Depakine Chronosphere, 1000mg granules, 30pcs

Composition

	of 1 pack.
sodium valproate	666.6 mg
valproic acid	290.27 mg
in terms of sodium valproate	1000 mg

Excipients: solid paraffin-1012.63 mg, glycerol dibegenate-1060.5 mg, colloidal water silicon dioxide*.

* added by spray after the melt cooling process and expressed as a percentage of the other four components: 0.7% (approximate amount absorbed on pellets: 0.56%).

Pharmacological action

The drug has a central muscle relaxant and sedative effect.

It shows antiepileptic activity on various types of epilepsy. It is obvious that the main mechanism of action is related to the effect of valproic acid on the GABA-ergic system: it increases the content of GABA in the central nervous system and activates GABA-ergic transmission.

Depakin ® Chronosphere™ is a long-acting granule that provides more uniform drug concentrations throughout the day.

Pharmacokinetics

Suction

The oral bioavailability of valproic acid is close to 100%. Food intake does not affect the pharmacokinetic profile. _{Cmax of} the drug in plasma is reached approximately 7 hours after oral use.

Compared to the enteric-coated dosage form, equivalent doses of Depakin® Chronosphere™ are characterized by longer absorption, identical bioavailability, and a more linear correlation between doses and plasma valproic acid concentrations (total and free fraction concentrations). In addition, the_cmax and_cmaxof the free fraction of valproic acid in plasma are lower (a decrease of about 25%), but there is a relatively more stable phase of the plateau of plasma concentrations from 4 to 14 hours after use, the magnitude of fluctuations in plasma concentrations when taking Depakin®Chronosphere™ in comparison with the dosage form covered with an enteric coating, it is halved, as a result of which valproic acid is more evenly distributed in the tissues during the day.

With a course of taking the drug, C_ss of valproic acid in the blood serum is reached within 3-14 days.

Usually effective are serum valproic acid concentrations of 40-100 mg / l (300-700 mmol / l) (determined before taking the first dose of the drug during the day) With serum valproic acid concentrations above 100 mg/l, an increase in side effects is expected up to the development of intoxication.

The distribution_of vd depends on age and is usually 0.13-0.23 l / kg of body weight, in young people 0.13-0.19 l/kg of body weight. Due to a decrease in the magnitude of fluctuations in plasma concentrations when taking Depakin®Chronosphere™, valproic acid is more evenly distributed in the tissues during 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 saturated. 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 concentration in the blood serum, that is, it is close to the concentration of the free fraction of valproic acid in the blood serum.

Valproic acid passes into the breast milk of nursing mothers. In the state of reaching C_ss valproic acid in the blood serum, 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 omega-1 oxidation. More than 20 metabolites were identified, and the metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not have an inducing effect on enzymes that are part of the cytochrome P 450 metabolic system: unlike most other antiepileptic drugs, valproic acid does not affect the degree of both its own metabolism and the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Deduction

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

When valproic acid is used in monotherapy, its T_1/2 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 T_1/2decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs. T_1/2 in children older than 2 months is close to that in adults.

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.

In patients with liver diseases, T_1/2 of valproic acid increases.

In case of overdose, an increase in T_1/2 to 30 h was observed. Only the free fraction of valproic acid in the blood (510%) is subjected to hemodialysis.

Features of pharmacokinetics during pregnancy

With_{an increase in} valproic acid Vd 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 serum concentrations of valproic acid. In addition, during pregnancy, the relationship of valproic acid with plasma proteins may change, which may 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):

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

In children (starting from 6 months of age) and children (as monotherapy or in combination with other antiepileptic drugs):

• for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gastaut syndrome;
• for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization;
• prevention of seizures at high temperature, when such prevention is necessary.

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.

Data from a meta-analysis that included registry and cohort studies showed that the incidence of congenital malformations in children born to mothers who received valproic acid as monotherapy during pregnancy was 10.73%. Available data indicate a dose-dependent adverse effect of valproic acid on the fetus.

Based on the available data, it is assumed that there is a causal relationship between intrauterine exposure to valproic acid and the risk of developmental delay, in particular, a decrease in verbal IQ in children born to mothers with epilepsy who took valproic acid. 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 (i. e., the risk of fetal disorders is lower when valproic acid is used as monotherapy).

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

In connection with the above, Depakin ® Chronosphere™ it 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 Chronosphere or the possibility of discontinuing its use should be decided before starting the drug, or reviewed if a woman receiving Depakin is not taking the drug. Chronosphere™, is planning a pregnancy.

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

Before prescribing the drug, pregnancy should be excluded.

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

• In the case of bipolar disorder, discontinuation of valproic acid treatment should be considered;
• in the case of epilepsy, continuation or discontinuation of valproic acid treatment is decided after a reassessment of the benefit-risk ratio.

If, after a reassessment of the benefit-risk ratio, a decision is made to continue treatment with Depakin Chronosphere 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 prolonged-release drug is preferable.

Before pregnancy, folic acid should be added to antiepileptic treatment (at a dose of 5 mg / day) to reduce 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 thrombocytopenia, hypofibrinogenemia and / or 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 during pregnancy, it is necessary to determine the number of platelets in the blood, plasma concentration of fibrinogen, blood clotting factors and coagulogram.

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

Cases of hypothyroidism have been reported in newborns whose mothers took valproic acid during 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, breast-feeding can be planned with Depakin Chronosphere monotherapy, but the side effect profile of the drug, especially the hematological disorders caused by it, should be taken into account.

Fertility

In men, valproic acid can reduce sperm motility and cause male infertility. In addition, due to the possibility of developing undesirable effects from the endocrine system and genitals in women (such as dysmenorrhea, amenorrhea, polycystic ovary disease, hyperandrogenism), it is possible to reduce fertility in women.

Use in children

Average daily dose for children, including children (starting from 6 months of life) – 30 mg / kg.

Contraindications

• 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;
• hepatic porphyria;
• hemorrhagic diathesis, thrombocytopenia;
• the combination with mefloquine;
• combination with preparations of Hypericum perforatum;
• children up to age 6 months;
• hypersensitivity to valproate sodium, valproic acid, valproate of Seminary, valpromide or to any component of the drug.
• With caution
• used in diseases of liver and pancreas in history;
• during pregnancy;
• in hereditary enzymopathies;
• when the oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia),
• renal failure (dose adjustment is required);
• if hypoproteinemia;
• in patients on multiple anticonvulsants due to the increased risk of liver injury;
• the simultaneous use of drugs that provoke seizures or reduce the seizure threshold, such as tricyclic antidepressants, selective inhibitors of the re-capture of serotonin derivatives of phenothiazine, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures);
• while receiving neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (possibility of potentiation of their effects);
• the simultaneous use of phenobarbital, primidone, phenytoin, lamotrigine, alone, felbamate, acetylsalicylic acid, anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine (due to pharmacokinetic interactions at the metabolic level or connection with blood plasma proteins may change in plasma concentrations of drugs and/or valproic acid);
• with simultaneous use of carbamazepine (risk of potentiation of toxic effects of carbamazepine and reduce plasma concentrations of valproic acid);
• while the use of topiramate (risk of encephalopathy).

Use in patients with liver function disorders

The drug is contraindicated in acute hepatitis, chronic hepatitis, in cases of severe hepatitis in the patient or in his family history, especially caused by medications, with severe liver function disorders.

Use in patients with impaired renal function

The drug should be used with caution in patients with renal insufficiency.

Side effects

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

From the hematopoietic system: often-anemia, thrombocytopenia; infrequently-pancytopenia, leukopenia. After discontinuation of the drug, the blood picture returns to normal. Rarely-disorders of bone marrow hematopoiesis (including isolated aplasia of red blood cells, agranulocytosis), macrocytic anemia, macrocytosis.

From the side of the blood coagulation system: often-bleeding and hemorrhage; rarely-a decrease in the content of blood clotting factors (at least one), such as an increase in prothrombin time, an increase in APTT, an increase in thrombin time, an increase in MHO. The appearance of spontaneous bruising and bleeding requires discontinuation of the drug and conducting a clinical and laboratory examination.

Nervous system disorders: very often – tremor; often – extrapyramidal disorders, stupor*, drowsiness, convulsions*, memory disorders, headache, nystagmus, dizziness (may occur a few minutes after IV injection and disappear spontaneously within a few minutes); infrequently – coma*, encephalopathy*, lethargy*, reversible Parkinsonism, ataxia, paresthesia; rarely – reversible dementia combined with reversible dementia. brain atrophy, cognitive disorders; frequency unknown – sedation, alertness.

*Stupor and lethargy sometimes led to transient coma/encephalopathy and were either isolated or combined with increased convulsive seizures during treatment, and also decreased when the drug was discontinued or the dose was reduced.Most of these cases have been reported during combination therapy, especially when phenobarbital or topiramate are used simultaneously, or after a sharp increase in the dose of valproic acid.

From the side of the psyche: infrequently-a state of confusion, aggressiveness, agitation, attention disorders (aggressiveness, agitation, attention disorders were mainly observed in children); rarely-behavioral disorders, psychomotor hyperactivity, learning disabilities (these adverse reactions were mainly observed in children).

From the side of the hearing organ: often – deafness.

From the digestive system: very often – nausea (including may occur a few minutes after intravenous use of the drug and spontaneously disappear in a few minutes); often – epigastric pain, diarrhea (which often occur in some patients at the beginning of treatment, but usually disappear after a few days and do not require discontinuation of therapy); infrequently – pancreatitis, sometimes fatal.

Liver and biliary tract disorders: often-liver damage, which is accompanied by a deviation from the normal indicators of the functional state of the liver, such as a decrease in the prothrombin index, especially in combination with a significant decrease in the content of fibrinogen and blood clotting factors, an increase in the concentration of bilirubin and an increase in the activity of hepatic transaminases in the blood; liver failure, in exceptional cases with a fatal outcome.

Respiratory system disorders: infrequently-pleural effusion.

From the urinary system: very rarely – enuresis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of renal tubular damage with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is still unclear.

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

Musculoskeletal disorders: infrequently-decreased bone mineral density, osteopenia, osteoporosis and fractures in patients taking Depakin Chronosphere™ for a long time (the mechanism of effect of Depakin Chronosphere™ on bone metabolism has not been established).

Skin and subcutaneous tissue disorders: often – transient or dose-dependent alopecia (including androgenetic alopecia due to hyperandrogenism, polycystic ovary disease, and alopecia due to hypothyroidism); infrequently-rash; rarely-toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme; very rarely-hirsutism, acne.

From the endocrine system: infrequently – syndrome of inadequate ADH secretion, hyperandrogenism; rarely-hypothyroidism.

From the side of metabolism: often-hyponatremia, weight gain (because weight gain is a factor contributing to the development of polycystic ovarian syndrome); rarely-hyperammonemia (cases of isolated and moderate hyperammonemia without changes in liver function indicators and the need to stop treatment; cases of hyperammonemia accompanied by the appearance of neurological symptoms, including the development of encephalopathy, vomiting, ataxia), which required discontinuation of valproic acid and additional examination.

From the side of blood vessels: infrequently – vasculitis.

From the side of the reproductive system: often-dysmenorrhea; infrequently-amenorrhea; rarely-male infertility.

Common disorders: infrequently – mild peripheral edema.

Interaction

Effect of valproic acid on other drugs

Antipsychotics, MAO inhibitors, antidepressants, benzodiazepines

Valproic acid may potentiate the effects of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, careful medical monitoring and, if necessary, dose adjustment are recommended when used concomitantly with valproic acid.

Lithium preparations

Valproic acid does not affect serum lithium concentrations.

Phenobarbital

Valproic acid increases the plasma concentrations of phenobarbital (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 plasma concentrations of phenobarbital.

Primidon

Valproic acid increases plasma concentrations of primidone with 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.

Phenytoin

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

Carbamazepine

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.

Lamotrigine

Valproic acid slows down the metabolism of lamotrigine in the liver and increases the half-life of lamotrigine by almost 2 times. This interaction can lead to an increase in 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.

Zidovudine

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

Felbamat

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

Nimodipine (for oral use and, by extrapolation, a solution for parenteral use)

Increased hypotensive effect of nimodipine 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 plasma concentrations of valproic acid. In the case of combination therapy, valproic acid doses should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

Felbamat

When combined with felbamate and valproic acid, the clearance of valproic acid decreases by 22-50% and, accordingly, plasma concentrations of valproic acid increase. Plasma concentrations of valproic acid should be monitored.

Mefloquine

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.

Preparations of St. John’s wort holed

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

Drugs with strong binding to plasma proteins (acetylsalicylic acid)

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

Indirect anticoagulants

When valproic acid and indirect anticoagulants are used simultaneously, careful monitoring of the prothrombin index is required.

Cimetidine, erythromycin

Serum valproic acid concentrations may increase with concomitant use of cimetidine or erythromycin (as a result of slowing its hepatic metabolism).

Carbapenems (panipenem, meropenem, imipenem)

Reduction of valproic acid concentrations in the blood when it is used simultaneously with carbapenems, leading to a 60-100% decrease in the concentration of valproic acid in the blood for two 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 quickly and intensively reduce the concentration of valproic acid in the blood. If treatment with carbapenems cannot be avoided, valproic acid concentrations in the blood should be carefully monitored.

Rifampicin

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

Other interactions

Topiramate

Concomitant use of valproic acid and topiramate has been associated with encephalopathy and / or hyperammonemia.Patients receiving these two medications at the same time should be closely monitored for symptoms of hyperammoniemic encephalopathy.

Estrogen-progestogenic drugs

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 methods of contraception.

Ethanol and other potentially hepatotoxic drugs

When used simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid.

Clonazepam

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

Myelotoxic drugs

When used concomitantly with valproic acid, the risk of inhibition of bone marrow hematopoiesis increases.

How to take, course of use and dosage

Depakin ® Chronosphere™ is a dosage form that is particularly well suited for the treatment of children (if they are able to swallow soft food) or adults with difficulty swallowing.

Depakin ® Chronosphere™ is a long-acting granule that provides a more uniform concentration of valproic acid in the blood and, accordingly, a more uniform distribution of valproic acid in the tissues during the day.

Bipolar affective disorders

The dose should be selected and monitored by the attending physician individually. The daily dose should be adjusted based on the patient’s age and body weight. The recommended starting dose is 20 mg (based on sodium valproate) per kg of body weight. The dose should be increased as quickly as possible to the minimum dose that provides the desired therapeutic effect.

The recommended maintenance dose for the treatment of bipolar disorders is between 1000 mg and 2000 mg (based on sodium valproate) per day. The dose should be selected according to the individual clinical response of the patient. For the prevention of manic states, an individually selected minimum clinically effective dose should be used.

Epilepsy

In monotherapy, the initial daily dose is usually 5-10 mg (based on sodium valproate) per kg of body weight, then it is increased by 5 mg / kg every 4-7 until the optimal dose is reached, which allows you to prevent the occurrence of seizures of epilepsy.

Average daily dose:

• for children (under 14 years old) – 30 mg / kg of body weight;
• for adolescents 14-18 years-25 mg/kg of body weight;
• for adults and elderly patients (body weight from 60 kg and above) – 20 mg / kg of body weight.

Therefore, the following daily doses are recommended.

Age of patients	Body weight	Average daily dose*
children aged 6-12 months	About 7.5-10 kg	150-300 mg
Children from 1 to 3 years old	About 10-15 kg	300-450 mg
Children from 3 to 6 years old	About 15-25 kg	450-750 mg
Children from 7 to 14 years old	About 25-40 kg	750-1200 mg
Teenagers over 14 years old	About 40-60 kg	1000-1500 mg
Adults	60 kg and above	1200-2100 mg

* dose based on the number of milligrams of sodium valproate

The average daily dose can be increased by controlling 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.

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

A clear correlation between the daily dose, the concentration of valproic acid in the blood serum and the therapeutic effect was not established. Therefore, the optimal dose of the drug should be selected mainly on the basis of the clinical response.

Determination of the valproic acid concentration in the blood serum can serve as an adjunct to clinical observation if epilepsy cannot be controlled or the development of side effects is suspected. Usually effective doses are those that provide serum valproic acid concentrations of 40-100 mg / l (300-700 mmol / L). If there is a reasonable need to achieve higher concentrations in the blood serum, the ratio of expected benefit and risk of side effects, especially dose-dependent ones, should be carefully weighed, since at serum concentrations of valproic acid above 100 mg/l, an increase in side effects is expected up to the development of intoxication. Therefore, the serum concentration determined before taking the first dose per day should not exceed 100 mg/l.

When switching from dosage forms of Depakin® For immediate-release or delayed-release patients who have well controlled epilepsy, the same daily dose is recommended for Depakin Chronosphere.

For patients who have previously taken antiepileptic drugs, the transition to Depakin Chronosphere should be carried out gradually, reaching the optimal dose of the drug over approximately 2 weeks. At the same time, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previously taken antiepileptic drug is discontinued, then its cancellation should be carried out gradually.

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

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, blood valproic acid concentrations 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 Depakin® Chronosphere™should be reduced.

Although there are changes in the pharmacokinetics of valproic acid in elderly patients, they are of limited clinical significance and the dose of valproic acid in elderly patients should be selected in accordance with the achievement of ensuring control over seizures.

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 plasma protein-bound fraction together), in order to avoid possible errors in dose selection.

Method of application

The drug is taken orally.

Depakin® Chronosphere™ 100 mg sachets are used only in children and infants.

Depakin ® Chronosphere™ 1000 mg sachets are used only in adults.

The daily dose is recommended to be taken in 1 or 2 doses, preferably with a meal. Use in 1 dose is possible with well-controlled epilepsy.

Depakin ® Chronosphere™ should be applied to the surface of soft food or drink, cold or at room temperature (yogurt, orange juice, fruit puree, etc. ).

Depakin ® Chronosphere™ should not be used with hot food or beverages (such as soups, coffee, tea, etc. ).

Depakin ® Chronosphere™ should not be placed in a bottle with a pacifier, as the granules can clog the opening of the nipple.

If Depakin ® Chronosphere™ is taken with a liquid, it is recommended to rinse the glass with a small amount of water and drink this water, as the granules may stick to the glass.

The mixture should always be swallowed immediately, without chewing. It should not be saved for later use.

Taking into account the duration of the Active ingredient release process and the nature of the excipients, the inert matrix of the granule is not absorbed from the digestive tract, but is excreted in the feces after the Active ingredient is completely released.

Overdose

Symptoms: clinical manifestations of acute massive overdose usually occur in the form of coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, and metabolic acidosis. Cases of intracranial hypertension associated with cerebral edema have been described. With a massive overdose, a fatal outcome is possible, but usually the prognosis for overdose is favorable.

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

Treatment: emergency care for overdose in the hospital should be as follows: gastric lavage, which is effective within 10-12 hours after taking the drug, monitoring the state of the cardiovascular and respiratory systems and maintaining effective diuresis. In some cases, naloxone was successfully used. In very severe cases of massive overdose, hemodialysis and hemoperfusion were effective.

Special instructions

Before starting the use of Depakin® 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 most antiepileptic drugs, valproic acid may cause a slight increase in the activity of liver enzymes, 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 it may be necessary to adjust the dose of the drug, and if necessary, repeat clinical and laboratory examinations.

Before starting therapy or surgery, 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).

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; patients taking salicylates at the same time (since salicylates are metabolized along the same metabolic pathway as valproic acid).

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, most often between 2 and 12 weeks of treatment, and usually when valproic acid is used as part of combined antiepileptic therapy.

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 the concentration of bilirubin and an increase in transaminase activity), as well as the appearance of other symptoms indicating liver damage, requires discontinuation of therapy.

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. In case of confirmation of pancreatitis, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment 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 Chronosphere 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 immune system disorders have been shown to be extremely rare during treatment with Depakin Chronosphere, the potential benefits of its use should be compared with the potential risks 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.

Patients with diabetes mellitus

Taking into account the possibility of adverse effects of valproic acid on the pancreas, when using the drug in patients with diabetes mellitus, the concentration of glucose in the blood should be carefully monitored. When examining urine for the presence of ketone bodies in patients with diabetes mellitus, false positive results may be obtained, since valproic acid is excreted by the kidneys, partly in the form of ketone bodies.

Use in pediatrics

In children under 3 years of age, if necessary, the use of valproic acid is recommended as monotherapy. 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 when taking combined anticonvulsant therapy or when combining Depakin Chronosphere with benzodiazepines.

Form of production

Granules of prolonged action are almost white or slightly yellowish in color, waxy, easily loose, without the formation of agglomerates.

Storage conditions

At a temperature not exceeding 25 °C

Shelf life

2 years

Active ingredient

Valproic Acid

Conditions of release from pharmacies

By prescription

Dosage form

granules

Purpose

Children as prescribed by a doctor, Children over 14 years of age, Adults as prescribed by a doctor

Indications

Epilepsy