chrono.

If the patient is already on treatment and taking other antiepileptic drugs, treatment with Depakine Chrono should be introduced gradually to reach the optimal dose over about 2 weeks, after which, if necessary, concomitant treatment is reduced based on the effectiveness of treatment

For patients not taking other antiepileptic drugs, the dosage should be increased in stages over 2-3 days in order to reach the optimal dose within about one week.

If necessary, you should gradually start combination therapy with other antiepileptic drugs (see "Drug Interactions").

Side effects

Often

Transient and / or dose-dependent side effects: fine postural tremor

Nausea at the start of treatment

Often

Headache

Drowsiness

Temporary and/or dose dependent hair loss

There have been cases of weight gain. In view of the fact that weight gain is a risk factor for the development of polycystic ovary syndrome, the patient's weight should be carefully monitored (see "Special Instructions")

At the beginning of treatment, stomach pain, diarrhea, which usually disappear after a few days after stopping treatment

Dose-dependent thrombocytopenia, which, in general, is detected systematically and without any clinical consequences. Among patients with asymptomatic thrombocytopenia, based on platelet count and control of the disease, if possible, simply lowering the dose of this drug will usually resolve the thrombocytopenia)

Isolated and moderate hyperammonemia without changes in liver function tests, especially during combination therapy. It is usually not a reason to stop treatment. However, cases of hyperammonemia with neurological symptoms (which may progress to a coma) have also been reported, and therefore additional tests are required (see "Special Instructions").

Confusion or convulsions: several cases of stupor*

Liver disease (see "Special Instructions")

Amenorrhea and irregular menstruation

Infrequently

Skin reactions such as exenthematous rashes

Ataxia

Lethargy*

Angioedema

Syndrome of inappropriate secretion of antidiuretic hormone (SIDAH)

With long-term treatment with Depakine Chrono, there are reports of a decrease in bone mineral density, osteopenia, osteoporosis and fractures. The mechanism of action of Depakine Chrono on bone metabolism is unknown.

Sometimes

Irreversible extrapyramidal disorders, which, however, may include reversible parkinsonism syndrome

Rarely

Anemia, macrocytosis, leukopenia

male infertility

Decreased fibrinogen levels and increased bleeding time, usually without clinical consequences, especially when high doses are used.

Valproate has an inhibitory effect on the 2nd phase of platelet aggregation.

Bone marrow aplasia or true erythrocyte aplasia

Agranulocytosis

DRESS syndrome (drug skin reaction accompanied by eosinophilia and systemic manifestations) or drug intolerance syndrome

Very rarely

Cognitive impairment with asymptomatic and progressive manifestations (which may progress to complete dementia) and which disappear several weeks after stopping treatment

Pancreatitis, which requires timely discontinuation of treatment. In some cases, the outcome can be fatal (see "Special Instructions").

Enuresis and stress incontinence

Hyponatremia

mild peripheral edema

In exceptional cases

Pancytopenia

Reversible or irreversible hearing loss

Toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme

Kidney damage

Frequency unknown

Risk of teratogenic effects (see "Pregnancy and lactation")

There are suggestions of an effect on spermatogenesis (in particular, a decrease in sperm motility) (see Fertility)

* sometimes lead to transient coma (encephalopathy), isolated or associated with a paradoxical increase in epileptic seizures, with regression when treatment is discontinued or the dose is reduced. Such conditions often appear during combination therapy (especially in combination with phenobarbital or topiramate) or after a sudden increase in valproate doses.

Contraindications

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

Acute and chronic hepatitis

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

Hepatic porphyria

Combination with mefloquine

Combined reception with St. John's wort

Children's age up to 6 years

Drug Interactions

Contraindicated combinations

In combination with mefloquine

The risk of epileptic seizures in patients with epilepsy due to increased metabolism of valproic acid and the convulsant effect of mefloquine.

In combination with St. John's wort

Risk of decreased plasma concentration and anticonvulsant efficacy.

In combination with lamotrigine

Higher risk of increased toxicity with lamotrigine, especially severe skin reactions (toxic epidermal necrolysis).

In addition, an increase in plasma concentrations of lamotrigine (decrease in the degree of hepatic metabolism due to sodium valproate) may occur.

In cases where co-administration is required, careful clinical monitoring should be carried out.

In combination with penems

The risk of epileptic seizures against the background of a rapid decrease in plasma concentrations of valproic acid, which may remain undetected.

Combinations requiring special precautions

In combination with aztreonam

The risk of seizures as a result of a decrease in plasma concentrations of valproic acid.

Recommended: clinical observation, determination of plasma concentrations of drugs and possible dose adjustment of the anticonvulsant during treatment with an anti-infective agent and after its withdrawal.

In combination with carbamazepine

An increase in the concentration of the active metabolite of carbamazepine in plasma with signs of an overdose. In addition, a decrease in plasma concentrations of valproic acid associated with an increase in hepatic metabolism of valproic acid under the action of carbamazepine.

In combination with Felbamate

An increase in the concentration of valproic acid in serum with a decrease in the clearance of valproic acid to 22% - 50%, with the risk of overdose.

Recommended: clinical observation, monitoring of laboratory parameters and, possibly, dose adjustment of valproic acid during treatment with felbamate and after its withdrawal. In addition, valproic acid can lead to a decrease in the average clearance of Felbamate up to 16%.

In combination with phenobarbital and, by extrapolation, primidone

An increase in plasma concentration of phenobarbital with signs of overdose, due to the suppression of hepatic metabolism, which is often observed in children. In addition, a decrease in the concentration of valproic acid in plasma, associated with an increase in hepatic metabolism by phenobarbital.

Clinical monitoring during the first 15 days of combined treatment with an immediate reduction in the dose of phenobarbital when signs of sedation appear; especially, monitoring plasma concentrations of both anticonvulsants.

In combination with phenytoin (and by extrapolation with fosphenytoin)

Changes in plasma phenytoin concentration. In addition, the risk of reducing the concentration of valproic acid in plasma associated with increased hepatic metabolism of the latter by phenytoin.

In combination with rifampicin

Risk of seizures as a result of increased hepatic metabolism of valproate due to rifampicin.

In combination with topiramate

Risk of hyperammonemia or encephalopathy commonly attributed to valproic acid when used concomitantly with topiramate.

In combination with zidovudine

The risk of increased incidence of side effects of zidovudine, especially hematological effects, against the background of a decrease in the metabolism of zidovudine due to valproic acid.

Combinations to consider

In combination with nimodipine (oral, and by extrapolation, as an injection)

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

Other forms of interaction

In combination with oral contraceptives

Valproate does not have an enzyme-inducing effect, it does not reduce the effectiveness of estrogen-progesterone hormonal contraception in women.

special instructions

The administration of an antiepileptic agent may, in rare cases, be accompanied by an increase in the number of epileptic seizures or the appearance of a new type of epileptic seizure in patients, regardless of the spontaneous fluctuations noted in some types of epilepsy. With regard to valproate, this mainly introduces changes in concomitant antiepileptic treatment or pharmacokinetic interaction (see "Drug Interactions"), toxicity (liver disease or encephalopathy - see "Special Instructions" and "Side Effects") or overdose.

Because this drug is metabolized to valproic acid, it should not be combined with other drugs undergoing the same transformation in order to avoid an overdose of valproic acid (eg divalproate, valpromide). liver disease Appearance conditions In rare cases, severe or sometimes fatal liver disease has been reported. Infants and children under 3 years of age with severe epilepsy, especially epilepsy associated with brain damage, mental retardation and/or congenital metabolic or degenerative diseases, are at increased risk. At the age of over 3 years, the frequency of such complications decreases significantly and gradually decreases with age. In most cases, liver dysfunction is observed during the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combined antiepileptic treatment. Warning signs Early diagnosis is predominantly based on the results of a clinical examination. In particular, two types of disease manifestation must be taken into account, especially in high-risk patients (see "Conditions of onset"), which may precede jaundice: - first, non-specific systemic signs, usually appearing suddenly, such as asthenia , anorexia, exhaustion, drowsiness, sometimes accompanied by recurrent vomiting and abdominal pain. - secondly, the recurrence of epileptic seizures, despite the appropriate treatment. It is recommended to inform patients, and if they are children, then their families, that if such clinical symptoms appear, they should immediately consult a doctor. In addition to the clinical examination, liver function tests should be performed immediately. Detection During the first 6 months of treatment, it is necessary to periodically monitor liver function tests. Among the classic tests, the most appropriate tests reflect protein synthesis by the liver, and, especially, prothrombin time (PT). If an abnormally low level of prothrombin time is confirmed, especially if other abnormal abnormalities in laboratory tests are also noted (a significant decrease in the level of fibrinogen and coagulation factors, an increase in the level of bilirubin and hepatic transaminases - see "Special Instructions"), treatment with Depakine Chrono should be suspended (as a precautionary measure, treatment with salicylate derivatives should also be interrupted when combined administration, since they use the same metabolic pathways). Pancreatitis In rare cases, pancreatitis has been reported, sometimes with a fatal outcome. These cases were observed regardless of the age of the patient and the duration of treatment, while younger children were at risk. Pancreatitis with poor outcome is usually seen in young children or patients with severe epilepsy, brain damage, or those who are being treated with multiple antiepileptic drugs. If pancreatitis appears along with liver failure, the risk of death increases. In the event of acute abdominal pain or gastrointestinal signs such as nausea, vomiting and/or anorexia, the diagnosis of pancreatitis should be considered and, in patients with elevated pancreatic enzyme levels, treatment should be discontinued and appropriate alternative measures instituted. Women of childbearing age This medicinal product should not be given to women of childbearing age unless absolutely necessary, i.e. when an alternative treatment is ineffective or poorly tolerated by patients. This should be assessed prior to the first appointment of Depakine Chrono or when a woman of childbearing age undergoing treatment with Depakine Chrono is planning a pregnancy. Suicide risk Suicidal ideation or behavior has been reported among patients treated with antiepileptic drugs for several indications. A meta-analysis of data from randomized, placebo-controlled trials of antiepileptic drugs also showed a slight increase in the risk of suicidal ideation and behavior. The reasons for this risk are unknown and the available data do not rule out an increased risk with valproate. Therefore, patients should be closely monitored for signs of suicidal ideation and behavior, and appropriate treatment should be considered. Patients (or their caregivers) should be informed that they should seek medical attention if suicidal ideation or behavior occurs. Interaction with other drugs This drug contains 47 mg of sodium per tablet. This should be considered in patients who are on a strict low sodium diet. It is not recommended to co-administer this drug with lamotrigine and penems (see Drug Interactions). Precautions when using the drug Before starting treatment, liver function tests should be checked (see "Contraindications"), and this should be done periodically during the first six months, especially for patients at risk (see "Special Instructions"). It should be emphasized that there may be an isolated and transient, moderate increase in transaminase levels, as occurs with the use of most antiepileptic drugs, without any clinical signs, especially at the beginning of treatment. If this happens, it is recommended to conduct more complete laboratory studies (especially prothrombin time). If necessary, doses should also be re-evaluated and studies re-run based on changes in parameters. For children under the age of three years, valproate is recommended only as monotherapy, after the therapeutic benefit has been weighed against the risk of developing liver disease and pancreatitis among patients in this age group (see "Special Instructions"). Before starting treatment, as well as before surgery and in the event of a hematoma or spontaneous bleeding, it is recommended to perform blood tests (complete blood count, including determination of platelet count, bleeding time and clotting parameters) (see "Side Effects"). Concerning children, the simultaneous appointment of salicylates derivatives should be avoided due to the increased risk of developing hepatotoxicity (see "Special Instructions") and the risk of bleeding. In patients with renal insufficiency, an increase in circulating concentrations of valproic acid in the blood should be taken into account, and therefore the dosage should be reduced accordingly. This drug is not recommended for patients with enzyme deficiency in the urea cycle. Among these patients, there have been several cases of hyperammonemia with stupor or coma. For children with a history of unexplained liver and gastrointestinal disorders (loss of appetite, vomiting, acute episodes of cytolysis), episodes of lethargy or coma, mental retardation, or with a family history of death in newborns or infants, up to Initiating treatment with any valproate, metabolic tests should be performed, especially fasting and postprandial blood ammonia levels. Although this medicinal product has been found to cause only immunological disturbances in exceptional cases, the benefit-risk ratio must be weighed in patients with systemic lupus erythematosus. Before starting treatment, the patient should be informed of the risk of weight gain and of the appropriate measures, mainly of a dietary nature, to be taken in order to minimize this effect. During the entire treatment with Depakine Chrono, it is not recommended to consume alcohol.

Pregnancy and lactation

Fertility

There are suggestions that valproic acid may affect spermatogenesis (especially in the form of a decrease in sperm motility). The implications of this observation remain unknown.

Pregnancy

This drug should not be given to pregnant women or women of childbearing potential unless absolutely necessary (for example, if alternative treatments have not worked or are not well tolerated by patients).

During treatment, women of childbearing age should use reliable contraception.

The risk of birth defects caused by sodium valproate is 3 to 4 times higher among women taking this drug than in the general population, at 3%. The most commonly observed malformations are neural tube closure defects (approximately 2 to 3%), facial abnormalities, facial clefts, craniostenosis, heart defects, hypospadias, renal and genitourinary malformations, and abnormal limb development.

Doses above 1000 mg/day and use in combination with anticonvulsants are significant risk factors for these malformations. The use of lower doses does not eliminate this risk.

Current epidemiological data demonstrate a reduction in overall intelligence in children exposed to sodium valproate in utero. These children have a mild decline in verbal abilities and/or an increase in speech pathologist referrals or medical support.

An increased incidence of invasive developmental problems (from a spectrum of autism disorders) has been noted among children exposed to sodium valproate in utero. The use of valproate, either as monotherapy or as combination therapy, is associated with abnormal pregnancy outcomes.

Based on the above information, Depakine Chrono should not be prescribed to women of childbearing age unless it is absolutely necessary, i.e., if alternative treatments are not effective or poorly tolerated by patients. This should be assessed prior to the first appointment of Depakine Chrono or when women of childbearing age who are being treated with Depakine Chrono are planning a pregnancy.

During treatment, women of childbearing age should use reliable contraception.

When planning a pregnancy

If pregnancy is planned, you should first undergo an appropriate consultation.

When planning a pregnancy, all stages of considering other treatments should be completed.

If the use of sodium valproate cannot be excluded (no other alternatives):

It is recommended to use the minimum effective daily dose. To date, there are no data to support the efficacy of folic acid supplementation in women exposed to sodium valproate during pregnancy. However, given this beneficial effect in other situations, such a supplement may be offered at a dosage of 5 mg/day, one month before conception and two months later. Screening for malformations is carried out equally, regardless of whether the patient is taking folic acid or not.

During pregnancy

In cases where there are absolutely no options, and there is a need to continue treatment with sodium valproate (no other alternatives), it is recommended to use the lowest effective dose, avoiding doses of more than 1000 mg / day if possible. Special prenatal monitoring is required to detect possible neural tube defects or other malformations.

Birth defects are controlled equally, regardless of whether the patient is taking folic acid or not.

Before giving birth

The mother should have coagulation tests before delivery, including platelet count, fibrinogen, and clotting time (activated partial thromboplastin time: APTT).

In newborns

This drug can cause hemorrhagic syndrome in newborns, which is related to vitamin K deficiency.

The hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia, and/or a decrease in other coagulation factors.

Routine studies of hemostasis in the mother do not allow to exclude abnormalities in hemostasis in newborns. Subsequently, the neonate should have blood tests consisting of, at a minimum, platelet count, fibrinogen levels, and activated partial thromboplastin time.

In addition, during the first week after birth among newborns whose mothers were treated with valproate until the birth itself, cases of hypoglycemia were noted. Cases of hypothyroidism have been reported in newborns whose mothers took valproate during pregnancy.

lactation period

Excretion of sodium valproate from the body with breast milk is low. However, given the issues addressed in the evidence related to reduced speech ability among newborns, it is advisable to advise patients to refrain from breastfeeding.

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

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

Overdose

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

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

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

Release form and packaging

30 tablets are placed in polypropylene containers sealed with polyethylene stoppers with a desiccant.

Depakine Chrono (valproic acid) is a drug for the therapeutic correction of various types of epilepsy. Valproic acid and its derivatives have been used in psychiatry and neurology for several decades. Despite its far from young "age", Depakine Chrono remains the drug of first choice (or, if you like, the "gold standard") in the treatment of epileptic disorders. Valproic acid was obtained in the laboratory in 1882, and its anticonvulsant properties were discovered in 1962. Five years later, the drug appeared on the pharmaceutical market, and a few years later it gained worldwide popularity, "winning" more than 100 countries. Depakine Chrono is a broad-spectrum drug in the sense that it is used in all models of convulsive conditions observed in the clinical setting. Valproic acid has 100% bioavailability. The half-life of the drug is 15-17 hours. A stable level of the active substance in the blood is achieved on the 3rd-4th day of pharmacotherapy. Valproic acid is excreted mainly by the kidneys. Depakine Chrono is a dosage form of valproate that provides a sustained release. It is characterized by no delay in absorption from the gastrointestinal tract after oral administration, prolonged absorption, the same degree of bioavailability as the enteric-coated dosage form. Depakine Chrono is contraindicated in case of individual intolerance to valproates, inflammation of the liver in the acute or chronic phase, pigment metabolism disorders with an increased content of porphyrins in the blood and tissues and their intensive excretion by the kidneys and intestines, when taken together with mefloquine, St. John's wort and lamotrigine.

In pediatrics, the drug can be used from the age of 6 and provided that the patient weighs at least 17 kg. When determining the daily dose of the drug, the age, body weight and susceptibility of the patient's body to valproic acid are taken into account. The frequency of taking the drug - 1-2 times a day. The best time to take it is with meals. Tablets should not be chewed or crushed. With the introduction of Depakine Chromo into the drug course instead of other antiepileptic drugs, the change of the drug is carried out gradually over two weeks. During the use of Depakine Chrono, care should be taken when engaging in activities that require increased attention and concentration. Depakine Chrono can be used in psychiatry for the treatment of manic-depressive psychosis. It demonstrates a pronounced effect in the treatment of acute manic states, dysphoric mania. A number of sources noted the success of the drug in the treatment of acute depression. Initial side effects of Depakine Chrono include dyspeptic disorders. In 30-40% of patients, there is an increase in body weight. In some cases, temporary alopecia may occur.

Pharmacology

Anticonvulsant drug, has a central muscle relaxant and sedative effect. Shows antiepileptic activity in all types of epilepsy.

The main mechanism of action seems to be related to the effect of valproic acid on the GABA-ergic system: the drug increases the content of GABA in the CNS and activates GABA-ergic transmission.

Pharmacokinetics

Suction

The bioavailability of sodium valproate and valproic acid when taken orally is close to 100%.

When taking Depakine ® Chrono 500 mg tablets at a dose of 1000 mg / day, C min in plasma is 44.7 ± 9.8 μg / ml, and C max in plasma is 81.6 ± 15.8 μg / ml. T max in plasma is 6.58 ± 2.23 hours. C ss in plasma is achieved within 3-4 days of regular administration of the drug.

The average therapeutic range of serum concentrations of valproic acid is 50-100 mg/L. With a reasonable need to achieve higher plasma concentrations of valproic acid, the ratio of the expected benefit and the risk of side effects, especially dose-dependent ones, should be carefully weighed. at a concentration of valproic acid of more than 100 mg / l, an increase in side effects is expected up to the development of intoxication. With a plasma concentration of valproic acid more than 150 mg / l, a dose reduction is required.

Compared to the enteric-coated dosage form, the sustained-release tablet formulation at equivalent doses is characterized by no latent absorption time, prolonged absorption, identical bioavailability, lower Cmax (approximately 25% reduction in Cmax), but with a more stable plateau phase from 4 to 14 hours after administration, a more linear correlation between dose and plasma concentration of the drug.

Distribution

Plasma protein binding (mainly albumin) is high (90-95%), dose-dependent and saturable.

V d depends on age and is usually 0.13-0.23 l / kg of body weight, or in young people 0.13-0.19 l / kg of body weight.

Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in CSF is 10% of the corresponding plasma concentration.

Valproic acid passes into breast milk from nursing mothers. At steady state, the concentration of valproic acid in breast milk is 1-10% of its plasma concentration.

Metabolism

It is metabolized by beta-, omega- and omega-1-oxidation and conjugation with glucuronic acid. More than 20 metabolites have been isolated, metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on the isoenzymes of the cytochrome P450 system: unlike most other antiepileptic drugs, valproic acid does not affect the degree of both its own metabolism and the degree of metabolism of other drugs, such as estrogens, progestogens and indirect anticoagulants.

breeding

It is excreted mainly in the urine after beta-oxidation and conjugation. T1 / 2 is 15-17 hours. Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml / min.

Pharmacokinetics in special clinical situations

In elderly patients, patients with renal and hepatic insufficiency, binding to plasma proteins decreases. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid may increase to 8.5-20%.

With hypoproteinemia, the total concentration of valproic acid (free + plasma protein-bound fraction) may not change, but may also decrease due to an increase in the metabolism of the free (non-plasma protein-bound) fraction of valproic acid.

When combined with antiepileptic drugs that induce microsomal liver enzymes, the plasma clearance of valproic acid increases, and T 1/2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

The values ​​of T 1/2 in children over the age of 2 months are close to those in adults.

In patients with liver disease, T 1/2 of valproic acid increases.

With an overdose, an increase in T 1/2 up to 30 hours was observed.

Only the free fraction of valproic acid in the blood (10%) is subjected to hemodialysis.

Features of pharmacokinetics during pregnancy

With an increase in Vd of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. In this case, despite taking the drug at a constant dose, a decrease in the concentration of valproic acid in plasma is possible. In addition, during pregnancy, a change in the degree of binding of valproic acid to plasma proteins is possible, which can lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum.

Release form

Long-acting tablets, film-coated, almost white, oblong, biconvex, notched on both sides.

Excipients: methylhydroxypropylcellulose 4000 mPa.s (hypromellose) - 105.6 mg, ethylcellulose (20 mPa.s) - 7.2 mg, sodium saccharin - 6 mg, colloidal hydrated 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.

* corresponds to 300 mg of valproic acid in 1 tab.

Dosage

Depakine ® chrono is intended only for adults and children over 6 years of age weighing more than 17 kg!

Depakine ® chrono is a sustained release dosage form, which avoids sharp rises in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood for a longer period of time.

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

Tablets are taken without crushing or chewing them.

Epilepsy

The doctor selects the daily dose individually.

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

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

No clear relationship was found between daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined mainly by clinical response. Determination of the level of valproic acid in plasma can serve as an addition to clinical observation if epilepsy is not controlled or there is a suspicion of the development of side effects. The range of therapeutic concentration in the blood is usually 40-100 mg/l (300-700 µmol/l).

With monotherapy, the initial dose is usually 5-10 mg of valproic acid per kg of body weight, then this dose is gradually increased every 4-7 days at the rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control of epileptic seizures.

Average daily doses (with prolonged use):

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

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

for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg of valproic acid / kg of body weight (1200-2100 mg).

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

If epilepsy is not controlled at such doses, they can be increased under the control of the patient's condition and the concentration of valproic acid in the blood. In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, do not increase the daily dose above the recommended average daily dose before this time.

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

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

Most patients who are already taking Depakine ® in a non-prolonged-release dosage form can be transferred to Depakine ® chrono immediately or within a few days, while patients should continue to take the previously selected daily dose.

For patients who have previously taken antiepileptic drugs, the transfer to the drug Depakine ® chrono should be carried out gradually, reaching the optimal dose of the drug within about 2 weeks. In this case, you should immediately reduce the dose of the antiepileptic drug that the patient has previously taken, especially if it is phenobarbital. Cancellation of the antiepileptic drug that the patient has previously taken should be carried out gradually.

Because other antiepileptic drugs can reversibly induce microsomal liver enzymes, it is necessary to monitor the plasma concentration of valproic acid within 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), reduce the daily dose of valproic acid.

If necessary, the combination of valproic acid with other antiepileptic drugs should be added to the treatment gradually.

Manic episodes in bipolar disorder

adults

The daily dose should be selected individually.

Depakine ® chrono can be taken 1 or 2 times / day. The dose should be increased as quickly as possible until the minimum effective therapeutic dose is reached.

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

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

With continued treatment of manic episodes in bipolar disorders, the drug is used in an individually selected minimum effective dose.

Children and teenagers

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

Special patient groups

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

Overdose

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

Treatment: in the hospital - gastric lavage, which is effective for 10-12 hours after ingestion of the contents of the vial with lyophilizate or solution for intravenous administration. To reduce the absorption of valproic acid, it may be effective to take activated charcoal, incl. its introduction through a nasogastric tube. Monitoring and correction of the functional state of the cardiovascular and respiratory systems, maintenance of effective diuresis, and symptomatic therapy are required.

It is necessary to control the functions of the liver and pancreas. Respiratory depression may require mechanical ventilation.

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

Interaction

Effect of valproic acid on other drugs

Valproic acid may potentiate the action of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (careful medical supervision and, if necessary, dose adjustment is 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 a sedative effect of the latter is possible, especially in children. Therefore, careful medical monitoring of the patient during the first 15 days of combination therapy is recommended, with an immediate reduction in the dose of phenobarbital in the event of a sedative effect and, if necessary, determination of the plasma concentration of phenobarbital.

Valproic acid increases the plasma concentration of primidone, leading to an increase in its side effects (such as sedation); with prolonged treatment, these symptoms disappear. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy with dose adjustment of primidone if necessary.

Valproic acid reduces the total plasma concentration of phenytoin. In addition, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing overdose symptoms (valproic acid displaces phenytoin from its association with blood plasma proteins and slows down its hepatic metabolism). Therefore, careful clinical monitoring of the patient and determination of the concentration of phenytoin and its free fraction in the blood is recommended.

With the simultaneous use of valproic acid and carbamazepine, the occurrence of clinical manifestations of carbamazepine toxicity has been reported, tk. 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 correction, if necessary, of the dose of carbamazepine.

Valproic acid slows down the metabolism of lamotrigine in the liver and increases T 1/2 of lamotrigine by almost 2 times. This interaction can lead to increased toxicity of lamotrigine, in particular to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical observation and, if necessary, dose adjustment (reduction) of lamotrigine is recommended.

Valproic acid may increase plasma concentrations of zidovudine, resulting in increased zidovudine toxicity.

Valproic acid can reduce the mean clearance of felbamate by 16%.

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

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.

With the combination of felbamate and valproic acid, the clearance of valproic acid is reduced by 22-50% and, accordingly, the plasma concentration of valproic acid increases. The plasma concentration of valproic acid should be monitored.

Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing convulsions, therefore, with their simultaneous use, the development of an epileptic seizure is possible.

With the simultaneous use of valproic acid and preparations of St. John's wort, a decrease in the anticonvulsant effectiveness of valproic acid is possible.

In the case of simultaneous use of valproic acid and drugs that have a high and strong connection with blood plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free fraction of valproic acid.

With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of the prothrombin index is required.

The concentration of valproic acid in the blood plasma may increase with the simultaneous use of cimetidine or erythromycin (as a result of slowing down its hepatic metabolism).

Decrease in the concentration of valproic acid in the blood when it is used simultaneously 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. The simultaneous use of carbapenems in patients with a selected dose of valproic acid should be avoided due to their ability to quickly and intensively reduce the concentration of valproic acid in plasma. If treatment with carbapenems cannot be avoided, blood levels of valproic acid should be carefully monitored.

Rifampicin can reduce the concentration of valproic acid in the blood, which leads to the loss of the therapeutic effect of the drug Depakine ® chrono. Therefore, it may be necessary to increase the dose of the drug Depakine ® chrono while using rifampicin.

Other interaction

The simultaneous use of valproic acid and topiramate was accompanied by encephalopathy and / or hyperammonemia. Patients receiving this combination should be carefully monitored for the development of symptoms of hyperammoniemic encephalopathy.

The simultaneous use of valproic acid and quetiapine may increase the risk of developing neutropenia / leukopenia.

Valproic acid does not have the ability to induce liver enzymes and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen drugs in women using hormonal contraception.

When taking ethanol and other potentially hepatotoxic drugs simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid.

The simultaneous use of clonazepam with valproic acid can lead in isolated cases to an increase in the severity of the absence status.

With the simultaneous use of drugs with a myelotoxic effect, with valproic acid, the risk of inhibition of bone marrow hematopoiesis increases.

Side effects

Determination of the frequency of adverse reactions (WHO): very often (≥10%), often (≥1% and<10%), нечасто (≥0.1% и <1%), редко (≥0.01% и <0.1%), очень редко (<0.01%), частота неизвестна (невозможно определить по имеющимся данным).

From the hematopoietic system: often - anemia, thrombocytopenia; infrequently - pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can be both with depression of bone marrow hematopoiesis, and without it. After discontinuation of the drug, the blood picture returns to normal. Rarely - disorders of bone marrow hematopoiesis, including isolated aplasia / hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis.

From the blood coagulation system: often - bleeding and hemorrhage; rarely - a decrease in the content of blood coagulation factors (at least one), a deviation from the norm of blood coagulation indicators (such as an increase in prothrombin time, an increase in APTT, an increase in thrombin time, an increase in MHO). The appearance of spontaneous bruising 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 an IV injection and disappear spontaneously within a few minutes); infrequently - coma *, encephalopathy *, lethargy *, reversible parkinsonism, ataxia, paresthesia; 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 associated with an increase in seizures during treatment, and also decreased when the drug was discontinued or when the dose was reduced. Most of these cases have been described against the background of combination therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

On the part of the psyche: infrequently - a state of confusion, aggressiveness **, agitation **, impaired attention **, depression (with a combination of valproic acid with other anticonvulsants); rarely - behavioral disorders **, psychomotor hyperactivity **, learning disabilities **, depression (with valproic acid monotherapy).

**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 gum hyperplasia), stomatitis, epigastric pain, diarrhea (which often occur in some patients at the beginning of treatment, but usually disappear after a few days and do not require discontinuation of therapy); infrequently - 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 control 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 a meal.

From the side of the liver and biliary tract: often - liver damage, which is accompanied by a deviation from the norm of 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 coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of hepatic transaminases in blood; liver failure, in exceptional cases with a fatal outcome.

From the respiratory system: infrequently - pleural effusion.

From the urinary system: infrequently - 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 development mechanism of which is still unclear.

From the immune system: often - hypersensitivity reactions, for example, urticaria; infrequently - angioedema; rarely - drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome), systemic lupus erythematosus.

On the part of the skin and subcutaneous tissues: often - transient or dose-dependent alopecia (including androgenetic alopecia against the background of developed hyperandrogenism, polycystic ovaries, as well as alopecia against the background of developed hypothyroidism); infrequently - rash, hair disorders (such as a violation of the normal structure of the hair, a change in hair color, abnormal hair growth [the disappearance of waviness and curly hair, or, conversely, the appearance of curly hair in individuals with initially straight hair]), hirsutism, acne; 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).

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

On the part of metabolism: often - hyponatremia, weight gain (because weight gain is a factor contributing to the development of polycystic ovary syndrome); rarely - biotin deficiency / biotinidase deficiency, - hyperammonemia (cases of isolated and moderate hyperammonemia without changes in liver function and the need to stop treatment; cases of hyperammonemia, accompanied by the appearance of neurological symptoms, including the development of encephalopathy, vomiting, ataxia), which required discontinuation taking valproic acid and conducting an additional examination.

From the side of the vessels: infrequently - vasculitis.

From the reproductive system: often - dysmenorrhea; infrequently - amenorrhea; rarely - male infertility, polycystic ovaries; frequency unknown - dysmenorrhea, breast enlargement, galactorrhea.

Benign, malignant and indeterminate tumors (including cysts and polyps): rarely - myelodysplastic syndrome.

General disorders: infrequently - hypothermia, mild peripheral edema.

Indications

adults

As monotherapy or in combination with other antiepileptic drugs:

• Lennox-Gastaut syndrome;

Treatment and prevention of bipolar affective disorders.

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 or without secondary generalization).

Contraindications

• hypersensitivity to sodium valproate, valproic acid, seminatrium valproate, valpromide or any of the auxiliary components of the drug;
• acute hepatitis;
• chronic hepatitis;
• severe liver disease (especially drug-induced hepatitis) in the history of the patient and his close blood relatives;
• severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;
• severe violations of the liver or pancreas;
• severe dysfunction of the pancreas;
• hepatic porphyria;
• combination with mefloquine;
• combination with St. John's wort;
• children under 6 years of age (risk of getting the tablet into the respiratory tract when swallowing).

Carefully

• diseases of the liver and pancreas in history;
• pregnancy;
• congenital fermentopathy;
• oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
• renal failure (dose adjustment required);
• hypoproteinemia;
• patients receiving multiple anticonvulsants (due to an increased risk of liver damage);
• concomitant use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors; phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures);
• simultaneous use of antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (the possibility of potentiating their effects);
• simultaneous administration of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine (due to pharmacokinetic interaction at the level of metabolism or binding to plasma proteins, changes in plasma concentrations or these drugs and / or valproic acid);
• simultaneous reception with carbamazepine (risk of potentiation of the toxic effects of carbamazepine and a decrease in the plasma concentration of valproic acid);
• simultaneous reception with topiramate (risk of developing encephalopathy);
• in patients with an existing insufficiency of carnitine palmitoyltransferase (CPT) type II (higher risk of developing rhabdomyolysis when taking valproic acid).

Application features

Use during pregnancy and lactation

During pregnancy, the development of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia can be a risk factor for death for both the mother and the fetus.

In experimental reproductive toxicity studies conducted in mice, rats and rabbits, valproic acid has been shown to be teratogenic.

Available clinical data confirm that neural tube defects were observed in children born to mothers with epilepsy who received valproic acid during pregnancy; craniofacial deformities; malformations of limbs, cardiovascular system; hypospadias, as well as multiple intrauterine malformations affecting different organ systems.

Data from a meta-analysis that included registry and cohort studies showed that the incidence of congenital malformations in children born to mothers who received valproic acid as monotherapy during pregnancy was 10.73% (95% confidence interval 8.16-13.29%). Available data indicate a dose-dependent nature of this adverse event.

The risk of congenital malformations in children born to mothers with epilepsy who took valproic acid as monotherapy was approximately 1.5 times higher compared with phenytoin monotherapy, approximately 2.3 times higher than with carbamazepine or phenobarbital monotherapy, and approximately 3.7 times higher compared with lamotrigine monotherapy.

Available data suggest a causal relationship between intrauterine exposure to valproic acid and the risk of developmental delay, in particular a decrease in verbal IQ, in children born to mothers with epilepsy who took valproic acid during pregnancy. Developmental delay is often combined with malformations and dysmorphic phenomena. However, in cases of developmental delay in such children, it is difficult to accurately establish a causal relationship with the use of valproic acid due to the possibility of simultaneous influence of other factors, such as the low level of intelligence of the mother or both parents; genetic, social factors, environmental factors; insufficient effectiveness of treatment aimed at preventing epileptic seizures in the mother during pregnancy.

Various autistic disorders have also been reported in children exposed to valproic acid in utero.

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

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

In connection with the foregoing, Depakine ® chrono should not be used during pregnancy and in women of childbearing age unless absolutely necessary. Its use is possible, for example, in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

The question of the need to use the drug Depakine ® chrono or the possibility of refusing its use should be decided before the start of the drug or reconsidered if a woman receiving Depakine ® chrono is planning a pregnancy.

Women of childbearing age should use effective methods of contraception during treatment with Depakine ® chrono. Women of childbearing age should be informed about the risks and benefits of using valproic acid during pregnancy.

Before prescribing the drug, pregnancy should be excluded.

If a woman is planning a pregnancy or she is diagnosed with pregnancy, then the need for treatment with valproic acid should be reassessed. The question of continuing treatment with valproic acid or its cancellation is decided after a reassessment of the benefit-risk ratio, depending on the indications:

If, after a reassessment of the benefit-risk ratio, a decision is made to continue treatment with Depakine ® chrono during pregnancy, then it is recommended to use it at the minimum effective daily dose, divided into several doses. It should be noted that during pregnancy, the use of sustained-release formulations of the drug is preferable;

When bipolar disorder is indicated, consideration should be given to discontinuing treatment with valproic acid.

Before pregnancy, folic acid (at a dose of 5 mg/day) should be added to antiepileptic treatment to reduce the risk of neural tube defects.

It is necessary to carry out a permanent (including in the III trimester of pregnancy) special prenatal diagnostics to identify possible malformations of the neural tube or other fetal malformations, including detailed ultrasound.

It was reported about the development of isolated cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia and / or a decrease in the content of blood clotting factors. Fatal afibrinogenemia has also been reported. This hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes.

Therefore, in newborns born to mothers who received valproic acid during pregnancy, coagulation tests should be performed (to determine the number of platelets in the blood, plasma fibrinogen concentration, blood clotting factors and a coagulogram).

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

There have been reports of cases of hypothyroidism in newborns whose mothers took valproic acid during pregnancy.

In newborns whose mothers took valproic acid in the third trimester of pregnancy, a withdrawal syndrome may occur (in particular, the appearance of agitation, irritability, hyperreflexia, trembling, hyperkinesia, muscle tone disorders, tremors, convulsions and difficulty feeding).

Excretion of valproic acid in breast milk is low, its concentration in breast milk is 1-10% of its plasma concentration.

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 literature data and little clinical experience, breastfeeding can be planned with monotherapy with Depakine ® chrono, but the side effect profile of the drug, especially the hematological disorders caused by it, should be taken into account.

Fertility

In men, valproic acid can decrease sperm motility and cause male infertility. In addition, due to the possibility of developing undesirable effects from the endocrine system and genital organs in women (such as dysmenorrhea, amenorrhea, polycystic ovaries, hyperandrogenism), a decrease in fertility in women is possible.

Application for violations of liver function

The drug is contraindicated in violations of liver function.

Application for violations of kidney function

Use in children

Use in elderly patients

special instructions

Before starting the use of the drug Depakin ® chrono and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, a study of liver function should be performed.

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

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

Severe liver damage

Clinical experience shows that patients at risk are patients receiving several antiepileptic drugs at the same time, children under 3 years of age with severe convulsive seizures, especially against the background of brain damage, mental retardation and / or congenital metabolic or degenerative diseases; patients simultaneously taking salicylates (because salicylates are metabolized along the same metabolic pathway as valproic acid).

In children older than 3 years, the risk of liver damage is significantly reduced and progressively decreases as the age of the patient increases. In most cases, liver damage occurs during the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually with the use of valproic acid as part of a combination antiepileptic therapy.

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

Non-specific symptoms, especially those of sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by recurrent vomiting and abdominal pain;

Recurrence of seizures in patients with epilepsy.

Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of these symptoms to the attending physician. If these symptoms appear, patients should immediately undergo a clinical examination and laboratory tests of liver function tests.

Determination of liver function tests should be carried out before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative studies reflect the state of the protein-synthetic function of the liver, especially the prothrombin index. Confirmation of an abnormal prothrombin index, especially in combination with abnormalities of other laboratory parameters (a significant decrease in fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in transaminase activity), as well as the appearance of other symptoms indicating liver damage, requires discontinuation of the use drug Depakine ® chrono. As a precaution, if patients were taking salicylates at the same time, their intake should also be discontinued.

Pancreatitis

There are registered rare 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 an increased risk of developing pancreatitis, with increasing age of the child, this risk decreases. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for developing pancreatitis. Liver failure associated with pancreatitis increases the risk of death.

Patients who develop severe abdominal pain, nausea, vomiting, and/or anorexia should be evaluated immediately. In case of confirmation of pancreatitis, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment initiated.

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 by 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 carried out. Patients and their caregivers are advised if the patient has suicidal thoughts or attempts to seek immediate medical attention.

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 not possible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Deficiency of urea cycle enzymes

If a deficiency of urea cycle enzymes is suspected, the use of valproic acid is not recommended. Several cases of hyperammonemia with stupor or coma have been described in these patients. In these cases, metabolic studies should be performed prior to treatment with valproic acid.

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of neonatal or infant death, metabolic studies should be performed prior to initiating treatment with valproic acid, in particular determination ammonemia (the presence of ammonia and its compounds in the blood) on an empty stomach and after eating.

Patients with systemic lupus erythematosus

Although it has been shown that during treatment with Depakine ® chrono, violations of the immune system are extremely rare, the potential benefit of its use must be compared with the potential risk when prescribing the drug to patients with systemic lupus erythematosus.

Weight gain

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

Patients with diabetes

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

HIV-infected patients

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

Patients with pre-existing carnitine palmitoyltransferase (CPT) type II deficiency

Patients with pre-existing type II CBT deficiency should be warned of a higher risk of developing
rhabdomyolysis while taking valproic acid.

Pediatric use

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

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

During treatment with valproic acid, alcohol is not recommended.

Influence on the ability to drive vehicles and control mechanisms

Patients should be warned about the risk of drowsiness, especially in the case of combined anticonvulsant therapy or the combination of Depakine® Chrono with benzodiazepines.