Instructions for use DEPAKINE CHRONOSPHERE

Nosological classification (ICD-10)

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

Compound

Pharmacokinetics

Absorption

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

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

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

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

Distribution

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

The binding of valproic acid to plasma proteins (mainly albumin) is high (90–95%), dose-dependent and saturable. In elderly patients, people with renal and hepatic insufficiency, the connection with blood plasma proteins decreases. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid may increase to 8.5–20%. With hypoproteinemia, the total concentration of valproic acid (free + fraction bound to plasma proteins) may not change, but may decrease due to an increase in the metabolism of the free (not bound to plasma proteins) fraction of valproic acid.

Valproic acid penetrates into the cerebrospinal fluid and brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding concentration in the blood serum, i.e. close to the concentration of the free fraction of valproic acid in blood serum.

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

Metabolism

Valproic acid is metabolized in the liver by glucuronidation, as well as beta, omega and omega1 oxidation. More than 20 metabolites have been identified; metabolites after omega-oxidation have a hepatotoxic effect.

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

Removal

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

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

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

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

Features of pharmacokinetics during pregnancy

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

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

Pregnancy: Based on experience in treating mothers with epilepsy, the risks associated with the use of valproate during pregnancy are described as follows:

Risk associated with epilepsy and antiepileptic drugs.

It has been shown that when using any antiepileptic drugs in women with epilepsy, the overall incidence of congenital defects in children born to them is 2-3 times higher than among the general population (about 3%). Although an increased number of children with congenital defects has been noted in the case of combination drug therapy, the respective role of the disease itself and the drugs taken by the mother has not yet been formally established. The most common malformations are cleft lip and malformations of the cardiovascular system. Sudden interruption of antiepileptic treatment may worsen the course of the mother's illness and lead to detrimental consequences for the fetus.

Risk associated with sodium valproate

The overall risk of malformations in women when taking valproate in the first trimester of pregnancy is no higher than when taking other antiepileptic drugs. Cases of facial dysmorphia have been described. Rare cases of multiple malformations, especially of the limbs, have been observed. The frequency of such effects has not yet been precisely established. Along with this, sodium valproate predominantly causes disruption of the development of the neural tube: myelomeningocele, spina bifida... The frequency of such complications is 1-2%.

In light of this data:

If a woman is planning a pregnancy, the indications for antiepileptic treatment should be reconsidered; It is recommended to consider the issue of additional administration of folates. During pregnancy, antiepileptic treatment with valproate should not be interrupted if it is effective. In such cases, monotherapy is recommended, the minimum effective daily dose of which should be divided into several doses per day. However, the patient should be referred for specific prenatal evaluation to identify any anomalies of the neural tube or other defects.

Risk to the newborn

Isolated cases of hemorrhagic syndrome have been described in newborns whose mothers took sodium valproate during pregnancy. This hemorrhagic syndrome is associated with hypofibrinogenemia; Afibrinogenemia, which can be fatal, has also been described. This hypofibrinogenemia is possibly due to a decrease in clotting factors. However, this syndrome must be distinguished from the decrease in vitamin K-dependent factors caused by phenobarbital and other enzyme inducers. Therefore, in newborns, platelet count, plasma fibrinogen levels, coagulation tests and determination of coagulation factors should be performed.

Lactation Excretion of valproate into milk is low and ranges from 1 to 10% of serum levels. Until now, we have monitored infants who received breast milk and did not develop any clinical manifestations during the neonatal period. Impact on the ability to drive and perform work requiring increased attention The patient should be warned about the danger of drowsiness, especially in the case of anticonvulsant polytherapy or combination with benzodiazepines. Interaction with other drugs

Neuroleptics, MAO inhibitors, antidepressants and benzodiazepines

Depakine® can potentiate the effect of other psychotropic drugs - antipsychotics, MAO inhibitors, antidepressants and benzodiazepines. Therefore, clinical monitoring and, if necessary, dose adjustment are recommended.

Phenobarbital

Depakine® increases the plasma concentration of phenobarbital (due to inhibition of hepatic catabolism) and signs of sedation may appear, especially in children. Therefore, clinical monitoring is recommended during the first 15 days of combination treatment, with immediate reduction of the phenobarbital dose if signs of sedation occur and determination of phenobarbital blood levels, if necessary.

Primidon

Depakine® increases the concentration of primidone with an increase in its side effects (for example, sedation); these phenomena cease with long-term treatment. Clinical monitoring is recommended, especially at the start of combination treatment, with dose adjustment if necessary.

Phenytoin

Depakine® reduces the concentration of phenytoin in plasma. Moreover, Depakine® increases the amount of free form of phenytoin with the possible appearance of signs of overdose (valproic acid replaces phenytoin in its binding to plasma proteins and reduces its catabolism in the liver). Therefore, clinical monitoring is recommended and free forms should be assessed when determining plasma levels of phenytoin.

Carbamazepine

Valproate may potentiate the toxic effects of carbamazepine. Clinical monitoring is recommended, especially at the beginning of combination therapy and, if necessary, dosage adjustment.

Lamotrigine

Valproate may slow the metabolism of lamotrigine and increase its elimination half-life; dosages should be adjusted if possible (reducing the dose of lamotrigine). There are suggestions, still awaiting proof, that the risk of rash increases when lamotrigine and valproic acid are used together.

Zidovudine

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

Antiepileptic drugs with an enzyme-inducing effect (phenytoin, phenobarbital, carbamazepine) reduce the concentration of valproate in the serum. If combination therapy is used, doses should be adjusted depending on the level of the drug in the blood. On the other hand, the combination of felbamate and valproate may increase serum concentrations of valproate. The dosage of valproate should be monitored. Mefloquine increases the metabolism of valproic acid and may cause convulsions. Therefore, during combination therapy, epileptic seizures may occur. In the case of simultaneous use of valproate and drugs that bind tightly to proteins (aspirin), the concentration of free valproate in the serum may increase. Careful monitoring of the prothrombin index should be carried out in case of simultaneous use of vitamin K-dependent anticoagulants. Serum levels of free valproate may increase (as a result of decreased hepatic metabolism) when administered concomitantly with cimetidine or erythromycin.

Other types of interaction

Valproate generally does not have an enzyme-inducing effect; as a result, valproate does not reduce the effectiveness of estroprogestogen drugs for women using hormonal contraceptives.

Indications of the drug Depakine® Chronosphere™

In adults - as monotherapy or in combination with other antiepileptic drugs:

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

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

treatment and prevention of bipolar affective disorders.

In children (including infants, starting from the 6th month of life) - as monotherapy or in combination with other antiepileptic drugs:

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

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

prevention of seizures at high temperatures, when such prevention is necessary.

Depakine chronosphere Granules, 30 pcs., 1000 mg

Directions for use and doses

Depakine Chronosphere is a dosage form that is particularly suitable for treating children (if they are able to swallow soft foods) or adults with difficulty swallowing. The drug is prescribed orally. The daily dose is determined depending on the age and body weight of the patient; the wide range of individual sensitivity to valproate should also be taken into account. The initial daily dose is 10-15 mg/kg body weight, then it is increased by 5-10 mg/kg per week until the optimal dose is reached. The average daily dose is 20-30 mg/kg. It is possible to increase the dose of the drug with careful monitoring of the patient's condition if epilepsy is not controlled when using average daily doses. The average daily dose for adults is 20 mg/kg; for adolescents - 25 mg/kg; for children, incl. infants (starting from 6 months of life) - 30 mg/kg. Age of patients Body weight Average daily dose*Infants aged 6 to 12 months About 7.5-10 kg 200-300 mg Children from 1 to 3 years About 10-15 kg 300-450 mg Children from 3 to 6 years About 15-25 kg 450-750 mg Children from 7 to 14 years old About 25-40 kg 750-1200 mg Adolescents from 14 years old About 40-60 kg 1000-1500 mg Adults From 60 kg and above 1200-2100 mg* dose in mg in terms of sodium valproate In elderly patients age, the dose should be adjusted according to their clinical condition. A good correlation has been established between the daily dose, the concentration of the drug in the serum and the therapeutic effect: the dose should be set primarily on the basis of clinical response. Determination of plasma valproic acid concentrations may serve as an adjunct to clinical monitoring if epilepsy is uncontrolled or side effects are suspected. The range of therapeutic efficacy is usually 40-100 mg/L (300-700 µmol/L). When switching from Depakine in the form of immediate release or sustained release of valproate, which provided disease control, to Depakine Chronosphere, it is recommended to maintain the daily dose for well-controlled epilepsy. For patients who have previously taken other antiepileptic drugs, their replacement with Depakine Chronosphere should be carried out gradually, reaching the optimal dose of valproate within approximately 2 weeks. In this case, depending on the patient’s condition, the dose of the previous drug is reduced. For patients not taking other antiepileptic drugs, doses should be increased after 2-3 days in order to reach the optimal dose within about a week. If it is necessary to combine the drug Depakine Chronosphere with other antiepileptic drugs, they should be administered gradually. Rules for using the drug Depakine Chronosphere in 100 mg sachets are used only in children and infants. Depakine Chronosphere in 1 g sachets is used only in adults. The daily dose is recommended to be taken in 1 or 2 doses, preferably during meals. Use in 1 dose is possible for well-controlled epilepsy. The contents of the sachet should be poured onto the surface of soft food or drinks at cold or room temperature (including yogurt, orange juice, fruit puree, etc.). If Depakine Chronosphere is taken with liquid, it is recommended to rinse the glass with a small amount of water and drink this water, because granules may stick to glass. The mixture should always be swallowed immediately without chewing. It should not be saved for later use. The drug Depakin Chronosphere should not be used with hot food or drinks (such as soups, coffee, tea, etc.). The drug Depakin Chronosphere cannot be poured into a bottle with a nipple, because granules can clog the nipple opening. Considering the duration of the process of releasing the active substance and the nature of the excipients, the inert matrix of the granule is not absorbed from the digestive tract; it is excreted in feces after complete release of the active substance.

Contraindications

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

acute hepatitis;

chronic hepatitis;

a history of severe liver disease (especially drug-induced hepatitis) in the patient and/or his close blood relatives;

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

severe dysfunction of the liver or pancreas;

hepatic porphyria;

established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), such as Alpers-Huttenlocher syndrome, and suspected diseases caused by defects in γ-polymerase in children under 2 years of age (see "Special Instructions" );

patients with established disorders of the carbamide cycle (urea cycle) (see “Special Instructions”);

hemorrhagic diathesis, thrombocytopenia;

combination with mefloquine;

combination with St. John's wort preparations;

children's age up to 6 months.

With caution: history of liver and pancreas diseases; pregnancy; congenital enzymopathies; inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia); renal failure (dose adjustment required); hypoproteinemia (see “Pharmacokinetics”, “Dosage and Administration”); simultaneous use of several anticonvulsants (due to an increased risk of liver damage); simultaneous use of drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, SSRIs, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures); simultaneous use of antipsychotics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiating their effects); simultaneous use of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, rufinamide (especially in children), protease inhibitors (lopinavir, ritonavir), cholestyramine (due to pharmacokinetic interactions at the level of metabolism or communication with plasma proteins may change the plasma concentrations of either these drugs and/or valproic acid, for more details see “Interaction”); simultaneous use of carbamazepine (risk of potentiation of the toxic effects of carbamazepine and a decrease in plasma concentrations of valproic acid); simultaneous use of topiramate or acetazolamide (risk of encephalopathy); existing deficiency of carnitine palmitoyltransferase (CPT) type II (higher risk of developing rhabdomyolysis when taking valproic acid).

DEPAKIN CHRONO

special instructions

Before starting the use of the drug Depakine® chrono and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed.
As with the use of most antiepileptic drugs, when using valproic acid, a slight increase in the activity of liver enzymes is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In these patients, a more detailed study of biological 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 the event of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine the bleeding time and the number of formed elements in the peripheral blood, including platelets.

Severe liver damage

Predisposing factors

There have been isolated reports of severe liver damage, sometimes fatal. Clinical experience shows that patients at risk are those taking multiple antiepileptic drugs at the same time; infants and children under three years of age with severe seizures, especially in the setting of brain damage, mental retardation and/or congenital metabolic or degenerative diseases; patients concomitantly taking salicylates (since salicylates are metabolized through the same metabolic pathway as valproic acid).

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

Symptoms suspicious for liver damage

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

- nonspecific symptoms, especially those that began suddenly, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;

- resumption of seizures in patients with epilepsy.

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

Revealing

Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative are studies reflecting the state of the protein-synthetic function of the liver, especially the determination of the prothrombin index. Confirmation of deviation from the norm of the prothrombin index in the direction of its decrease, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood clotting factors, an increase in the concentration of bilirubin and an increase in the activity of “liver” transaminases), as well as the appearance of other symptoms indicating for liver damage (see above), requires discontinuation of the drug Depakine® Chrono. As a precaution, if patients were taking salicylates concomitantly, their use should also be discontinued.

Pancreatitis

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

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

Patients who experience severe abdominal pain, nausea, vomiting and/or anorexia should be evaluated immediately. If 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 should be initiated.

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

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 mental and physical development disorders in children who were exposed to valproic acid in utero. The benefit/risk ratio should be carefully re-evaluated in the following cases: during regular review of treatment, when a girl reaches puberty and, urgently, if a woman taking valnroic acid plans or becomes pregnant.

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

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

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

— the need to use effective contraception;

- the need for regular review of treatment;

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

A woman planning a pregnancy should definitely try, if possible, to switch to an alternative treatment before she attempts to conceive (see section “Use during pregnancy and breastfeeding”). Treatment with valproic acid should be continued only after a physician experienced in the treatment of epilepsy and bipolar disorders has re-evaluated the benefits and risks of treatment.

Suicidal thoughts and attempts

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

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

Carbapenems

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

Patients with known or suspected mitochondrial diseases

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

In accordance with current clinical practice, testing for mutations in the polymerase γ gene (POLG) should be performed to diagnose such diseases (see section “Contraindications”).

Increased seizures

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

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

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

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

Kidney failure

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

Enzyme deficiency of the carbamide cycle (urea cycle)

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

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

Patients with systemic lupus erythematosus

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

Weight gain

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

Patients with diabetes mellitus

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

Patients infected with human immunodeficiency virus (HIV)

In in vitro

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

Patients with existing deficiency of carnitine palmitoyltransferase (CPT) tin II

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

Ethanol

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

Other special instructions

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

One tablet of Depakine® Chrono 300 mg contains 1.2 mmol (27.6 mg) sodium. One tablet of Depakine® Chrono 500 mg contains 2 mmol (46.1 mg) sodium. This must be taken into account in patients on a strict low sodium diet.

Use during pregnancy and breastfeeding

Risk associated with developing epileptic seizures during pregnancy

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

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

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

Congenital malformations

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

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

Mental and physical development disorders

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Risk to newborns

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

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

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

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

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

Breastfeeding period

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

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

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

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

Depakine Chronosphere, 30 pcs., 250 mg, extended-release granules

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

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

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

Severe liver damage

Predisposing factors.

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

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

Symptoms indicating possible liver damage.

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

- nonspecific symptoms, especially those that began suddenly, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;

- resumption of seizures in patients with epilepsy.

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

Identification.

Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative are studies reflecting the state of the protein-synthetic function of the liver, especially the determination of the prothrombin index. Confirmation of abnormal prothrombin index, especially in combination with abnormalities in other laboratory parameters (significant decrease in fibrinogen and coagulation factors, increased bilirubin concentration and increased transaminase activity), as well as the appearance of other symptoms indicating liver damage (see above ), requires discontinuation of the use of the drug Depakine® Chronosphere™. As a precaution, if patients were concomitantly receiving salicylates, their use should also be discontinued.

Pancreatitis.

There are rare reported cases of severe forms of pancreatitis in children and adults, developing regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis have been observed with rapid progression of the disease from the first symptoms to death. Young children are at increased risk of developing pancreatitis; the risk decreases as the child ages. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for developing pancreatitis. Liver failure combined with pancreatitis increases the risk of death. Patients who experience severe abdominal pain should be evaluated immediately. If pancreatitis is confirmed, in particular with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment should be initiated.

Suicidal thoughts and attempts.

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

Carbapenems.

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

Patients with established or suspected mitochondrial diseases.

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

Women of childbearing potential, pregnant women.

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

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

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

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

— the need to use effective contraception;

- the need for regular review of treatment;

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

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

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

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

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

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

Kidney failure.

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

Enzyme deficiency of the carbamide cycle (urea cycle).

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

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

Patients with systemic lupus erythematosus.

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

Increase in body weight.

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

Patients with diabetes.

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

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

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

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

Ethanol.

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

Other special instructions.

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

Impact on the ability to drive vehicles and operate machinery.

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

Side effects

The WHO classification is used to indicate the incidence of adverse reactions (HP): very common ≥10%; often ≥1 and <10%; uncommon ≥0.1 and <1%; rarely ≥0.01 and <0.1%; very rare <0.01%, unknown frequency (when it is not possible to estimate the incidence of HP from the available data).

Congenital, hereditary and genetic disorders: teratogenic risk (see “Use during pregnancy and lactation”).

From the blood and lymphatic system: often - anemia, thrombocytopenia (see "Special Instructions"); uncommon - pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can occur 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; decrease in the content of blood coagulation factors (at least one), deviation from the norm of blood coagulation parameters (such as an increase in PT, APTT, thrombin time and INR) (see “Use during pregnancy and lactation” and “Special instructions”). 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 pass); uncommon - 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 combined with an increase in seizures during treatment, and also decreased when the drug was discontinued or its dose was reduced. Most of these cases have been described during combination therapy, especially with the simultaneous use of phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid.

From the organ of hearing and labyrinthine disorders: often - reversible and irreversible deafness.

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

From the respiratory system, chest and mediastinum: uncommon - pleural effusion.

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

From the 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 mechanism of development 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 androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary syndrome (see Genital and breast disorders and Endocrine system disorders), as well as alopecia against the background of developed hypothyroidism ( see Endocrine system disorders), disorders of the nails and nail bed; infrequently - angioedema, rash, hair disorders (such as disruption of the normal structure, discoloration, abnormal growth (disappearance of wavy and curly hair or, conversely, the appearance of curly hair in people with initially straight hair), hirsutism, acne; 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 bone mineral density, osteopenia, osteoporosis and fractures in patients taking Depakine® drugs for a long time. The mechanism of influence of Depakine® drugs on bone metabolism has not been established; rarely - systemic lupus erythematosus (see "Special Instructions"), rhabdomyolysis (see "Contraindications", With caution, "Special Instructions").

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

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 * (see "Special Instructions"), obesity.

* Cases of isolated and moderate hyperammonemia may occur without changes in liver function tests, which 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 of valproic acid and additional examination (see “Special Instructions”).

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

From the blood vessels: often - bleeding and hemorrhage (see "Special instructions" and "Use during pregnancy and lactation"); infrequently - vasculitis.

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

From the liver and biliary tract: often - liver damage: deviation from the norm in indicators of the functional state of the liver, such as a decrease in the prothrombin index, especially in combination with a significant decrease in the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of liver transaminases in the blood; liver failure, in exceptional cases - fatal; It is necessary to monitor patients for possible liver dysfunction (see “Special Instructions”).

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

Mental disorders: often - 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).

* ADRs mainly observed in pediatric patients.

Instructions for use DEPAKINE CHRONOSPHERE

During treatment with an anticonvulsant drug, resumption or development of new seizures is occasionally possible, regardless of the spontaneous changes in the course of the disease observed in some epileptic conditions. With regard to valproate, this primarily concerns the combination regimen for the treatment of epilepsy, pharmacokinetic interactions, toxicity (hepato- or encephalopathy) and overdose.

Since sodium valproate is converted into valproic acid in the body, it should not be combined with other drugs that share common metabolic pathways (for example, divalproate, valpromide) in order to prevent an overdose of valproic acid.

Before starting treatment and during the first 6 months of treatment, liver function should be periodically monitored, especially in patients at risk.

It should be emphasized that during treatment with Depakine Chronosphere, as with other antiepileptic drugs, a slight, isolated and temporary increase in transaminase levels may be observed, especially at the beginning of treatment, in the absence of any clinical symptoms. In this case, it is recommended to conduct a more complete laboratory examination (including, in particular, determination of the prothrombin index) in order to revise the dose, if necessary, and repeat the tests depending on changes in parameters.

There are extremely rare reports of severe and fatal cases of liver disease.

At increased risk are 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. In children over 3 years of age, the frequency of such complications decreases significantly and gradually decreases with age. In most cases, liver dysfunction was observed during the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combined antiepileptic treatment.

Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk. On the one hand, there are nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain. On the other hand, there is a relapse of epileptic seizures.

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

Among the standard parameters, the most important are tests that reflect liver protein synthesis, and especially the prothrombin index. If an abnormally low level of prothrombin, a significant decrease in the level of fibrinogen and coagulation factors, an increase in the level of bilirubin and the activity of liver transaminases are detected, treatment with Depakine Chronosphere should be suspended. It is also necessary to interrupt treatment with salicylates if they were included in the treatment regimen, since their metabolism uses common pathways with valproate.

In extremely rare cases, severe forms of pancreatitis, sometimes fatal, have been reported. These cases were observed regardless of the patient's age or duration of treatment, although the risk was particularly increased for young children. Pancreatitis with an unfavorable outcome was usually observed in children of a younger age group, or in patients with severe epilepsy, brain damage, or when using complex anticonvulsant therapy.

Liver failure due to pancreatitis increases the risk of death.

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

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

In case of acute abdominal pain and gastrointestinal symptoms such as nausea, vomiting and/or anorexia, it is necessary to keep in mind the risk of developing pancreatitis and, if the level of pancreatic enzymes is elevated, discontinue the drug, taking alternative therapeutic measures.

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

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

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

Use in pediatrics

In children under 3 years of age

The use of valproate (in the recommended dosage form) as monotherapy is recommended, but before starting treatment, the potential benefits of treatment with the drug should be assessed in relation to the risk of developing liver disease or pancreatitis.

Combined use with salicylates should be avoided in children under 3 years of age.

due to the risk of hepatotoxicity.

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

Impact on the ability to drive vehicles and operate machinery

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