Glutamic acid Depakine Chrono 500. Depakine Chrono

in a blister pack 10 pcs.; in a box 10 packages (150 and 500 mg) or in a blister pack 20 pcs.; There are 5 packs in a box (300 mg).

in 100 ml bottles, complete with a measuring syringe; 1 set in box.

in bottles of 100 ml; 1 bottle in a box.

in polyethylene bottles or dark glass bottles of 50 or 100 pcs.; 1 bottle in a cardboard box

Description of the dosage form

Capsules: brownish-pink soft gelatin capsules, enteric-coated; on the capsule there is an inscription in black ink “150”, “300” or “500”.

Syrup for children: colorless or slightly yellowish syrup with a peach aroma and a sweet peach taste.

Drops for oral administration: colorless or slightly yellowish solution.

Extended-release film-coated tablets: oval, biconvex tablets white, with the smell of vanilla, film-coated, with a dividing line and engraving “CC3” (300 mg tablets) or “CC5” (500 mg tablets) on one side; on cross section white.

Pharmacodynamics

Inhibits GABA transferase and increases the content of GABA in the central nervous system. GABA inhibits pre- and postsynaptic discharges and thereby prevents the spread of seizure activity into the central nervous system. In addition, in the mechanism of action of the drug, a significant role is played by the effect of valproic acid on GABA A receptors, as well as the effect on voltage-dependent sodium channels. According to another hypothesis, it acts on sites of postsynaptic receptors, simulating or enhancing the inhibitory effect of GABA. A possible direct effect on membrane activity is associated with changes in potassium conductance. Improves the mental state and mood of patients, has antiarrhythmic activity.

Pharmacokinetics

Quickly and completely absorbed from the gastrointestinal tract, bioavailability is 100%. Eating does not reduce the rate of absorption. C max is determined after 3–4 hours. Equilibrium concentration is achieved on days 2–4 of treatment (depending on dosing intervals). Therapeutic concentration in plasma is 50–150 mg/l. Plasma protein binding is 90–95% at plasma concentrations up to 50 mg/l and 80–85% at concentrations 50–100 mg/l; with uremia, hypoproteinemia and cirrhosis, protein binding is reduced. Cerebrospinal fluid concentration levels correlate with the non-protein bound fraction of the drug. Valproic acid penetrates the placental barrier and is excreted in breast milk. Concentrations in breast milk are 1–10% of maternal plasma concentrations. The drug undergoes glucuronidation and oxidation in the liver; metabolites and unchanged valproic acid (1–3% of the dose) are excreted by the kidneys, small amounts - with feces and exhaled air. T1/2 in healthy subjects and with monotherapy - 8–20 hours, when combined with inducers of metabolic enzymes T1/2 - 6–8 hours; in patients with impaired liver function and elderly patients, it can be significantly prolonged.

The prolonged form is characterized by slow absorption, lower (25%), but relatively more stable plasma concentrations between 4 and 14 hours.

Depakine Chrono: Indications

epilepsy of any origin;

epileptic seizures (including generalized and partial, as well as against the background organic diseases brain);

character and behavior disorders associated with epilepsy;

febrile seizures in children;

manic-depressive syndrome with a bipolar course that cannot be treated with lithium or other drugs.

Depakine Chrono: Contraindications

hypersensitivity;

severe dysfunction of the liver and/or pancreas;

porphyria;

severe thrombocytopenia;

hemorrhagic diathesis;

pregnancy (first trimester);

breast-feeding;

children under 3 years of age (tablets).

Use during pregnancy and breastfeeding

During treatment, pregnancy should be protected.

Experiments on animals revealed the teratogenic effect of valproic acid. The incidence of neural tube defects in children, born by women who took valproate in the first trimester of pregnancy is 1–2%. In this regard, it is advisable to use folic acid preparations.

If a pregnant woman is already receiving the drug, treatment should not be interrupted due to the risk of increased seizures. The drug should be used in the lowest effective doses, avoiding combination with other anticonvulsants and, if possible, regularly monitoring plasma drug levels.

During lactation, the drug should be taken with caution. At the same time, breastfeeding is possible, because the concentration in milk does not exceed 1–10% of the drug level in the mother’s blood plasma.

Directions for use and doses

Inside.

Capsules: without chewing, regardless of food, with a small amount of liquid, 2-3 times a day.

Syrup and drops: regardless of food, with a small amount of liquid, 2-3 times a day.

Tablets: without chewing, regardless of food, with a small amount of liquid, 1-2 times a day.

For adults, the initial daily dose is 600 mg with a gradual increase in dose every 3 days until a clinical effect is achieved (disappearance of seizures).

For monotherapy, the initial dose is 5–15 mg/kg/day, then the dose is gradually increased by 5–10 mg/kg per week.

The average daily dose is about 1000–2000 mg/day, i.e. 20–30 mg/kg. If necessary, the dose is increased to 2500 mg/day.

The maximum dose is 30 mg/kg/day (can be increased if it is possible to monitor the plasma concentration to 60 mg/kg/day).

With combination therapy - 10–30 mg/kg/day, followed by an increase in dose by 5–10 mg/kg per week.

Children weighing more than 25 kg: the initial daily dose is 300 mg (regardless of body weight), which can be gradually increased until a clinical effect is achieved (disappearance of seizures) to 20–30 mg/kg per day. The initial dose for monotherapy is 5–15 mg/kg/day, then it is gradually increased by 5–10 mg/kg per week. The maximum dose is 30 mg/kg/day (can be increased if it is possible to monitor plasma concentrations up to 60 mg/kg/day).

Children weighing 17–25 kg (tablets), 7.5–25 kg (capsules, syrup, drops): the average daily dose for monotherapy is 15–45 mg/kg, the maximum is 50 mg/kg. With combination therapy - 30–100 mg/kg/day.

Average daily doses - see table.

Average daily doses of Convulex ®

Body weight of a child, teenager or adult, kg	Dose, mg/day	Number of capsules (150 mg)	Number of capsules or tablets (300 mg)	Number of capsules or tablets (500 mg)	Amount of syrup, ml	Number of drops
7,5–14	150–450	1–3			3–9	15–45
14–21	300–600	2–4	1–2		6–12	30–60
21–32	600–900	4–6	2–3		12–18	60–90
32–50	900–1500		3–5	2–3
50–90	1500–2500			3–5

Elderly patients and patients with renal failure may be prescribed smaller doses of the drug (careful dose selection is required).

Depakine Chrono: Side effects

In general, Konvulex ® is well tolerated by patients. Side effects are possible mainly when the drug level in plasma is above 100 mg/l or during combination therapy.

From the gastrointestinal tract: nausea, vomiting, gastralgia, anorexia or increased appetite, diarrhea, hepatitis; rarely - constipation, pancreatitis, up to severe injuries with a fatal outcome (in the first 6 months of treatment, more often at 2–12 weeks).

From the side of the central nervous system: tremor; rarely - changes in behavior, mood or mental state(depression, feeling tired, hallucinations, aggressiveness, hyperactive state, psychosis, unusual agitation, motor restlessness or irritability), ataxia, dizziness, drowsiness, headache, encephalopathy, dysarthria, stupor, impaired consciousness, coma.

From the senses: diplopia, nystagmus, flashing “spots” before the eyes.

From the hematopoietic organs and hemostasis system: anemia, leukopenia, thrombocytopenia, decreased fibrinogen content, platelet aggregation and blood clotting, accompanied by prolongation of bleeding time, petechial hemorrhages, bruises, hematomas, bleeding, etc.

From the side of metabolism: loss or increase in body weight.

Allergic reactions: skin rash, urticaria, angioedema, photosensitivity, Stevens-Johnson syndrome.

Laboratory indicators: hypercreatininemia, hyperammonemia, hyperbilirubinemia, slight increase in the activity of “liver” transaminases, LDH (dose-dependent).

From the outside endocrine system: dysmenorrhea, secondary amenorrhea, breast enlargement, galactorrhea.

Others: peripheral edema, hair loss (usually stops after discontinuation of the drug).

Overdose

Symptoms: nausea, vomiting, dizziness, diarrhea, respiratory dysfunction, muscle hypotonia, hyporeflexia, miosis, coma.

Treatment: gastric lavage (no later than 10–12 hours), appointment activated carbon, hemodialysis, forced diuresis, respiratory support and of cardio-vascular system.

Interaction

Pharmacodynamic interaction

Increased CNS depression may occur when valproic acid is used concomitantly with ethanol and other CNS depressants. Ethanol and other hepatotoxic drugs increase the likelihood of developing liver damage. Tricyclic antidepressants, MAO inhibitors, antipsychotics and other drugs that lower the threshold for seizure activity reduce the effectiveness of valproic acid.

Convulex ® enhances the effects, incl. side effects, other antiepileptic drugs (phenytoin, lamotrigine), antidepressants, antipsychotics, tranquilizers, barbiturates, MAO inhibitors, ethanol. The addition of valproate to clonazepam in isolated cases can lead to increased severity of absence status.

Pharmacokinetic interaction

With the simultaneous use of valproic acid with barbiturates or primidone, an increase in their concentration in the blood plasma is observed. Increases T1/2 of lamotrigine (inhibits liver enzymes, causes a slowdown in the metabolism of lamotrigine, as a result of which T1/2 is extended to 70 hours in adults and to 45–55 hours in children). Reduces the clearance of zidovudine by 38%, while its T1/2 does not change.

When combined with salicylates, an increase in the effects of valproic acid is observed (displacement from plasma proteins). Konvulex ® enhances the effect of antiplatelet agents (acetylsalicylic acid) and indirect anticoagulants.

When combined with phenobarbital, phenytoin, carbamazepine, mefloquine, the content of valproic acid in the blood serum decreases (acceleration of metabolism).

Felbamate increases plasma concentrations of valproic acid by 35–50% (dose adjustment required).

Valproic acid does not induce liver enzymes and does not reduce the effectiveness of oral contraceptives.

special instructions

During treatment, it is advisable to monitor the activity of “liver” transaminases, bilirubin levels, peripheral blood patterns, blood platelets, the state of the blood coagulation system, amylase activity every 3 months (especially when combined with other antiepileptic drugs).

In patients receiving other antiepileptic drugs, transfer to valproic acid should be carried out gradually, reaching a clinically effective dose after 2 weeks, then gradual withdrawal of other antiepileptic drugs is possible. In patients not treated with other antiepileptic drugs, a clinically effective dose should be achieved after 1 week.

Development risk side effects from the liver is increased during combined anticonvulsant therapy and in children.

During the treatment period, it is necessary to refrain from potentially active activities dangerous species activities that require increased concentration and speed of psychomotor reactions.

Drinks containing ethanol are not allowed.

Before surgical intervention necessary general analysis blood (including platelet count), determination of bleeding time, coagulogram parameters.

If symptoms of an “acute” abdomen occur during treatment before surgical intervention It is recommended to determine the level of amylase in the blood to exclude acute pancreatitis.

During treatment, one should take into account the possible distortion of the results of urine tests in diabetes mellitus (due to an increase in the content of keto products) and indicators of thyroid function.

If any acute serious side effects develop, you should immediately discuss with your doctor the advisability of continuing or stopping treatment.

To reduce the risk of developing dyspeptic symptoms, it is possible to take antispasmodics and enveloping agents.

Abrupt cessation of taking Convulex ® may lead to an increase in epileptic seizures.

Composition and release form

Depakine® chrono, 300 mg

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

Depakine® chrono, 500 mg

Film-coated tablets, prolonged action - 1 tablet:

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

Extended-release film-coated tablets, 300 mg. 50 tablets each in a polypropylene bottle, closed with a PE stopper, with a desiccant. 2 fl. placed in a cardboard box.

Extended-release film-coated tablets, 500 mg. 30 tablets each. in a polypropylene bottle, closed with a PE stopper, with a desiccant. 1 fl. placed in a cardboard box.

Description of the dosage form

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

pharmachologic effect

Antiepileptic, anticonvulsant, normothymic.

Pharmacokinetics

Absorption

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

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

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

Distribution

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

The binding to plasma proteins (mainly albumin) is high (90–95%), dose-dependent and saturable. In elderly patients, patients 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.

Valproic acid penetrates into breast milk nursing mothers. When the Css of valproic acid in the blood serum is reached, its concentration in breast milk ranges from 1 to 10% of its concentration in the blood serum.

Metabolism

Metabolism occurs in the liver through 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 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. Less than 5% of valproic acid is excreted unchanged by the kidneys.

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

T1/2 is 15–17 hours. When combined with antiepileptic drugs that induce liver microsomal enzymes, plasma clearance of valproic acid increases and T1/2 decreases, the degree of their change depends on the degree of induction of liver microsomal enzymes by other antiepileptic drugs. T1/2 values ​​in children over 2- one month old close to those 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 (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 connection of valproic acid with blood plasma proteins may change, which can lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum.

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

• lack of absorption delay after administration;
• prolonged absorption;
• identical bioavailability;
• a lower Cmax value (approximately 25% decrease in Cmax), but with a more stable plateau phase from 4 to 14 hours after administration;
• more linear correlation between dose and plasma concentration of the drug.

Pharmacodynamics

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

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

Indications for use

Adults

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

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

Contraindications for use

• hypersensitivity to sodium valproate, valproic acid, 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 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), for example Alpers-Huttenlocher syndrome and suspected diseases due to defects (POLG), in children under 2 years of age (applies to the use of dosage forms of the drug Depakine ®, which are intended for use by children);
• combination with mefloquine;
• combination with St. John's wort preparations;
• children under 6 years of age (risk of tablets entering the respiratory tract when swallowed).

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; patients taking multiple anticonvulsants (due to 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, olanzapine, propofol, aztreonam, 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, it is possible to change the plasma concentrations of these drugs and/or valproic acid); simultaneous use of carbamazepine (risk of potentiating the toxic effects of carbamazepine and reducing plasma concentrations of valproic acid), topiramate or acetazolamide (risk of developing encephalopathy); existing deficiency of carnitine palmitoyltransferase (CPT) type II (higher risk of developing rhabdomyolysis when taking valproic acid).

Use during pregnancy and children

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

Risk associated with the development of 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 to both the mother and the fetus due to the possibility of death.

Risk associated with the use of Depakine® Chrono 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 cardiovascular system, hypospadias, and multiple malformations affecting different systems organs, 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 birth defects development 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 to monotherapy with phenytoin, carbamazepine, phenobarbital and lamotrigine, respectively.

Data from a meta-analysis that included registry and cohort studies showed that the incidence of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was 10.73% (95% CI: 8.16–13. 29). This risk is greater than the 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. 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 such children had early developmental delays (including delays in learning to walk and speech development), as well as lower intellectual abilities, poor language skills (own speech and language comprehension) and memory problems.

Intelligence quotient (IQ) scores measured in children aged 6 years with a history of prenatal exposure to valproate were on average 7 to 10 points lower than those measured in children with prenatal exposure 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 increased risk development of a spectrum of autism disorders (approximately 3-fold increase in risk), including childhood autism (approximately 5-fold increase in risk). Limited evidence suggests that children exposed to valproic acid in utero are more likely to develop attention-deficit/hyperactivity disorder.

Monotherapy with valproic acid 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 more high risk adverse pregnancy outcome compared to monotherapy with valproic acid (i.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® Chrono should not be used during pregnancy and in women with childbearing potential unless absolutely necessary, i.e. its use is possible only in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

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

Women should be informed about the need to plan pregnancy and monitor its progress.

Women of childbearing potential should use effective methods of contraception during treatment with Depakin® Chrono.

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

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

• if bipolar disorder is indicated, discontinuation of treatment with valproic acid should be considered;
• when 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 Depakine® Chrono must still be continued during pregnancy, it is recommended to use it in the minimum effective daily dose, divided into several doses. It should be noted that during pregnancy, it is more preferable to use extended-release dosage forms of the drug.

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 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, including detailed ultrasound.

Before childbirth. Before delivery, the mother should undergo coagulation tests, in particular platelet count, fibrinogen concentration and clotting time (aPTT).

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 thrombocytopenia, 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.

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

Fertility

Due to the possibility of developing dysmenorrhea, amenorrhea, polycystic ovaries, and an increase in the concentration of testosterone in the blood, fertility in women may decrease. In men, valproic acid can reduce sperm motility and impair fertility.

These fertility problems have been found to be reversible after cessation of treatment.

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

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

Based on literature data and small clinical experience, you can consider breastfeeding during monotherapy with Depakine® Chrono, but you should take into account the side effect profile of the drug, especially the hematological disorders it causes.

Side effects

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

Congenital, hereditary and genetic disorders: teratogenic risk.

From the side of blood and lymphatic system: often - anemia, thrombocytopenia; 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; a decrease in the content of blood coagulation factors (at least one), deviations from the norm of blood coagulation parameters (such as an increase in PT, APTT, thrombin time, INR). The appearance of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct an examination.

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

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

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: infrequently - pleural effusion.

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

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 androgenetic alopecia against the background of developed hyperandrogenism, polycystic ovary syndrome (see below From the genital organs and mammary glands and from the endocrine system), as well as alopecia against the background of developed hypothyroidism (see below From the endocrine system, From the nails and nail bed); uncommon - angioedema, rash, hair disorders (such as hair loss normal structure hair, change in hair color, abnormal hair growth (disappearance of wavy and curly hair, or vice versa - the appearance of curly hair in people with initially straight hair); rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

From the musculoskeletal and connective tissue: uncommon - decreased BMD, osteopenia, osteoporosis and fractures in patients taking Depakine® drugs for a long time. The mechanism of influence of Depakine® drugs on metabolism bone tissue not installed; rarely - systemic lupus erythematosus, rhabdomyolysis.

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

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 (cases of isolated and moderate hyperammonemia may occur without changes in liver function tests, which do not require cessation of treatment. Hyperammonemia has also been reported, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and others neurological symptoms), which required discontinuation of valproic acid and additional examination, obesity.

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

From the side of blood vessels: often - bleeding and hemorrhage; 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; patients need to be monitored for possible violations liver functions.

From the genital organs and mammary glands: 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).

*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.

** Adverse reactions mainly observed in pediatric patients.

Drug interactions

Effect of valproic acid on other drugs

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

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

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

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

Phenytoin. Valproic acid reduces total plasma concentrations of phenytoin. In addition, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of overdose (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 concentrations of phenytoin and its free fraction in the blood are recommended.

Carbamazepine. With the simultaneous use of valproic acid and carbamazepine, an increase in the plasma concentration of the active metabolite of carbamazepine is possible with signs of overdose. Clinical manifestations of carbamazepine toxicity have been reported because valproic acid may potentiate the toxic effects of carbamazepine. Close clinical monitoring of such patients is recommended, especially when initiating combination therapy, with appropriate carbamazepine dose adjustments if necessary.

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

Zidovudine. Valproic acid may increase plasma concentrations of zidovudine, resulting in increased toxicity of zidovudine, especially hematological effects, by inhibiting its metabolism by valproic acid. Continuous clinical observation and monitoring of laboratory parameters is necessary. A blood test should be done to rule out the development of anemia during the first 2 months of combination therapy.

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

Olanzapine. Valproic acid may decrease plasma concentrations of olanzapine.

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

Propofol. Valproic acid may lead to increased plasma concentrations of propofol. Consideration should be given to reducing the dose of propofol when used concomitantly with valproic acid.

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

Temozolomide. Concomitant use of temozolomide with valproic acid leads to a mild, but statistically significant, decrease in the clearance of temozolomide.

Effect of other drugs on valproic acid

Antiepileptic drugs that can induce liver microsomal enzymes (including phenytoin, primidone, phenobarbital, carbamazepine) reduce plasma concentrations of valproic acid. In the case of combination therapy, doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

Serum concentrations of valproic acid metabolites may be increased when used concomitantly with phenytoin or phenobarbital. Therefore, patients receiving treatment with these two drugs should be carefully monitored for signs and symptoms of hyperammonemia because some metabolites of valproic acid can inhibit enzymes of the carbamide cycle (urea cycle).

Aztreons. The risk of developing seizures due to a decrease in the concentration of valproic acid in the blood plasma. Clinical observation, determination of plasma concentrations of valproic acid and possible dose adjustment of the anticonvulsant drug are necessary during treatment with this antibacterial drug and after its cessation.

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

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

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

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

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

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

Indirect anticoagulants, including warfarin and other coumarin derivatives. When valproic acid and indirect anticoagulants are used simultaneously, careful monitoring of the INR and prothrombin index is required.

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

Carbapenems (panipenem, meropenem, imipenem). Reduced concentrations of valproic acid in the blood when used simultaneously with carbapenems: after 2 days of joint therapy, a 60-100% decrease in the concentration of valproic acid in the blood was observed, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems should be avoided in patients receiving a dose of valproic acid due to their ability to rapidly and intensely reduce valproic acid blood concentrations. If treatment with carbapenems cannot be avoided, close monitoring of valproic acid blood concentrations should be performed during carbapenem treatment and after its discontinuation.

Rifampicin. Rifampicin may decrease blood concentrations of valproic acid, resulting in loss of the therapeutic effect of valproic acid. Therefore, it may be necessary to increase the dose of valproic acid during simultaneous use of rifampicin and after its discontinuation.

Protease inhibitors. Protease inhibitors, such as lopinavir, ritonavir, reduce the plasma concentration of valproic acid when used simultaneously.

Cholestyramine. Cholestyramine may lead to a decrease in plasma concentrations of valproic acid when administered concomitantly.

Other interactions

With topiramate or acetazolamide. Concomitant use of valproic acid and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia. Patients taking these drugs concomitantly with valproic acid should be closely monitored for the development of symptoms of hyperammonemic encephalopathy.

With quetiapine. Concomitant use of valproic acid and quetiapine may increase the risk of developing neutropenia/leukopenia.

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

With ethanol and other potentially hepatotoxic drugs. When used simultaneously with valproic acid, the hepatotoxic effect of valproic acid may be enhanced.

With clonazepam. The simultaneous use of clonazepam with valproic acid can lead in isolated cases to increased severity of absence status.

With myelotoxic drugs. When used simultaneously with valproic acid, the risk of suppression of bone marrow hematopoiesis increases.

Dosage

This drug is intended only for adults and children over 6 years of age weighing more than 17 kg.

Depakine® Chrono is a sustained release form active substance. Prolonged release 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 throughout the day for a longer period of time.

Extended-release tablets Depakine® Chrono 300/500 mg can be divided to facilitate the administration of an individually selected dose.

The tablets are taken without crushing or chewing them.

Dosage regimen for epilepsy

The daily dose is selected individually by the attending physician.

The minimum dose effective to prevent the development of epileptic attacks should be selected (especially during pregnancy). The daily dose should be set according to age and body weight. A stepwise (gradual) increase in dose is recommended until the minimum effective dose is achieved. No clear relationship has been established between daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined primarily by clinical response. Determination of plasma valproic acid levels can serve as an addition to clinical monitoring if epilepsy is uncontrolled or if side effects are suspected. The therapeutic blood concentration range is usually 40–100 mg/L (300–700 µmol/L).

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

Average daily doses (with long-term use):

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

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

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

In some cases complete therapeutic effect valproic acid does not appear immediately, but develops over 4–6 weeks. Therefore you should not increase daily dose above the recommended daily average before this date.

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

One-time use is possible for well-controlled epilepsy.

Most patients who are already taking dosage form non-extended-release Depakine® can be switched to a long-acting dosage form of this drug immediately or over several days, while patients must continue to take the previously selected daily dose.

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

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

Dosage regimen for manic episodes in bipolar disorders

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

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

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

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

Use of the drug in special groups of patients

Female children and adolescents, women of childbearing potential and pregnant women. Treatment with Depakine® Chrono should be started under the supervision of a specialist experienced in the treatment of epilepsy and bipolar disorders. Treatment should only be started if other treatments are ineffective or not tolerated, and the balance of benefit and risk should be carefully re-evaluated when treatment is regularly reviewed. It is preferable to use Depakine® drugs in monotherapy and in the lowest effective doses and, if possible, in extended-release dosage forms. During pregnancy, the daily dose should be divided into at least 2 single doses.

Elderly patients. Although there are changes in the pharmacokinetics of valproic acid in elderly patients, they are of limited clinical significance, and the dose of valproic acid in elderly patients should be adjusted according to the achievement of control of epileptic seizures.

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

Overdose

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

Cases have been described intracranial hypertension associated with cerebral edema.

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

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

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

Treatment: emergency care for overdose in a hospital should be as follows: gastric lavage, which is effective within 10–12 hours after taking the drug. To reduce the absorption of valproic acid, it may be effective technique activated carbon, incl. its introduction through nasogastric tube. Monitoring of the state of the cardiovascular system is required and respiratory system and maintaining effective diuresis. It is necessary to monitor the functions of the liver and pancreas. If respiratory depression occurs, mechanical ventilation may be required. Naloxone has been used with success in some cases. In very severe cases of massive overdose, hemodialysis and hemoperfusion have been effective.

Precautionary measures

Before starting the use of 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, amount shaped elements in peripheral blood, including platelets.

Severe liver damage

Predisposing factors. There have been isolated reports of severe liver damage, sometimes fatal. Clinical experience shows that the risk group includes patients taking several antiepileptic drugs at the same time; infants and children under three years of age with severe seizures, especially in the setting 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 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 suddenly begin, 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. Definition functional tests liver 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 a deviation from the norm of the prothrombin index in the direction of its decrease, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of liver transaminases), as well as the appearance of other symptoms indicating damage liver (see above), requires discontinuation of use 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 fatal outcome. Children are at increased risk of developing pancreatitis; 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 initiated.

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

Warning for female patients. If pregnancy occurs, valproic acid medications can cause serious harm to the unborn baby. Always need to apply effective ways contraception during treatment. If a woman is planning a pregnancy or becomes pregnant, she should tell her doctor immediately.

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 reassessed. following cases: during regular review of treatment, when a girl reaches puberty and urgently if a woman taking valproic acid is planning or becomes pregnant.

During treatment with valproic acid, women of childbearing potential should use reliable methods of contraception and be informed of the risks associated with taking Depakin® Chrono during pregnancy. 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 teratogenic effects, as well as disorders of the mental and physical development of the child;
• the need to use effective contraception;
• the need for regular review of treatment;
• the need for urgent consultation with her doctor if she suspects that she is pregnant or suspects the possibility of pregnancy. A woman planning a pregnancy should definitely try, if possible, to switch to an alternative treatment before she attempts to conceive. 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 thoughts and attempts in all patients taking antiepileptic drugs (including a 0.24% increase in this risk in patients taking antiepileptic drugs for for epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown. Therefore, patients taking Depakine® Chrono 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.

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 POLG. In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding POLG; for example, in patients with Alpers-Huttenlocher syndrome, valproic acid was associated with a higher incidence of acute liver failure and liver-related deaths. Diseases due to POLG defects may be suspected in patients with a family history of such diseases or symptoms suggestive of their presence, including unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura. In accordance with modern clinical practice To diagnose such diseases, testing for mutations in the POLG gene should be performed.

Paradoxical increase in the frequency and severity of seizures (including the development of status epilepticus) or the emergence of new types of seizures

As with other antiepileptic drugs, when taking valproic acid, 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 become more severe, patients should consult their physician immediately.

Children (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 use of the drug is necessary, monotherapy in the dosage form recommended for children is recommended. 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 concomitant 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 performed before starting treatment with valproic acid. In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or child, metabolic studies, in particular determination of ammonemia, should be performed before treatment with valproic acid. the presence of ammonia and its compounds in the blood) on an empty stomach and after meals.

Patients with systemic lupus erythematosus

Although it has been shown that during treatment with 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 the need to take measures, mainly prescribing diet, 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, because valproic acid is excreted by the kidneys, partly in the form of ketone bodies.

Patients infected with human immunodeficiency virus (HIV)

In vitro studies have shown that valproic acid stimulates HIV replication under certain experimental conditions. The clinical significance of this fact, if any, is unknown. Additionally, the significance of these in vitro data 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 CBT type II deficiency

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

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.

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

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

I've been taking it for about 10 years. I'm 30. My hair was falling out at first. I have a problem with my nails. Gave birth. I drank during pregnancy. I'm not complaining about my life. Without him there were attacks. As soon as I started taking it they disappeared.

My son is 17 years old. We had a lot of attacks, we went to doctors for almost two years. The epileptologist did not diagnose us. In Moscow, they urgently installed a cardioverter because the pulse reached 250 beats. It takes a long time to write what and how. Ultimately, in the past year we went to I. Cherevashchenko, in Pyatigorsk. He prescribed Depakin 500. And now we have been living almost without attacks for a year. I no longer believed that they would go away. There are side effects: lethargy, drowsiness and weight loss. Good health to everyone.

There are people who don't want to take medications. I myself refused... But I love life very much, give me adrenaline, high speed, parachutes, shooting. I'll tell you this, about those who are afraid to take medicine. It’s better to take 50 tablets a day and plant the liver and plant anything, as long as these attacks do not occur. It's impossible to live full life with this diagnosis. Therefore, drink what the doctor advised you (a competent doctor is very important, I went to St. Petersburg to some special clinic I don’t remember now). I’m already taking the pills with pleasure, I’ll take everything if only I don’t have any more attacks. And by the will of the Almighty they are no more. Drink and under no circumstances quit immediately. You can reduce the dose, but you can’t just take these pills and throw them away. This also leads to seizures. For those who are afraid to take pills: I’ve been taking them for five years now. I do what I want. No seizures. Stress happens, but it passes just like normal people healthy people. I look great. Good luck and don't be afraid to take your medications. Be careful not to drink them.

At the age of 19 I had my first attack. They prescribed Depokin Chrono 500. Now I’m 25. I haven’t had a single attack since taking it. The doctor guaranteed that within three years I would be able not to take medications at all, but since I lead a lifestyle that is not for me. I don’t deny myself anything, so to speak... Clubs, I can go without sleep for days. Yes, there are no attacks, but I can’t stop drinking them. I reduced the dose... But I didn’t leave it because my lifestyle is not the most favorable with this diagnosis.

My husband was diagnosed with epilepsy at the age of 65. Depakine was prescribed. The attacks decreased, but did not go away completely. And with constant use of Depakine for 2 years, the composition of the blood changed (decreased platelets and their characteristics), and hemoptysis developed. Now he is in the hospital in pulmonology.

My daughter is 12 years old. She had one generalized attack, frontal epilepsy. We take Depakine Chrono 300, 1 tablet 2 times. From the positive, there were no more attacks, according to the EEG there is no epiactivity. From the negative, multiple erosive-ulcerative gastritis developed in the lower part of the stomach. For any rotavirus infection opens stomach bleeding and the pancreas becomes inflamed. The liver is still normal, since we constantly drink hepatoprotectors. Now we will have to take gastroprotectors as well. Very aggressive effect on the gastrointestinal tract.

At the end of the first month, severe pain began, I couldn’t even sleep, I had difficulty falling asleep, and I was sweating.
The doctors prescribed me to take two tablets for seven days and then three tablets for a long time. 16 years old 54 kilograms 500 milligrams

My 9.5 year old daughter has been taking Valproate 300 mg morning and evening for the last three years. I also took it before, but in small doses, but I still had attacks and the doctor increased the dose. She is very short and underweight. My memory has deteriorated, although before the attacks I was a very smart girl. Constant pain in her legs, nightmares and nausea from eating

We prescribed a child, 13 years old, 500 mg at night, and zinc preparations, the result was positive, memory, behavior, thinking, our relationships improved, sleep became smooth, lost 7 kg, began to eat little. After the examination, positive dynamics. The first week there was pain in the stomach, chest pain, and all the side effects for that. Then it went away.

Hello. I have been taking Depakine Chrono 300 for 7 months, 2 times a day. My periods have stopped, sometimes I feel dizzy, and get hot very often. Everything is fine in gynecology. Tell me how to get menstruation. I am 36 years old.

I’m 24, I’ve been taking it for 6 years, I had one attack at the age of 16 with loss of consciousness, then I had myoclonus in my arms and legs for a long time. Dorziovka was 1000, then 800, now I drink 600 at night, trying to equalize the EEG.
After the first year of taking it, my hair began to fall out a lot, which of course was sad, but I didn’t go bald, I took care of it with all my might and after 6-7 months everything got better and started to grow. The menstrual cycle was disrupted from the beginning and did not improve; due to the appearance of a cyst, hormones were prescribed, in short, another drug. My hands don't shake, but my memory is very bad.
It’s much easier for me to understand that I’m a little slow (because there are healthy people who are much slower) than to wake up in the morning and wait for these twitches in all parts of the body.

Good afternoon, please tell me, I’ve been taking Depakine Chrono 300 for a week now. Almost from the first days my hands began to shake a little, my attentiveness worsened. And for the last two days I’ve felt like I’ve been in a state of deprivation of sleep for a long time. This is fine? They were assigned to me after one attack was recorded. It was when I drank a lot of coffee and slept little. I went to bed at 24-1 at night and woke up at 5:30 on weekdays. Tell me, is this a normal state when you start taking it?

I am 22 years old. I have been taking Depakine 300 for 9 years now, once a day at night. My hands are shaking very much. Memory deteriorates. The mood often changes by 100 degrees. I have problems with my nails. Everything else is fine.

And my daughter was prescribed Suxilep 20 at the age of 13. The diagnosis was Childhood absence epilepsy. She had freezing, memory lapses of 2-3 seconds or even more. A year later, an epileptic attack began. She is taking Depakine chrono. She has not had her period for almost 17 years now. There have been no attacks for a year. Her EEG is excellent! There were 2 of these attacks in total... Maybe the gradual withdrawal of Depakine will normalize menstruation?

Good afternoon my son is 22 years old, 11 months ago he had an accident with a head injury, he was in a coma, despite the fact that there were no seizures and epilepsy, the doctor prescribed Depakine Chrono 500, 250 ml g in the morning and 500 ml g in the evening, he is worried about all the side effects ..... there are no packs... well, there is a little bit of irritation but not significant, I am worried about the fact of infertility, and in general: will the side effects that are listed go away after taking it or not??? thanks in advance

Tell me, I used to take Depakine 3 times a day. Now I have enkarat chrono. how should I take it?

In general, we have been drinking for 3 years. Epilepsy was as it was, and together with Depakine 500, using it, we are also degrading our memory at full speed, there are no perceptions of reality, no, and it’s just that the child somewhere, but not with us, often withdraws into himself and sleeps just on the go... .. How to live and how to study further We are 15 years old, she has no desires
And everyone says it’s like a transitional age. Everyone would move like this...

What to take to improve memory? We have been accepting for over 10 years. 1500 per day.

I am 28 years old, I had several attacks with loss of consciousness (I don’t know what they are called correctly). The doctor prescribed 2.5 tablets a day, and if the seizures do not recur within 3 years, then the diagnosis can be removed. I have been taking the pills themselves for almost 3 months, at first I had headaches and nausea, they went away, now my hair has started to fall out a lot, but judging by the instructions this temporary effect. I saw an increase in body weight as side effects - I try to eat less and exercise, I believe in the best!!

Started taking it in September 2014 due to loss of consciousness (adolescence). They told me to take it for about a year. If it doesn't help, another year. And I’ve been taking it for 4 months now. During the period of taking it, I have already gained 10 kg, although I am only 17 (!) years old. According to my parents, I feel lethargic and my mood changes dramatically... I take 3.5 tablets a day.

Registration number: P N013004/01.
Trade name of the drug: Depakine® chrono.
International generic name: valproic acid.
Dosage form: extended-release, film-coated tablets.

Compound:
1 tablet of Depakine® Chrono with a dosage of 300 mg contains:
active ingredients: sodium valproate - 199.8 mg, valproic acid - 87.0 mg;
Excipients: methylhydroxypropylcellulose 4000 mPa.s (hypromellose) - 105.6 mg, ethylcellulose (20 mPa.s) - 7.2 mg, sodium saccharinate - 6.0 mg, hydrated colloidal silicon dioxide - 32.4 m, methylhydroxypropylcellulose 6 mPa.s (hypromellose) - 4.8 mg, 30% polyacrylate dispersion - 16.0 mg, macrogol 6000 - 4.8 mg, talc - 4.8 mg, titanium dioxide - 0.8 mg.
1 tablet of Depakine® Chrono with a dosage of 500 mg contains:
active ingredients: sodium valproate - 333 mg, valproic acid - 145.0 mg;
Excipients: anhydrous colloidal silicon dioxide - 4.0 mg, methylhydroxypropylcellulose 4000 mPa.s (hypromellose) - 176.0 mg, ethylcellulose (20 mPa.s) - 12.0 mg, sodium saccharinate - 10.0 mg, hydrated colloidal silicon dioxide - 50 .0 mg, methylhydroxypropylcellulose 6 mPa.s (hypromellose) - 7.2 mg, 30% polyacrylate dispersion - 24.0 mg, macrogol 6000 - 7.2 mg, talc - 7.2 mg, titanium dioxide - 1.2 mg .

Description: oblong, film-coated tablets, almost white, scored on both sides, odorless or with a slight odor.

Pharmacotherapeutic group: antiepileptic drug.

ATX code: N03AG01.

Pharmacological properties

Pharmacodynamics
An antiepileptic drug that has a central muscle relaxant and sedative effect.
Shows antiepileptic activity in various types of epilepsy. The main mechanism of action appears to be related to the effect of valproic acid on the GABAergic system: an increase in the content of gamma-aminobutyric acid (GABA) in the central nervous system(CNS) and activation of GABAergic transmission.

Pharmacokinetics
Absorption
The bioavailability of sodium valproate and valproic acid when taken orally is close to 100%. When taking Depakine® Chrono 500 mg tablets at a dose of 1000 mg/day, the minimum plasma concentration (Cmin) is 44.7±9.8 mcg/ml, and the maximum plasma concentration (Cmax) is 81.6±15.8 mcg/ml . The time to reach maximum concentration (Tmax) is 6.58±2.23 hours. Equilibrium concentration is achieved within 3-4 days of regular use of the drug.
The average therapeutic range for serum concentrations of valproic acid is 50-100 mg/L. If there is a justified need to achieve higher concentrations in the blood plasma, the ratio of the expected benefit and the risk of side effects, especially dose-dependent ones, should be carefully weighed, since at concentrations above 100 mg/l an increase in side effects is expected, up to the development of intoxication. At plasma concentrations above 150 mg/l, a reduction in the dose of the drug is required.
Distribution
The volume of distribution depends on age and is usually 0.13-0.23 l/kg body weight or in young people 0.13-0.19 l/kg body weight.
The connection with blood plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, the connection with blood plasma proteins decreases. In severe renal failure, the concentration of the free (therapeutically active) fraction of valproic acid can 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 the cerebrospinal fluid and the brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding concentration in the blood serum.
Valproic acid passes into the breast milk of nursing mothers. In the state of achieving equilibrium concentration of valproic acid in the blood serum, its concentration in breast milk ranges from 1% to 10% of its concentration in the blood serum.
Metabolism
Metabolism occurs in the liver through glucuronidation, as well as beta, omega, and omega-1 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 included in the cytochrome a P450 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.
Removal
Valproic acid is primarily excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted unchanged by the kidneys.
Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml/min.
The half-life is 15-17 hours. When combined with antiepileptic drugs that induce liver microsomal enzymes, the plasma clearance of valproic acid increases and the half-life decreases, the degree of their change depends on the degree of induction of liver microsomal enzymes by other antiepileptic drugs.
The half-life values ​​in children over 2 months of age are close to those in adults.
In patients with liver disease, the half-life of valproic acid is increased.
In case of overdose, an increase in the half-life to 30 hours was observed.
Only the free fraction of valproic acid in the blood (10%) is subject to hemodialysis.
Features of pharmacokinetics during pregnancy
With an increase in the volume of distribution 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 connection of valproic acid with blood plasma proteins may change, which can lead to an increase in the content of the free (therapeutically active) fraction of valproic acid in the blood serum.
Compared to the enteric-coated form, the extended-release form at equivalent doses is characterized by the following:
- no delay in absorption after administration;
- prolonged absorption;
- identical bioavailability;
- a lower Cmax value (decrease in Cmax by approximately 25%), but with a more stable plateau phase from 4 to 14 hours after administration;
- a more linear correlation between the dose and the concentration of the drug in plasma.

Indications for use

In adults


- For the treatment and prevention of bipolar affective disorders.
In children
- For the treatment of centralized epileptic seizures: clinical, tonic, tonic-clinical, absence seizures, myoclonic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs).
- For the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs).

Contraindications

Hypersensitivity to valproate, sodium, valproic acid, semisodium valproate, valpromide or any of the components of the drug;
- Acute hepatitis.
- Chronic hepatitis.
- Serious illnesses liver disease (especially drug-induced hepatitis) in the patient’s and his close blood relatives’ history.
- Severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient.
- Severe violations liver or pancreas functions.
- Hepatic porphyria.
- Combination with mefloquine.
- Combination with St. John's wort.
- Children under 6 years of age (risk of tablets getting into Airways when swallowing).

Carefully

With a history of liver and pancreas diseases.
- During pregnancy.
- For congenital enzymopathies.
- When bone marrow hematopoiesis is suppressed (leukopenia, thrombocytopenia, anemia).
- In case of renal failure (dose adjustment required).
- For hypoproteinemia (see sections “Pharmacokinetics”, “Dosage and Administration”).
- In patients receiving multiple anticonvulsants due to an increased risk of liver damage.
- While taking drugs that provoke seizures or lower the seizure threshold, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of provoking seizures).
- When taking antipsychotics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines simultaneously (possibility of potentiating their effects).
- When taking phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine simultaneously (due to pharmacokinetic interactions at the level of metabolism or plasma protein binding, plasma concentrations or these drugs and/or valproic acid, for more details see the section “Interaction with other drugs”).
- With simultaneous use of carbamazepine (risk of potentiation of the toxic effects of carbamazepine and a decrease in plasma concentrations of valproic acid).
- With simultaneous use of topiramate (risk of developing encephalopathy).

Pregnancy and lactation period

Pregnancy
Risk associated with developing epileptic seizures during pregnancy
During pregnancy, the development of generalized tonic-clinical 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® Chrono during pregnancy.
Experimental reproductive toxicity studies conducted in mice, rats and rabbits have demonstrated that valproic acid is teratogenic.
Available clinical data confirm that children born to mothers with epilepsy treated with valproic acid have an increased incidence of disorders. intrauterine development varying degrees severity (malformations of the neural tube; craniofacial deformities; malformations of the limbs, cardiovascular system; as well as multiple malformations of intrauterine development affecting different organ systems) compared with the frequency of their occurrence when pregnant women take certain other antiepileptic drugs. Available data suggest an association between prenatal exposure to valproic acid and the risk of developmental delays (especially language development) in children born to mothers with epilepsy who took valproic acid. Developmental delay is often combined with developmental defects and dysmorphism. However, in cases of developmental delay in such children, it is difficult to accurately establish a causal relationship with valproic acid due to the possibility of simultaneous influence of other factors, such as low level intelligence of the mother or both parents; genetic, social factors, factors external environment; insufficient effectiveness of treatment aimed at preventing epileptic seizures in the mother during pregnancy.
The development of various travel disorders has also been reported in children exposed in utero to valproic acid.
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 ionotherapy.
In connection with the above, Depakine® Chrono should not be used during pregnancy and in women of childbearing age unless absolutely necessary. Its use is possible, for example, in situations where other antiepileptic drugs are ineffective or the patient cannot tolerate them.
The question of the need to use the drug Depakine® Chrono or the possibility of refusing its use should be resolved before starting to use the drug or reviewed if a woman receiving Depakine® Chrono plans to become pregnant.
Women of childbearing age should use effective methods of contraception during treatment with Depakine® Chrono.
Women of childbearing age should be informed about the risks and benefits of using valproic acid during pregnancy.
If a woman is planning a pregnancy or has been diagnosed with pregnancy, the need for treatment with valproic acid should be re-evaluated depending on the indications.
- If bipolar disorder is indicated, discontinuation of treatment with valproic acid should be considered.
- When 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 Depakine® Chrono must nevertheless be continued during pregnancy, it is recommended to use it in the minimum effective daily dose, divided into several doses.
It should be noted that during pregnancy, it is preferable to use slow-release dosage forms of the drug.
One month before conception and for 2 months after it, antiepileptic treatment should be added folic acid(at a dose of 5 mg per day), as this may minimize the risk of neural tube defects.
Constant special prenatal monitoring should be carried out to identify possible defects in the formation of the neural tube or other malformations of the fetus.

Risk to newborns
The development of isolated cases of hemorrhagic syndrome has 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 the content of blood coagulation 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 receiving valproic acid, it is necessary to determine the number of platelets in the blood, plasma fibrinogen concentration, blood coagulation factors and coagulogram.
Cases of hypoglycemia have been reported in newborns whose mothers took valproic acid during the third trimester of pregnancy.

Breastfeeding period
Excretion of valproic acid into breast milk is low, its concentration in milk is 1-10% of its concentration in serum.
Based on the literature data and small clinical experience, when monotherapy with Depakine® Chrono, mothers can plan to breastfeed, but the side effect profile of the drug, especially the hematological disorders it causes, should be taken into account.

Directions for use and doses

This drug is intended only for adults and children over 6 years of age weighing more than 17 kg!
This dosage form is not recommended for children under 6 years of age (risk of the tablet entering the respiratory tract when swallowed)!
Depakine® chrono is a slow-release form of the active substance from the Depakine® group of drugs. Slow release 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 throughout the day for a longer period of time.
Extended-release tablets Depakine® Chrono 300 mg/500 mg can be divided to facilitate the administration of an individually selected dose.
The tablets are taken without crushing or chewing them.

Dosage regimen for epilepsy

The minimum dose effective to prevent the development of epileptic attacks should be selected (especially during pregnancy). The daily dose should be set according to age and body weight. A stepwise (gradual) dose increase is recommended until the minimum effective dose is reached.
No clear relationship has been established between daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined primarily by clinical response. Determination of plasma valproic acid levels can serve as an addition to clinical monitoring if epilepsy is uncontrolled or if side effects are suspected. The therapeutic blood concentration range is usually 40 - 100 mg/L (300 - 700 µmol/L).
For monotherapy, the initial dose is usually 5-10 mg valproic acid per kg body weight, which is then gradually increased every 4-7 days at a rate of 5 mg valproic acid per kg body weight to the dose required to achieve control of epileptic seizures.
Average daily doses (with long-term use):
- for children 6-14 years old (body weight 20-30 kg) - 30 mg valproic acid/kg body weight (600-1200 mg);
- for adolescents (body weight 40-60 kg) - 25 mg valproic acid/kg body weight (1000-1500 mg);
- for adults and elderly patients (body weight 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; The wide range of individual sensitivity to valproate should be taken into account.
If epilepsy is not controlled at these doses, they can be increased under monitoring 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, the daily dose should not be increased above the recommended average daily dose before this date.
The daily dose can be divided into 1-2 doses, preferably with meals.
One-time use is possible for well-controlled epilepsy.
Most patients who are already taking the non-extended-release dosage form of Depakine® can be switched to the extended-release dosage form of this drug 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 taking Depakin® Chrono should be carried out gradually, reaching the optimal dose of the drug within approximately 2 weeks. In this case, the dose of the previously taken antiepileptic drug, especially phenobarbital, is immediately reduced. If a previously taken antiepileptic drug is discontinued, its withdrawal should be carried out gradually.
Since other antiepileptic drugs can reversibly induce liver microsomal enzymes, the concentrations of valproic acid in the blood should be monitored for 4-6 weeks after taking the last dose of these antiepileptic drugs and, if necessary (as the metabolism-inducing effect of these drugs decreases), reduce the daily dose of valproic acid .
If it is necessary to combine valproic acid with other antiepileptic drugs, they should be added to treatment gradually (see “Interaction with other drugs”).

Dosage regimen for manic episodes with bipolar disorders
Adults
The daily dose is selected individually by the attending physician.
The recommended initial daily dose is 750 mg. In addition, in clinical studies An initial dose of 20 mg sodium valproate per kg body weight also showed an acceptable safety profile.
Slow-release formulations can be taken once or twice daily. The dose should be increased as quickly as possible until the minimum therapeutic dose that produces the desired clinical effect is reached.
The average daily dose is in the range of 1000-2000 mg sodium valproate.
Patients receiving a daily dose higher than 45 mg/kg/day should be under close medical supervision.
Continuation of treatment of manic episodes in bipolar disorders should be carried out by taking an individually selected minimum effective dose.

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

Use of the drug in patients of special groups
In patients with renal failure and/or hypoproteinemia, the possibility of increasing the concentration of the free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and if necessary, reduce the dose of valproic acid, focusing on the dose selection, mainly on the clinical picture, and not on general content valproic acid in blood serum (free fraction and fraction bound to plasma proteins) to avoid possible errors in dose selection.

Side effect

To indicate the frequency of adverse reactions (ARs), the World Health Organization classification of ADRs is used: very common ≥10%; frequent ≥1% and<10 %; нечастые ≥0,1 % и <1 %; редкие ≥0,01 % и <0,1 %; очень редкие <0,01 %, неизвестная частота (когда по имеющимся данным не представляется возможным оценить частоту развития НР).
Congenital, hereditary and genetic disorders
Teratogenic risk (see section "Pregnancy and lactation").
Blood and lymphatic system disorders
Frequent
Thrombocytopenia.
Rare
Pancytopenia, anemia, leukopenia, disorders of bone marrow hematopoiesis, including isolated red blood cell aplasia; agranulocytosis.
An isolated decrease in fibrinogen levels in the blood and an increase in prothrombin time have been reported, usually not accompanied by clinical manifestations, especially when using high doses (valproic acid has an inhibitory effect on the second phase of platelet aggregation).
Nervous system disorders
Infrequent
Ataxia.
Very rare
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 transient coma/encephalopathy. They can be isolated or combined with an increased frequency of convulsive seizures (despite treatment), which decreases when the drug is discontinued or its dose is reduced. These cases were mainly observed during combination therapy (particularly with phenobarbital or topiramate) or after a sharp increase in the dose of valproic acid.
Extrapyramidal disorders that 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) (see section “Special instructions”).
Hearing and labyrinth disorders
Rare
Reversible or irreversible deafness.
Visual disorders
Unknown frequency
Diplopia, nystagmus, flashing “spots” before the eyes.
Gastrointestinal disorders
Frequent
At the beginning of treatment, nausea, vomiting, epigastric pain, diarrhea, which usually disappear after a few days with continued use of the drug.
Very rare
Pancreatitis, sometimes fatal.
Renal and urinary tract disorders
Very rare
Enuresis.
There have been several isolated reports of the development of reversible Fanconi syndrome, the mechanism of development of which is still unclear.
Skin and subcutaneous tissue disorders
Frequent
Transient or dose-dependent alopecia.
Very rare
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash.
Metabolic and nutritional disorders
Frequent
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 rare
Hyponatremia.
Syndrome of impaired secretion of antidiuretic hormone.
Vascular disorders
Vasculitis.
General disorders
Very rare
Minor peripheral edema.
Increase in body weight. Because obesity is a risk factor for the development of polycystic ovary syndrome, patients should be closely monitored for weight gain.
Immune system disorders
Angioedema, drug eruption syndrome with eosinophilia and systemic symptoms (DRESS syndrome), allergic reactions such as urticaria.
Disorders of the liver and biliary tract
Rare
Liver damage.
Disorders of the genital organs and breast
Unknown frequency
Amenorrhea and dysmenorrhea.
Male infertility.
Mental disorders
Infrequent
Irritability, hyperactive state, confusion, especially at the beginning of treatment.
Rare
Changes in behavior, mood, depression, feeling tired, aggressiveness, psychosis, unusual agitation, restlessness, dysarthria.
Unknown frequency
Hallucinations.

Overdose

Clinical manifestations of acute massive overdose usually occur in the form of a coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, and metabolic acidosis. Cases of intracranial hypertension associated with cerebral edema have been described. With a massive overdose, death is possible, but usually the prognosis for an overdose is favorable. Symptoms of overdose may vary, and seizures have been reported at very high plasma concentrations of valproic acid. Emergency care in case of overdose in a 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. Naloxone has been used with success in some cases. In very severe cases of massive overdose, hemodialysis and hemoperfusion have been effective.

Interaction with other drugs and other forms of interaction

Effect of valproic acid on other drugs
Neuroleptics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines.
Valproic acid may potentiate the effect of other psychotropic drugs such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; Therefore, when used simultaneously with the drug Depakin® Chrono, careful medical supervision and, if necessary, dose adjustment are recommended.
Lithium preparations
Valproic acid does not affect serum lithium concentrations.
Phenobarbital
Valproic acid increases plasma concentrations of phenobarbital (by reducing its hepatic metabolism), and therefore the sedative effect of the latter may develop, especially in children. Therefore, careful medical monitoring of the patient is recommended during the first 15 days of combination therapy with an immediate reduction in the dose of phenobarbital in 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 long-term treatment these symptoms disappear. Careful clinical monitoring of the patient is recommended, especially at the beginning of combination therapy, with dose adjustment of primidone if necessary.
Phenytoin
Valproic acid reduces total plasma concentrations of phenytoin. In addition, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing overdose symptoms (valproic acid displaces phenytoin from binding to plasma proteins and slows down its hepatic metabolism). Therefore, careful clinical monitoring of the patient and determination of the concentrations of phenytoin and its free fraction in the blood are 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 dose of carbamazepine.
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 may result in increased toxicity of lamotrigine, particularly severe skin reactions including toxic epidermal necrolysis. Therefore, careful clinical monitoring and, if necessary, dose adjustment (reduction) of lamotrigine are recommended.
Zidovudine
Valproic acid may increase plasma concentrations of zidovudine, resulting in increased zidovudine toxicity.
Felbamate
Valproic acid may reduce the mean clearance of felbamate by 16%.
Nimodipine (oral and, by extrapolation, solution for parenteral administration)
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 that can induce liver microsomal enzymes (including phenytoin, phenobarbital, carbamazepine) reduce plasma concentrations of valproic acid. In the case of combination therapy, doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.
Felbamate
When felbamate and valproic acid are combined, the clearance of valproic acid is reduced by 22-50% and plasma concentrations of valproic acid increase accordingly. Plasma concentrations of valproic acid should be monitored.
Mefloquine
Mefloquine accelerates the metabolism of valproic acid and is itself capable of causing convulsions, therefore, with their simultaneous use, the development of an epileptic seizure is possible.
Preparations of St. John's wort
With the simultaneous use of valproic acid and St. John's wort preparations, a decrease in the anticonvulsant effectiveness of valproic acid is possible.
Drugs that have a high and strong binding to blood plasma proteins (acetylsalicylic acid)
In the case of simultaneous use of valproic acid and drugs that have a high and strong connection with blood plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free fraction of valproic acid.
Indirect anticoagulants
When valproic acid and indirect anticoagulants are used simultaneously, careful monitoring of the prothrombin index is required.
Cimetidine, erythromycin
Serum concentrations of valproic acid may increase with simultaneous use of cimetidine or erythromycin (as a result of slowing its hepatic metabolism).
Carbapenems (panipenem, meropenem, imipenem)
A decrease in the concentration of valproic acid in the blood when used simultaneously with carbapenems, leading to a 60-100% decrease in the concentration of valproic acid in the blood within two days of joint therapy, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems should be avoided in patients receiving a dose of valproic acid due to their ability to rapidly and intensely reduce valproic acid blood concentrations. If treatment with carbapenems cannot be avoided, close monitoring of valproic acid blood concentrations should be performed.
Rifampicin
Rifampin can reduce the concentration of valproic acid in the blood, which leads to the loss of the therapeutic effect of the drug Depakine ® Chrono. Therefore, it may be necessary to increase the dose of Depakine® Chrono while using rifampicin.
Other interactions
With topiramate
Concomitant use of valproic acid and topiramate has been associated with encephalopathy and/or hyperammonemia. Patients receiving these two drugs simultaneously should be closely monitored for the development of symptoms of hyperammonemic encephalopathy.
With estrogen-progestogen 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.
With ethanol and other potentially hepatotoxic drugs
When used simultaneously with valproic acid, the hepatotoxic effect of valproic acid may be enhanced.
With clonazepam
The simultaneous use of clonazepam with valproic acid can lead in isolated cases to increased severity of absence status.
With myelotoxic drugs
When used simultaneously with valproic acid, the risk of suppression of bone marrow hematopoiesis increases.

special instructions

Severe liver damage
Predisposing factors
Clinical experience shows that patients at risk include patients receiving multiple antiepileptic drugs at the same time, children under three years of age with severe seizures, especially in the presence of brain damage, mental retardation and/or congenital metabolic or degenerative diseases.
After the age of three, the risk of liver damage decreases significantly and decreases progressively as the patient ages. In most cases, liver damage occurred during the first 6 months of treatment.
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 begin 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. If they occur, 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 prothrombin index. Confirmation of deviations from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in transaminase activity) requires discontinuation of the use of the drug Depakin® Chrono. As a precaution, if patients were concomitantly receiving salicylates, their use should also be discontinued, since they are metabolized through the same metabolic pathway as valproic acid.
Pancreatitis
Children are at increased risk of developing pancreatitis, and 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, nausea, vomiting and/or anorexia should be evaluated immediately. If the diagnosis of pancreatitis is confirmed, in particular with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment initiated.
Suicidal thoughts and attempts
Suicidal thoughts or attempts have been reported in patients receiving antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a small increase in the risk of suicidal ideation and attempts. The mechanism of this effect is unknown. Therefore, patients receiving Depakine® Chrono should be constantly monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be provided. Patients and caregivers are advised to immediately
consult a doctor.
Carbapenems
The simultaneous use of carbapenems is not recommended (see section “Interaction with other drugs”).
Women of childbearing age
When using the drug in women of childbearing age, it is necessary to exclude pregnancy and make sure that the woman is using a reliable method of contraception.
Methods for monitoring the safety of treatment with Depakin® chrono
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, there may be 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 laboratory parameters, including the prothrombin index, is necessary, and dose adjustment of the drug may be required, and, if necessary, repeated clinical and laboratory examinations.
Before starting therapy or, if 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).
Children (information applies to dosage forms of the drug Depakine®, which 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, concomitant use of salicylates should be avoided due to the risk of hepatotoxicity and bleeding.
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.
Carbamide cycle enzyme deficiency
If a deficiency of carbamide cycle enzymes is suspected, the use of valproic acid is not recommended. 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.
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, in particular the determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after meals.
Patients with systemic lupus erythematosus
Although it has been shown that during treatment with Depakin® Chrono, dysfunction of the immune system is extremely rare, the potential benefits of its use must be compared with the potential risks when 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, mainly dietary, should be taken to minimize this phenomenon.
Ethanol
During treatment with valproic acid, ethanol consumption is not recommended.

Impact on the ability to drive vehicles or engage in other potentially hazardous activities

Patients should be warned about the risk of drowsiness, especially when receiving combination anticonvulsant therapy or when valproic acid is combined with benzodiazepines.
During the treatment period, you must be careful and discuss with your doctor the possibility of driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Depakine Chrono: instructions for use and reviews

Latin name: Depakine chrono

ATX code: N03AG01

Active substance: sodium valproate + valproic acid (valproic acid + valproate sodium)

Manufacturer: Sanofi Winthrop-Industrie (France)

Update description and photo: 21.11.2018

Depakine chrono is an antiepileptic drug that has a central muscle relaxant and sedative effect.

Release form and composition

Depakine Chrono is produced in the form of long-acting, film-coated tablets: oblong, almost white, with a score line on both sides (dosage 500 mg - 30 pcs. in a polypropylene bottle, 1 bottle in a cardboard pack; dosage 300 mg - 50 pcs. in a polypropylene bottle, 2 bottles in a cardboard box).

1 tablet contains:

• active ingredients: valproic acid - 87 and 145 mg, sodium valproate - 199.8 and 333 mg (for dosages of 300 and 500 mg, respectively);
• additional components: ethylcellulose 20 mPa.s, hydrated colloidal silicon dioxide, methylhydroxypropylcellulose 4000 mPa.s (hypromellose), macrogol 6000, methylhydroxypropylcellulose 6 mPa.s (hypromellose), titanium dioxide, sodium saccharinate, talc, 30% polyacrylate dispersion.

Pharmacological properties

Pharmacodynamics

Depakine chrono is an anticonvulsant that demonstrates antiepileptic activity against all types of epilepsy, and also has a normothimic effect. The main mechanism of action is likely related to the drug's effect on the GABAergic system, through increasing gamma-aminobutyric acid (GABA) levels in the central nervous system (CNS) and stimulating GABAergic transmission.

Pharmacokinetics

The bioavailability of the drug after oral administration reaches almost 100%.

When taking Depakine Chrono 500 mg tablets in a daily dose of 1000 mg, the minimum plasma concentration (Cmin) of valproic acid is 44.7±9.8 mcg/ml, and the maximum (Cmax) is 81.6±15.8 mcg/ml, the period of reaching the maximum plasma concentration (Tmax) is 6.58±2.23 hours. Steady-state concentration (Css) in plasma is observed over 3-4 days of regular use.

The average therapeutic range for serum valproic acid concentrations is 50–100 mg/L. If it is necessary to achieve a higher level of substance content, it is necessary to carefully evaluate the ratio of the expected benefit and the possible threat of adverse reactions, especially dose-dependent ones. At concentrations of valproic acid in the blood exceeding 100 mg/l, the risk of developing disorders is aggravated, including the occurrence of intoxication. If the plasma level of the drug rises above 150 mg/l, a dose reduction is necessary.

The volume of distribution depends on age and, as a rule, can be 0.13–0.23 l/kg body weight, and in young patients – 0.13–0.19 l/kg. The drug is characterized by a high (90–95%), dose-dependent and saturable association with plasma proteins, mostly with albumin.

The active substance is found in the brain and cerebrospinal fluid. Its concentration in the cerebrospinal fluid is approximately 10% of the concentration in the serum. Metabolic transformation occurs in the liver through conjugation with glucuronic acid and omega-, omega1- and beta-oxidation. More than 20 metabolites have been discovered that have a hepatotoxic effect as a result of omega-oxidation.

Valproic acid is excreted in breast milk at a concentration of 1–10% of the total serum level. The drug is excreted mostly by the kidneys after glucuronidation and beta-oxidation; less than 5% is excreted unchanged. In patients with epilepsy, the plasma clearance of the drug is 12.7 ml/min, the half-life (T 1/2) is 15–17 hours.

The drug does not have the ability to induce enzymes belonging to the cytochrome P450 family.

Indications for use

• generalized epileptic seizures: tonic, clonic, tonic-clonic, atonic, myoclonic, absence seizures;
• Lennox–Gastaut syndrome;
• partial epileptic seizures (with or without secondary generalization).

In adult patients, Depakine Chrono is also used for the prevention and treatment of bipolar affective disorders.

Contraindications

Absolute:

• severe functional disorders of the liver or pancreas;
• acute/chronic hepatitis;
• severe liver disease (especially drug-induced hepatitis), indicated in the patient’s individual or family history;
• severe liver pathologies with fatal outcomes when using valproic acid in close blood relatives;
• hepatic porphyria;
• established disorders of the carbamide cycle (urea cycle), due to the threat of developing hyperammonemia;
• combined use with mefloquine, St. John's wort preparations;
• age up to 6 years;
• diagnosed mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), including Alpers-Huttenlocher syndrome and suspected pathologies caused by defects (POLG);
• hypersensitivity to any component of the drug, as well as to valpromide or semisodium valproate.

• congenital enzymopathies;
• history of liver and pancreas damage;
• renal failure;
• hypoproteinemia;
• inhibition of bone marrow hematopoiesis (thrombocytopenia, leukopenia, anemia);
• pregnancy;
• simultaneous use of several anticonvulsants (increases the risk of liver damage);
• combination with antipsychotics, monoamine oxidase inhibitors (MAO), antidepressants, benzodiazepines;
• simultaneous use of drugs that provoke seizures or lower the seizure threshold, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, phenothiazine/butyrophenone derivatives, tramadol, bupropion, chloroquine (threat of seizures);
• combination with the following drugs: lamotrigine, primidone, phenobarbital, phenytoin, felbamate, zidovudine, aztreonam, propofol, olanzapine, acetylsalicylic acid, carbapenems, indirect anticoagulants, erythromycin, cimetidine, nimodipine, rifampicin, rufinamide, ritonavir, lopinavir, cholestyramine, mat, acetazolamide , carbamazepine;
• insufficiency of carnitine palmitoyltransferase (CPT) type II (while taking valproic acid, the risk of developing rhabdomyolysis is aggravated).

Instructions for use of Depakine Chrono: method and dosage

Depakine Chrono is intended only for adults and children over 6 years of age with a body weight exceeding 17 kg.

The drug is taken orally. The tablets are swallowed without chewing or crushing, but to make it easier to take an individually selected dose, they can be divided. The daily dose is recommended to be taken in one or two doses, preferably with meals.

When using Depakine Chrono, due to the slow release of the active substance, after administration there are no sharp peaks in the level of its content in the blood, and the uniform concentration of the drug in the plasma remains longer throughout the day.

The daily dose of the drug is determined individually by the attending physician. In order to prevent attacks of epilepsy, Depakine Chrono must be taken in the minimum effective dose.

The optimal dose for the treatment of epilepsy should be established primarily based on clinical response, since a clear relationship between the plasma concentration of the drug, the daily dose and the therapeutic effect has not been found. Plasma valproic acid levels can be determined in addition to clinical monitoring when side effects are suspected or seizure control cannot be achieved.

The range of therapeutic concentrations of the drug in the blood is usually 40–100 mg/l. The daily dose is determined taking into account age and body weight. When conducting monotherapy, Depakine Chrono is usually prescribed at an initial dose of 5–10 mg/kg, which is then gradually increased every 4–7 days at the rate of 5 mg of valproic acid per 1 kg of body weight until the most favorable dose is reached, allowing control of epileptic attacks.

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

When setting the daily dose, individual sensitivity to valproate should also be taken into account.

If epilepsy is not controlled, these doses may be increased while monitoring the patient's condition and blood levels of the drug. The full therapeutic effect of Depakine Chrono can sometimes not be achieved immediately, but only 4-6 weeks after the start of treatment. Therefore, you should not increase the daily dose above the recommended dose before this period. In case of adequately controlled epilepsy, the dose can be taken once a day.

If it is necessary to replace the non-extended-release dosage form of Depakine with Depakine Chrono, this can usually be done immediately or over several days, continuing to take it at the previously selected daily dose.

Patients who have previously received other antiepileptic drugs should switch to taking Depakine Chrono gradually, reaching the optimal dose of valproic acid within approximately 14 days. In this case, the dose of the previously taken drug should be immediately reduced, especially if it is phenobarbital, and withdrawal should be carried out gradually.

Since other antiepileptic drugs have the ability to reversibly induce liver microsomal enzymes, the level of valproic acid in the blood should be monitored for 4-6 weeks after taking their last dose, and the daily dose should be reduced if necessary.

If combination therapy with other anticonvulsants is prescribed, they must be started gradually.

For the treatment of manic episodes in bipolar disorders in adults, it is recommended to take the drug at an initial dose of 750 mg. Also, according to the results of clinical studies, you can use the product in an initial daily dose of 20 mg of sodium valproate per 1 kg of body weight. The initial dose should be increased as quickly as possible to the minimum effective dose to achieve the desired clinical effect. The average daily dose can vary from 1000 to 2000 mg of sodium valproate. If patients receive Depakine Chrono at a dose exceeding 45 mg/kg body weight per day, they need careful medical supervision.

While continuing the treatment of manic episodes in bipolar disorders, Depakine chrono should be taken in the minimum individually selected effective dose.

Side effects

• blood coagulation system: often - hemorrhages and bleeding; rarely - a decrease in the level of blood clotting factors; increase in prothrombin time (PTT), activated partial thromboplastin time (aPTT), thrombin time, international normalized ratio (MHO) (the occurrence of spontaneous bleeding and ecchymosis requires discontinuation of the drug);
• hematopoietic system: often – thrombocytopenia, anemia; uncommon – leukopenia, pancytopenia (with or without depression of bone marrow hematopoiesis), neutropenia (reversible after discontinuation of use);
• nervous system: very often – tremor; often – drowsiness, headache, dizziness, memory impairment, nystagmus, convulsions*, stupor*, extrapyramidal disorders; uncommon – paresthesia, ataxia, reversible parkinsonism, increasing severity of seizures, lethargy*, encephalopathy*, coma*; rarely - cognitive disorders, reversible dementia with reversible brain atrophy; with unknown frequency – sedation;
• mental disorders: infrequently - impaired attention**, aggressiveness**, agitation**, confusion, depression (when combined with other anticonvulsants); rarely – learning disabilities**, psychomotor hyperactivity**, behavioral disorders**, depression (with monotherapy);
• sense organs: often – reversible/irreversible deafness; with unknown frequency – diplopia;
• liver and biliary tract: often - liver damage, accompanied by a decrease in the prothrombin index (PTI) (especially in combination with a pronounced decrease in the level of blood coagulation factors and fibrinogen), an increase in the concentration of bilirubin and an increase in the activity of liver transaminases in the blood; liver failure, in exceptional cases - with death;
• digestive system: very often – nausea; often - hyperplasia and other changes in the gums, vomiting, epigastric pain, stomatitis, diarrhea (usually occur at the beginning of the course and go away on their own after a few days; the frequency of effects can be reduced by taking the drug during or after meals); uncommon – pancreatitis, sometimes fatal; with unknown frequency - increased appetite, anorexia, abdominal cramps;
• urinary system: uncommon – renal failure; rarely - tubulointerstitial nephritis, enuresis, reversible Fanconi syndrome (expressed as a complex of clinical and biochemical manifestations of renal tubular damage with changes in tubular reabsorption of glucose, phosphate, bicarbonate and amino acids);
• respiratory system: infrequently - pleural effusion;
• vascular disorders: infrequently – vasculitis;
• musculoskeletal system and connective tissue: infrequently - osteopenia, decreased mineral density of bone tissue, fractures and osteoporosis (with long-term treatment); rarely – rhabdomyolysis, systemic lupus erythematosus;
• endocrine system: uncommon – syndrome of inadequate secretion of antidiuretic hormone (ADH), hyperandrogenism (acne, virilization, hirsutism, male pattern alopecia and/or increased levels of androgens in the blood); rarely – hypothyroidism;
• reproductive system and mammary glands: often – dysmenorrhea; infrequently - amenorrhea; rarely – polycystic ovary syndrome, male infertility; with unknown frequency - enlarged mammary glands, irregular menstruation, galactorrhea;
• immune system: often – hypersensitivity reactions (including urticaria); uncommon – angioedema; rarely - drug rash syndrome with eosinophilia and systemic symptoms;
• skin and subcutaneous tissues: often - transient/dose-dependent alopecia (including androgenic alopecia against the background of polycystic ovary syndrome, hyperandrogenism, hypothyroidism), disorders of the nail bed and nails; uncommon – rash, change in color and/or disruption of the normal structure of the hair, abnormal hair growth (disappearance of curly and wavy hair or the appearance of curl in initially straight hair); rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme;
• benign, indeterminate and malignant tumors (including cysts and polyps): rarely - myelodysplastic syndrome;
• laboratory and instrumental studies: rarely - biotinidase deficiency or biotin deficiency;
• metabolism: often – hyponatremia, increase in body weight (for prevention, diet correction is necessary; weight gain must be controlled, since this is a factor contributing to the appearance of polycystic ovary syndrome); rarely - obesity, hyperammonemia with the possible appearance of neurological symptoms (including ataxia, vomiting, encephalopathy - in this case discontinuation of therapy is required);
• general disorders: mild peripheral edema, hypothermia.

*lethargy and stupor sometimes caused transient coma/encephalopathy and were isolated or occurred with an increase in convulsive attacks during the treatment period, and also decreased in case of cancellation or reduction of the dose of Depakine Chrono; the predominant part of such reactions was described against the background of combined use.

**disorders observed mainly in children.

Overdose

Symptoms of acute overdose are coma with miosis, hyporeflexia, muscle hypotonia, marked decrease in blood pressure, respiratory depression, metabolic acidosis and vascular collapse/shock. Due to the presence of chrono sodium in Depakine, hypernatremia may occur.

Cases of intracranial hypertension caused by cerebral edema and seizures have been described at very high plasma concentrations of valproic acid. A significant overdose can be fatal, however, in most cases the prognosis is favorable.

This condition requires emergency care in a hospital: gastric lavage (no later than 10–12 hours after an overdose), taking activated charcoal, maintaining effective diuresis, monitoring indicators of the function of the cardiovascular and respiratory systems, pancreas, and liver. In extremely severe cases, artificial ventilation, hemoperfusion and hemodialysis are prescribed.

special instructions

Before using the drug or before surgery, as well as when observing spontaneous subcutaneous bleeding or hematomas, the number of peripheral blood cells (including the number of platelets) and bleeding time should be determined.

Before treatment with Depakine chrono and periodically during the first 6 months of the course, liver function indicators should be assessed, especially in patients at risk. It should be taken into account that during therapy, mainly at the beginning of treatment, an isolated and transient increase in transaminase levels may occur that is not clinically manifested. In case of this violation, it is recommended to conduct a detailed study of biological indicators, including the determination of PTI, and, if necessary, revise the dosage, and subsequently perform a repeated laboratory examination.

There have been very rare reports of severe (fatal) cases of liver damage when taking Depakine Chrono. According to clinical experience, the increased risk group includes patients receiving several antiepileptic drugs at the same time, children under three years of age with severe epilepsy, as well as patients using concomitant salicylates. In children over 3 years of age, the risk of liver damage is significantly reduced, and the frequency of its occurrence decreases with age. This complication is usually observed during the first 6 months of therapy, mainly between 2 and 12 weeks, against the background of combined antiepileptic treatment.

Monitoring of patients is necessary to detect early signs of liver damage. It is necessary to pay attention to the development of symptoms that may indicate the subsequent occurrence of jaundice, such as anorexia, asthenia, drowsiness, lethargy, sometimes accompanied by abdominal pain and repeated vomiting (especially those that appear suddenly), as well as recurrence of seizures in patients with epilepsy. If you observe any of these symptoms, you should consult a doctor and undergo a clinical examination and liver function test.

To identify liver dysfunction before starting the course and during its first 6 months, it is recommended to periodically monitor liver function, including the mandatory determination of IPT. When a significant decrease in the level of prothrombin, fibrinogen and blood coagulation factors, an increase in the activity of liver transaminases and bilirubin concentration is detected, it is necessary to stop using Depakine Chrono. You should also avoid concomitant therapy with salicylates if it has been previously administered.

Cases of severe forms of pancreatitis have been observed in children and adults. Risk factors for this complication may include anticonvulsant treatment, neurological disorders, and severe seizures. The risk was highest in young children, but decreased with increasing age. Liver failure in pancreatitis increased the risk of death. Patients who experience vomiting, anorexia, nausea, or acute abdominal pain during therapy require immediate medical examination. If pancreatitis is diagnosed, including increased activity of pancreatic enzymes, Depakine Chrono should be discontinued.

There is information about the occurrence of suicidal thoughts/attempts in patients taking antiepileptic drugs, but the mechanism of this effect is not clear. As a result, patients receiving Depakine Chrono should be carefully monitored for timely identification of possible suicidal thoughts or tendencies, and if they develop, immediately seek medical help.

Due to the threat of polycystic ovary syndrome, amenorrhea, dysmenorrhea, and an increase in testosterone levels, women may experience a decrease in fertility during therapy. In men, sperm motility may deteriorate and fertility may decrease. These disorders resolve on their own after completion of treatment.

In patients with diabetes mellitus, it is necessary to carefully monitor blood glucose levels due to the possible negative effects of the drug on the pancreas. When testing ketone bodies in urine, false positive results may be obtained.

While taking valproic acid, some patients may develop a reversible paradoxical increase in the severity and frequency of seizures or new types of seizures. If seizures worsen, you should immediately consult a doctor.

In children with mental retardation, or with a history of unexplained gastrointestinal symptoms (vomiting, anorexia, cases of cytolysis), lethargy or coma, as well as with a family history of the death of a newborn or child, it is necessary to conduct studies before starting treatment with the drug metabolism, in particular ammonemia (on an empty stomach and after eating).

Patients on a low-sodium diet should remember that the Depakine Chrono 300 mg tablet contains 27.6 mg of sodium, and the Depakine Chrono 500 mg tablet contains 46.1 mg.

Impact on the ability to drive vehicles and complex mechanisms

Patients driving vehicles and other complex equipment during treatment, especially when combining Depakine Chrono with benzodiazepines, must take into account the risk of developing drowsiness.

Use during pregnancy and lactation

Depakine Chrono should not be used in women of reproductive age, pregnant women and female children (adolescents), unless other methods of therapy are not tolerated by the patient or do not achieve the desired effect. When regularly reviewing treatment, the balance of benefit and risk should be carefully assessed.

Women of childbearing potential must use effective contraceptives while taking the drug. When planning pregnancy (before conception), it is necessary to take all possible measures to transfer the patient to an appropriate alternative treatment.

The occurrence of generalized tonic-clonic epileptic seizures, status epilepticus with the development of hypoxia during pregnancy, due to the possible fatal outcome, can pose a particular threat to the woman and the fetus.

In experimental reproductive toxicity studies in animals, valproic acid was found to have a teratogenic effect.

According to available clinical data, in children whose mothers took valproic acid as a monotherapy during pregnancy, the risk of congenital malformations was approximately 3.7/2.3/2.3/1.5 times greater than the similar risk when compared with monotherapy with lamotrigine/phenobarbital/carbamazepine/phenytoin, respectively. The risk associated with valproic acid was 10.73% and was higher than the risk of major birth defects in the general population, which was 2–3%. This threat is dose-dependent, but it is impossible to determine the threshold dose below which there is no threat. The most frequently noted defects were congenital craniofacial deformities, neural tube defects, hypospadias, malformations of the cardiovascular system and limbs, and defects of other systems and organs.

It has been established that due to intrauterine exposure to valproic acid, disturbances in the physical and mental development of children may occur. In the process of studying children at risk of preschool age, 30–40% were found to have delayed early development, memory impairment, a lower level of intellectual abilities, and poor speech skills. Also, children aged 6 years had an IQ score that was on average 7 to 10 points lower compared to children exposed in utero to other antiepileptic drugs.

There is limited data on long-term outcomes indicating that children whose mothers took Depakine Chrono during pregnancy were at increased risk of developing autism spectrum disorders (including childhood autism) and attention-deficit/hyperactivity disorder (ADHD).

Risk factors for fetal malformations include pregnant women taking daily doses of more than 1000 mg (the use of lower doses does not eliminate this threat) and the combination of valproic acid with other anticonvulsants.

Based on the above, the use of Depakine Chrono during pregnancy and in women of reproductive age is allowed only when absolutely necessary.

In the case when a woman is planning a pregnancy, or pregnancy has already occurred, the need for valproic acid therapy should be urgently reconsidered, taking into account the indications. When treating bipolar disorders with the drug, consideration should be given to discontinuing its use. If a patient receives valproic acid for epilepsy, the question of continuing or discontinuing the drug is decided after reassessing the ratio of expected benefits and possible risks. If it is necessary to continue treatment during pregnancy, Depakine Chrono is prescribed in the lowest effective dose, which should be divided into several doses per day. During pregnancy, receiving an extended-release drug is preferable to taking other dosage forms.

In addition to therapy, even before pregnancy is diagnosed, the use of folic acid at a dose of 5 mg per day can be added to reduce the risk of neural tube malformations (at present, its preventive effect has not been confirmed). Special antenatal monitoring should be carried out on a continuous basis (including the third trimester of pregnancy) for possible detection of malformations, including neural tube defects. Before delivery, a woman is required to undergo coagulation tests, including platelet count, fibrinogen level and aPTT.

Valproic acid is excreted in breast milk in small amounts (1–10% of serum concentrations). But due to limited clinical data on the use of the substance during breastfeeding, taking Depakine chrono during lactation is not recommended.

Use in childhood

In newborns whose mothers received valproic acid during pregnancy, isolated cases of hemorrhagic syndrome associated with hypofibrinogenemia, thrombocytopenia, and/or decreased levels of other coagulation factors have been reported. Fatal afibrinogenemia has also been reported. Therefore, coagulation tests must be carried out in newborns from this risk group.

There is evidence of the development of hypothyroidism, and when mothers use Depakine Chrono in the third trimester of pregnancy - hypoglycemia and withdrawal syndrome (difficulty with feeding, irritability, tremors, hyperreflexia, hyperkinesia, muscle tone disorders, convulsions) in newborns.

Depakine Chrono is contraindicated for use in children under 6 years of age due to the possibility that the tablet may enter the respiratory tract if swallowed. For children over 6 years of age, the drug is prescribed at an average daily dose of 30 mg/kg.

The safety and effectiveness of the drug for the treatment of manic episodes associated with bipolar disorders have not been assessed in patients under 18 years of age.

For impaired renal function

In the presence of renal failure, it may be necessary to reduce the dosage of Depakine Chrono.

For liver dysfunction

Taking Depakine chrono is contraindicated in case of functional liver disorders.

Use in old age

In elderly patients, the dose should be adjusted to ensure effective control of epileptic seizures.

Drug interactions

Effect of valproic acid on concomitantly used substances/drugs:

• antidepressants, MAO inhibitors, antipsychotics, benzodiazepines and other psychotropic drugs: their effect is enhanced (dosage changes are required if necessary);
• primidone: its plasma concentration increases, which causes increased adverse reactions (including sedative effects); with long-term combined use, these symptoms disappear, but dose adjustment may be required;
• lithium preparations: serum lithium concentration does not change;
• carbamazepine: clinical manifestations of toxicity may develop due to an increase in the content of the active metabolite Depakine chrono in plasma, with signs of overdose (dose adjustment may be required);
• phenobarbital: the level of the drug in the blood increases, a sedative effect may occur, especially in children; requires careful monitoring during the first 15 days of therapy with immediate dose reduction if sedation develops;
• phenytoin: total plasma concentration decreases, free fraction concentration increases, overdose symptoms may develop;
• lamotrigine: metabolism in the liver slows down, and T1/2 increases almost 2 times; possible worsening toxicity (severe skin reactions, including toxic epidermal necrolysis); Dose reduction may be required;
• zidovudine: plasma levels increase, toxicity increases (mainly hematological effects); monitoring of laboratory parameters and condition is necessary, especially during the first two months of combined treatment;
• olanzapine: plasma concentration decreases;
• felbamate: its average clearance decreases (by 16%);
• rufinamide: plasma levels increase (the effect is especially pronounced in children);
• propofol: plasma concentrations increase;
• nimodipine: the hypotensive effect is enhanced as a result of an increase in its plasma level;
• temozolomide: a mild, but statistically significant, decrease in clearance is noted.

The effect of simultaneously taken substances/drugs on valproic acid:

• ritonavir, lopinavir, cholestyramine, rifampicin, antiepileptic drugs leading to the induction of microsomal liver enzymes (phenobarbital, phenytoin, carbamazepine, primidone, etc.): reduce the plasma concentration of valproic acid, dose adjustment is required taking into account the clinical response;
• phenytoin, phenobarbital: the level of metabolites in the serum increases, the condition should be monitored to identify possible signs of hyperammonemia;
• aztreonam: the risk of seizures increases due to a decrease in the concentration of the antiepileptic drug; the dose should be adjusted during and after taking aztreonam;
• preparations of St. John's wort: inhibit the anticonvulsant effectiveness of the drug;
• mefloquine: the metabolism of valproic acid increases and there is a risk of developing an epileptic seizure;
• felbamate, cimetidine, erythromycin: plasma levels increase, it may be necessary to change the dose of Depakine Chrono during and after combined use;
• panipenem, meropenem, imipenem (carbapenems): the concentrations of valproic acid decrease intensively and quickly (in 2 days the decrease can be 60–100%), which can cause the development of seizures; during combined use and after its completion, the level of Depakine chrono should be monitored;
• acetylsalicylic acid: the concentration of the free fraction of valproic acid increases;
• warfarin and other coumarin derivatives: it is necessary to monitor PTI and INR.

Other types of valproic acid interactions:

• topiramate or acetazolamide: the combination is associated with the development of encephalopathy and/or hyperammonemia; careful monitoring is necessary for the development of symptoms of these complications;
.

Terms and conditions of storage

Store in a place protected from moisture at temperatures below 25 °C. Keep away from children!

Shelf life – 3 years.