Instructions for use DEPAKINE CHRONOSPHERE

Nosological classification (ICD-10)

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

Compound

Pharmacokinetics

Absorption

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

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

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

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

Distribution

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

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

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

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

Metabolism

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

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

Removal

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

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

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

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

Features of pharmacokinetics during pregnancy

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

Reviews of Depakin Chronosphere

Reviews of Depakine Chronosphere report the effectiveness of the drug. This is a new form of Depakine, which is enjoying great success. Many parents are scared by the unusual form of the well-known drug, but in this case there is no need to be afraid. This remedy can also be given to children. This is just a new form for the treatment of epilepsy , which makes it easier for young patients to take the drug.

Many also note that, thanks to its improved shape, Depakine Chronosphere is very convenient to carry.

Indications of the drug Depakine® Chronosphere™

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

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

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

treatment and prevention of bipolar affective disorders.

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

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

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

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

Overdose

An overdose of the drug is fraught with the appearance of coma , accompanied by muscle hypotonia , metabolic acidosis , hyporeflexia , and respiratory depression . There are known cases of intracranial hypertension and seizures. In general, overdose symptoms can vary. At very large doses, death is possible.

As an emergency, gastric lavage is performed, effective diuresis , and the functioning of the cardiovascular and respiratory systems is monitored. , hemodialysis and hemoperfusion are effective .

Contraindications

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

acute hepatitis;

chronic hepatitis;

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

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

severe dysfunction of the liver or pancreas;

hepatic porphyria;

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

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

hemorrhagic diathesis, thrombocytopenia;

combination with mefloquine;

combination with St. John's wort preparations;

children's age up to 6 months.

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

Drug interactions

Effect of valproic acid on other drugs

Valproic acid may potentiate the effect of other psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines

(with simultaneous use, careful medical monitoring and, if necessary, dose adjustment are recommended).

Valproic acid does not affect serum lithium

.

Valproic acid increases phenobarbital

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

Valproic acid increases primidone

in plasma, which leads to 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.

Valproic acid reduces total phenytoin

in plasma. 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 concentration of phenytoin and its free fraction in the blood is recommended.

With the simultaneous use of valproic acid and carbamazepine

clinical manifestations of carbamazepine toxicity have been reported because 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.

Valproic acid slows the metabolism of lamotrigine

in the liver and increases T1/2 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.

Valproic acid may increase plasma concentrations of zidovudine,

which leads to an increase in the toxicity of zidovudine, especially hematological effects, by slowing down its metabolism by valproic acid. 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 two months of combination therapy.

Valproic acid may reduce the mean clearance of felbamate.

by 16%.

Valproic acid may decrease plasma concentrations of olanzapine.

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, especially in children, because this effect is more pronounced in this population.

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.

Strengthening the hypotensive effect of nimodipine

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

Co-administration 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, phenobarbital, carbamazepine)

reduce plasma concentrations of valproic acid. In case of combination therapy, the dose of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

Serum concentrations of valproic acid metabolites may be increased when administered concomitantly with phenytoin or phenobarbital.

. Therefore, patients receiving these combinations should be carefully monitored for signs and symptoms of hyperammonemia, as some metabolites of valproic acid can inhibit enzymes of the carbamide cycle (urea cycle).

When used simultaneously with aztreonam

there is a 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 during treatment with aztreonam and after its cessation are necessary.

When combining felbamate

and valproic acid, the clearance of valproic acid decreases by 22-50% and, accordingly, the plasma concentration of valproic acid increases. Plasma concentrations of valproic acid should be monitored.

Mefloquine

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

With the simultaneous use of valproic acid and St. John's wort preparations

the anticonvulsant effectiveness of valproic acid may be reduced.

In case of simultaneous use of valproic acid and drugs that have a high and strong connection with blood plasma proteins (acetylsalicylic acid)

it is possible to increase the concentration of the free fraction of valproic acid.

With the simultaneous use of valproic acid and indirect anticoagulants (warfarin and other coumarin derivatives)

careful monitoring of INR and prothrombin index is required.

Plasma concentrations of valproic acid may increase with concomitant use of cimetidine or erythromycin

(as a result of a slowdown in its hepatic metabolism).

Reduced concentrations of valproic acid in the blood when used simultaneously with carbapenems (panipenem, meropenem, imipenem):

within 2 days of joint therapy, a 60-100% decrease in the concentration of valproic acid in the blood plasma was observed, which was sometimes combined with the occurrence of seizures. Concomitant use of carbapenems should be avoided in patients receiving a dose of valproic acid due to their ability to rapidly and intensely reduce plasma concentrations of valproic acid. 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

may reduce the concentration of valproic acid in the blood, which leads to 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 such as lopinavir, ritonavir

, reduce the plasma concentration of valproic acid when used simultaneously with it.

Cholestyramine

may lead to a decrease in plasma concentrations of valproic acid when used simultaneously.

Other interaction

Concomitant use of valproic acid and topiramate

or
acetazolamide
was accompanied by encephalopathy and/or hyperammonemia. Patients receiving these combinations should be closely monitored for the development of symptoms of hyperammonemic encephalopathy.

Concomitant use of valproic acid and quetiapine

may increase the risk of developing neutropenia/leukopenia.

Valproic acid does not have the ability to induce liver enzymes and, as a result, valproic acid does not reduce the effectiveness of estrogen-progestogen

drugs in women using hormonal contraception.

When taking ethanol and other potentially hepatotoxic drugs

simultaneously with valproic acid, it is possible to enhance the hepatotoxic effect of valproic acid.

Concomitant use of clonazepam

with valproic acid can lead in isolated cases to increased severity of absence status.

With the simultaneous use of drugs that have myelotoxic effects

, with valproic acid the risk of suppression of bone marrow hematopoiesis increases.

Use during pregnancy and breastfeeding

Risk associated with developing epileptic seizures during pregnancy

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

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

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

Congenital malformations

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

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

Mental and physical development disorders

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Risk to newborns

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

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

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

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

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

Breastfeeding period

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

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

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

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

Dosage

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

Depakine Chrono is a slow-release dosage form, which 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 or 500 mg can be divided to facilitate the administration of an individually selected dose.

The tablets are taken without crushing or chewing them.

Epilepsy

The doctor selects the daily dose individually.

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

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

No clear relationship 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 of valproic acid per kg of body weight, then this dose is gradually increased every 4-7 days at the rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control of epileptic seizures.

Average daily doses (with 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 teenagers (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)

- on average 20 mg of valproic acid/kg body weight (1200-2100 mg).

Although the daily dose is determined by 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 Depakine in a non-extended-release dosage form can be switched to Depakine chrono immediately or within a few 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 of the drug within approximately 2 weeks. In this case, you should immediately reduce the dose of the antiepileptic drug that the patient was taking previously, especially if it is phenobarbital. The withdrawal of an antiepileptic drug that the patient was previously taking should be done gradually.

Because other antiepileptic drugs can reversibly induce liver microsomal enzymes, the plasma concentration of valproic acid 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), the daily dose of valproic acid should be reduced.

If it is necessary to combine valproic acid with other antiepileptic drugs, they should be added to treatment gradually.

Manic episodes in bipolar disorders

Adults

The doctor selects the daily dose individually.

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

Depakine Chrono can be taken 1 or 2 times a day. The dose should be increased as quickly as possible until the minimum effective therapeutic dose that produces the desired clinical effect is achieved.

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

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

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

Children and teenagers

The 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.

Special patient groups

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

Treatment with Depakine Chrono should be started under the supervision of a specialist with experience 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 for 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.

Although in elderly patients

There are changes in the pharmacokinetics of valproic acid, they are of limited clinical significance, and the dose of valproic acid in elderly patients should be adjusted in accordance with achieving control of epileptic seizures.

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 the total content valproic acid in blood serum (free fraction and fraction bound to plasma proteins) to avoid possible errors in dose selection.

Side effects

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

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

From the blood and lymphatic system: often - anemia, thrombocytopenia (see "Special Instructions"); uncommon - pancytopenia, leukopenia, neutropenia. Leukopenia and pancytopenia can occur with or without bone marrow depression. After discontinuation of the drug, the blood picture returns to normal; rarely - disorders of bone marrow hematopoiesis, including isolated aplasia/hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis; decrease in the content of blood coagulation factors (at least one), deviation from the norm of blood coagulation parameters (such as an increase in PT, APTT, thrombin time and INR) (see “Use during pregnancy and lactation” and “Special instructions”). The appearance of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct an examination.

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

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

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

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

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

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

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

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

From the skin and subcutaneous tissues: often - hypersensitivity reactions, such as urticaria, itching; transient (reversible) and/or dose-dependent pathological hair loss (alopecia), including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary syndrome (see Genital and breast disorders and Endocrine system disorders), as well as alopecia against the background of developed hypothyroidism ( see Endocrine system disorders), disorders of the nails and nail bed; infrequently - angioedema, rash, hair disorders (such as disruption of the normal structure, discoloration, abnormal growth (disappearance of wavy and curly hair or, conversely, the appearance of curly hair in people with initially straight hair), hirsutism, acne; rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

On the part of the musculoskeletal and connective tissue: infrequently - a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients taking Depakine® drugs for a long time. The mechanism of influence of Depakine® drugs on bone metabolism has not been established; rarely - systemic lupus erythematosus (see "Special Instructions"), rhabdomyolysis (see "Contraindications", With caution, "Special Instructions").

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

Metabolism and nutrition: often - hyponatremia, weight gain (weight gain should be carefully monitored, since weight gain is a factor contributing to the development of polycystic ovary syndrome); rarely - hyperammonemia * (see "Special Instructions"), obesity.

* Cases of isolated and moderate hyperammonemia may occur without changes in liver function tests, which do not require discontinuation of treatment. Hyperammonemia has also been reported, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and other neurological symptoms), which required discontinuation of valproic acid and additional examination (see “Special Instructions”).

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

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

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

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

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

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

* ADRs mainly observed in pediatric patients.