Depakine chrono 500, pills, 30pcs

Composition

of 1 tab. sodium valproate**333 mgvalproic acid**145 mg

Auxiliary substances:

colloidal anhydrous silicon dioxide – 4 mg,

methylhydroxypropylcellulose 4000 MPa. c (hypromellose) – 176 mg,

ethylcellulose (20 MPa. c) – 12 mg,

sodium saccharin-10 mg,

colloidal hydrated silicon dioxide-50 mg,

methylhydroxypropylcellulose-6 MPa. c (hypromellose) – 7.2 mg,

30% polyacrylate dispersion-24 mg,

macrogol 6000-7

.2 mg, talc-7.2 mg,

titanium dioxide-1.2 mg

. * * corresponds to 500 mg of valproic acid in 1 tab.

Pharmacological action

The drug has a central muscle relaxant and sedative effect. It shows antiepileptic activity in all types of epilepsy.

The main mechanism of action is probably related to the effect of valproic acid on the GABA-ergic system: the drug increases the content of GABA in the central nervous system and activates GABA-ergic transmission.

Pharmacokinetics

Suction

The oral bioavailability of sodium valproate and valproic acid is close to 100%.

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

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

Compared to the enteric-soluble coated dosage form, the drug in the form of a delayed-release tablet in equivalent doses is characterized by the absence of latent absorption time, prolonged absorption, identical bioavailability, a lower Cmax value (a decrease in Cmax by about 25%), but with a more stable plateau phase from 4 to 14 hours after use, a more linear correlation between dose and drug concentration in plasma.

Distribution

Binding to plasma proteins (mainly albumin) is high (90-95%), dose-dependent and saturated.

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

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

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

Metabolism

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

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

Deduction

It is mainly excreted 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 cases

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

In hypoproteinemia, the total concentration of valproic acid (free + plasma protein-bound fractions) may not change, but it 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 T1/2 decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

T1 / 2 values in children over the age of 2 months are close to those in adults.

In patients with liver disease, valproic acid T1/2 increases.

In case of overdose, an increase in T1/2 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

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

Indications

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

• treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic);
• Lennox-Gastaut syndrome;
• treatment of partial epileptic seizures (partial seizures with or without secondary generalization);
• treatment and prevention of bipolar affective disorders.

In children, 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).

Use during pregnancy and lactation

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

Experimental studies of reproductive toxicity in mice, rats, and rabbits have shown the teratogenic effect of valproic acid.

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; as well as multiple intrauterine malformations affecting different organ systems) compared to the frequency of their occurrence when pregnant women take certain other antiepileptic drugs.

Based on the available data, it is assumed that there is a relationship 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 dysmorphism phenomena. However, in cases of developmental delay in such children, it is difficult to accurately establish a causal relationship with valproic acid intake due to the possibility of simultaneous exposure to other factors, such as low intelligence of the mother or both parents; genetic, social, 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 are associated with an unfavorable pregnancy outcome, but according to available data, combined antiepileptic therapy with valproic acid is associated with a higher risk of an unfavorable pregnancy outcome compared to valproic acid monotherapy.

In view of the above, Depakin® 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 need for Depakin chrono or the possibility of discontinuing its use should be decided before starting the drug or reviewed if a woman receiving Depakin chrono is planning to become pregnant.

Women of childbearing age should use effective methods of contraception during treatment with Depakin ® chrono. Women of childbearing age should be informed about the risks and benefits of using valproic acid during pregnancy. When prescribing the drug, it is necessary to exclude pregnancy.

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

• In bipolar disorder, discontinuation of valproic acid treatment should be considered;
• in epilepsy, continuation or discontinuation of valproic acid treatment is decided after a reassessment of the benefit-risk ratio. If, after reviewing the benefit-risk ratio, a decision is made to continue treatment with Depakin® chrono during pregnancy, 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 dosage forms of the drug with a delayed release is preferable.

One month before conception and for 2 months after it, folic acid (at a dose of 5 mg/day) should be added to antiepileptic treatment, as this can minimize the risk of neural tube malformations.

Special prenatal monitoring should be carried out at all times to detect possible neural tube malformations or other fetal malformations.

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 may be due to a decrease in 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, it is necessary to determine the number of platelets in the blood, the plasma concentration of fibrinogen, 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.

The excretion of valproic acid in breast milk is low, its concentration in breast milk is 1-10% of its concentration in plasma. Based on literature data and a small amount of clinical experience, mothers may plan to breastfeed when using Depakin chrono monotherapy, but the side effect profile of the drug, especially the hematological disorders it causes, should be taken into account.

Use in children

For children aged 6 years and older, the average daily dose is 30 mg / kg.

Contraindications

• hypersensitivity to valproate sodium, valproic acid, valproate of Seminary, valpromide or any of the auxiliary components of the drug;
• acute hepatitis;
• chronic hepatitis;
• severe liver disease (especially drug-induced hepatitis) in history from the patient and his close blood relatives;
• severe liver injury with fatal outcome when use of valproic acid have close blood relatives of a patient;
• severe violations of the liver or pancreas;
• severe impairment of pancreatic function;
• hepatic porphyria;
• combination with mefloquine;
• combination with preparations of Hypericum perforatum;
• children up to age 6 years (risk of tablets in the airway when swallowing).

Be wary

• of diseases of the liver and pancreas in history;
• pregnancy;
• congenital fermentopathy;
• the oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia),
• renal failure (requires correction of the doses);
• patients receiving a few anticonvulsants (due to the increased risk of liver damage);
• simultaneous reception of drugs causing seizures or reduce the seizure threshold, such as tricyclic antidepressants, selective inhibitors of serotonin reuptake; phenothiazine derivatives, derivatives of butirofenona, chloroquine, bupropion, tramadol (risk of provoking seizures);
• concomitant use of neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiation of their effects);
• simultaneous reception of phenobarbital, the primidon, phenytoin, lamotrigine, alone, felbamate, acetylsalicylic acid, anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine (due to pharmacokinetic interactions at the level of metabolism or svyazyvaniya with blood plasma proteins may change in plasma concentrations of drugs and/or valproic acid);
• concomitant use with carbamazepine (risk of potentiation of toxic effects of carbamazepine and reduce plasma concentrations of valproic acid);
• concomitant use with topiramate (risk of encephalopathy).

Use in patients with liver function disorders

The drug is contraindicated in patients with impaired liver function.

Use in patients with impaired renal function

When using Depakin Chrono in patients with renal insufficiency, it may be necessary to reduce the dose of the drug.

Use in elderly patients

In elderly patients, the dose should be adjusted according to their clinical condition.

Side effects

Determination of the frequency of adverse reactions (WHO): very common (≥10%), common (≥1% and

From the hematopoietic system: often-thrombocytopenia; rarely-pancytopenia, anemia, leukopenia, disorders of bone marrow hematopoiesis, including isolated aplasia of red blood cells; agranulocytosis.

From the side of the blood coagulation system: isolated decreases in blood fibrinogen levels and prothrombin time prolongation have been reported, which are usually not accompanied by clinical manifestations, especially when used in high doses (valproic acid has an inhibitory effect on the second phase of platelet aggregation).

Nervous system disorders: infrequently – ataxia; very rarely – dementia combined with brain atrophy, reversible within a few weeks or months after discontinuation of the drug, several cases of stupor and lethargy (sometimes leading to temporary coma/encephalopathy; they may be isolated or combined with increased convulsive seizures (despite treatment), which become less frequent when the drug is discontinued or the dose is reduced; these cases were mainly observed during combination therapy, in particular with phenobarbital or topiramate, or after a sharp increase in the dose of valproic acid), extrapyramidal disorders (may be irreversible), including reversible Parkinsonism, transient and/or dose-dependent mild postural tremor and drowsiness, hyperammonemia combined with neurological symptoms (in this case, the patient requires additional examination).

From the side of the psyche: infrequently-irritability, hyperactivity, confusion, especially at the beginning of treatment; rarely-changes in behavior, mood, depression, fatigue, aggressiveness, psychosis, unusual agitation, motor restlessness, dysarthria; frequency unknown-hallucinations.

From the side of the hearing organ: rarely-reversible or irreversible deafness.

From the side of the visual organ: the frequency is unknown – diplopia, nystagmus, flickering of “flies” in front of the eyes.

From the digestive system: often – at the beginning of treatment, nausea, vomiting, epigastric pain, diarrhea, which usually disappear after a few days with continued use of the drug; rarely-liver damage; very rarely-pancreatitis, sometimes with a fatal outcome.

From the urinary system: very rarely – enuresis. There have been several isolated reports of reversible Fanconi syndrome, the mechanism of which is still unclear.

Skin and subcutaneous tissue disorders: often – transient or dose-dependent alopecia; very rarely-toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash.

From the side of metabolism: often-isolated and moderate hyperammonemia in the absence of changes in liver function tests and neurological manifestations, which does not require discontinuation of the drug; very rarely – hyponatremia, ADH secretion disorder syndrome, weight gain (since obesity is a risk factor for the development of polycystic ovarian syndrome, patients with weight gain should be carefully monitored).

From the side of blood vessels: vasculitis.

Common disorders: very rarely-small peripheral edema.

From the immune system: angioedema, drug rash syndrome with eosinophilia and systemic symptoms (DRESS-syndrome), allergic reactions, for example, urticaria.

From the side of the reproductive system: frequency unknown-amenorrhea and dysmenorrhea, male infertility.

Interaction

Effect of valproic acid on other drugs

Valproic acid can potentiate the effect of other psychotropic drugs, such as neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (clinical monitoring is recommended and, if necessary, dose adjustment of the corresponding drug).

Valproic acid does not affect the serum lithium concentration.

Valproic acid increases the concentration of phenobarbital in plasma (due to a decrease in its hepatic metabolism), and therefore it is possible to develop a sedative effect of the latter, especially in children.Therefore, careful medical monitoring of the patient during the first 15 days of combination therapy is recommended, with immediate reduction of the dose of phenobarbital in case of sedation and, if necessary, determination of the plasma concentration of phenobarbital.

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

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

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

Valproic acid can increase plasma concentrations of zidovudine, which leads to an increase in the toxicity of zidovudine.

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

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

Effect of other drugs on valproic acid

Antiepileptic drugs capable of inducing 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.

When combined with felbamate and valproic acid, the clearance of valproic acid decreases 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 seizures, so when they are used simultaneously, an epileptic seizure may develop.

With the simultaneous use of valproic acid and St. John’s wort preparations, it is possible to reduce the anticonvulsant effectiveness of valproic acid.

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

When valproic acid and indirect anticoagulants are used simultaneously, 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 its hepatic metabolism).

A decrease in the concentration of valproic acid in the blood when it is used simultaneously with carbapenems (panipenem, meropenem, imipenem), leading to a 60-100% decrease in the concentration of valproic acid in the blood plasma for 2 days of co-therapy, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems in patients with a selected dose of valproic acid should be avoided due to their ability to rapidly and intensively reduce the concentration of valproic acid in plasma. If treatment with carbapenems cannot be avoided, valproic acid concentrations in the blood should be carefully monitored.

Rifampicin can reduce the concentration of valproic acid in the blood, which leads to a loss of the therapeutic effect of Depakin ® chrono. Therefore, it may be necessary to increase the dose of Depakin ® chrono with simultaneous use of rifampicin.

Other interactions

Concomitant use of valproic acid and topiramate was associated with encephalopathy and / or hyperammonemia. Patients receiving this combination should be closely monitored for symptoms of hyperammoniemic encephalopathy.

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.

Concomitant use of clonazepam with valproic acid may lead in isolated cases to an increase in the severity of the absent status.

Concomitant use of myelotoxic drugs with valproic acid increases the risk of inhibition of bone marrow hematopoiesis.

How to take, course of use and dosage

Depakin ® chrono is intended only for adults and children over 6 years of age with a body weight of more than 17 kg!

Depakin ® chrono is a slow-release dosage form that avoids sudden increases in the concentration of valproic acid in the blood after taking the drug and maintains a constant concentration of valproic acid in the blood for a longer time during the day.

Long-acting tablets Depakin ® chrono 300 mg or 500 mg can be divided to facilitate the use of an individually selected dose.

Tablets are taken without crushing or chewing them.

Epilepsy

The doctor selects the daily dose individually.

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

The daily dose is set according to the patient’s age and body weight. A gradual increase in the dose is recommended until the minimum effective dose is reached.

No clear relationship was found between the daily dose, plasma concentration, and therapeutic effect. Therefore, the optimal dose should be determined mainly based on the clinical response. Determining the level of valproic acid in plasma can serve as an adjunct to clinical observation if epilepsy is not controlled or there is a suspicion of developing side effects. The therapeutic blood concentration range is usually 40-100 mg / L (300-700 micromol/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 over seizures.

Average daily doses (for long-term use):

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

for adolescents (body weight 40-60 kg) – 25 mg of valproic acid/kg of 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 cannot be 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 can be divided into 1-2 doses, preferably with a meal.

Use in one dose is possible with well-controlled epilepsy.

Most patients who are already taking Depakin ® in the non-prolonged-acting dosage form can be switched to Depakin ® 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 transition to Depakin® chrono should be carried out gradually, reaching the optimal dose of the drug for about 2 weeks. In this case, you should immediately reduce the dose of the antiepileptic drug that the patient took earlier, especially if it is phenobarbital. Discontinuation of the antiepileptic drug that the patient has previously taken should be carried out gradually.

Becauseother antiepileptic drugs may reversibly induce microsomal liver enzymes; the plasma valproic acid concentration should be monitored for 4-6 weeks after the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), the daily dose of valproic acid should be reduced.

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

Manic episodes in bipolar disorder

Adults

The daily dose should be selected individually.

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

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

The average 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.

When continuing 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 younger than 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 mainly on the clinical picture, and not on the total content of valproic acid in the blood serum (free fraction and fraction bound to plasma proteins), in order to avoid possible errors in dose selection.

Overdose

Symptoms: coma with muscular hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis; cases of intracranial hypertension associated with cerebral edema are described. Symptoms may vary, and convulsive seizures have been reported at very high plasma concentrations of valproic acid.

With a significant overdose, a fatal outcome is possible, but usually the prognosis is favorable.

Treatment: in the hospital-gastric lavage, which is effective for 10-12 hours after taking the drug; monitoring and correction of the functional state of the cardiovascular and respiratory systems, maintaining effective diuresis. In some cases, naloxone was successfully used. In very severe cases of significant overdose, hemodialysis and hemoperfusion were effective.

Special instructions

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 seizures, especially against the background of brain damage, mental retardation and/or congenital metabolic or degenerative diseases.

In children over 3 years of age, the risk of liver damage is significantly reduced and progressively decreases as the patient’s age increases. In most cases, liver damage occurs during the first 6 months of treatment.

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

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

Patients or their families (if using the drug for children) should be warned that they should immediately report any of these symptoms to the attending physician. If these symptoms occur, patients should immediately undergo a clinical examination and laboratory examination of liver function indicators.

Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among the usual studies, the most informative are those that reflect the state of protein-synthetic liver function, especially the prothrombin index. Confirmation of abnormalities in the prothrombin index, especially in combination with abnormalities in other laboratory parameters (a significant decrease in the content of fibrinogen and blood clotting factors, an increase in bilirubin concentration and an increase in transaminase activity), requires discontinuation of Depakin chrono. As a precaution, if patients receive salicylates at the same time, they should also be discontinued, since they are metabolized through the same metabolic pathway as valproic acid.

Pancreatitis

Children are at an increased risk of developing pancreatitis, and the risk decreases with increasing age. 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, 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.

Suicidal thoughts and attempts

Suicidal thoughts or attempts have been reported in patients receiving antiepileptic drugs for certain 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 Depakin ® chrono should be constantly monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be provided. Patients and their caregivers are advised to seek immediate medical attention if the patient has suicidal thoughts or attempts.

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.

Insufficiency of urea cycle enzymes

If urea cycle enzymes are suspected to be insufficient, the use of valproic acid is not recommended. Several cases of hyperammonemia with stupor or coma have been reported in these patients. In these cases, metabolic studies should be performed before starting valproic acid treatment.

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), lethargy or coma in the anamnesis, with mental retardation or with a family history of death of a newborn or child, before starting treatment with valproic acid, metabolic studies should be conducted, in particular the determination of ammonemia (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 immune system disorders are extremely rare during treatment with Depakin® chrono, the potential benefit of its use should be compared with the potential risk of prescribing the drug to patients with systemic lupus erythematosus.

Weight gain

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

Monitoring of laboratory parameters

Before starting Depakin 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 most antiepileptic drugs, there may be a slight increase in the activity of liver enzymes, 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 required, and dose adjustments may be required, and if necessary, repeated clinical and laboratory examinations.

Before starting therapy or if surgery is necessary, in case of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to conduct a hematological blood test (determine the leukocyte formula of the blood, including the number of platelets; bleeding time and coagulogram).

Use in pediatrics

In children under 3 years of age, if the use of valproic acid is necessary, it is recommended to use Depakin® as monotherapy and in a special dosage form intended for children. At the same time, before starting treatment, it is necessary to evaluate the ratio of the potential benefit of valproic acid and the risk of liver damage and pancreatitis when using it.

Concomitant use of salicylates should be avoided in children under 3 years of age due to the risk of hepatotoxicity and bleeding.

Ethanol

Alcohol consumption is not recommended during treatment.

Influence on the ability to drive motor vehicles and manage mechanisms

Patients should be warned about the risk of drowsiness, especially in the case of combined anticonvulsant therapy or when combining valproic acid with benzodiazepines.

During the treatment period, care should be taken and discuss with the attending physician the possibility of driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Tablets

Storage conditions

The drug should be stored out of the reach of children, in a dry place at temperatures below 25°C.

Shelf

life is 3 years.

Active ingredient

Valproic Acid

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as prescribed by a doctor, Children over 6 years of age, Children as prescribed by a doctor

Indications

Epilepsy