Instructions for use DEPAKINE CHRONO

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 (T1/2) is 15–17 hours.

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

Terms of sale and storage

Purchasing Depakine from a pharmacy requires permission (prescription) from the attending medical professional. The average price of a package of Depakina Chrono 300 of 100 tablets is 1,148 rubles. A package of “Depakine Chrono” 500 of 30 tablets (this packaging is available for sale today) costs 530 rubles.

To store the medicine, you need to find a hard-to-reach place where the air temperature will not be higher than +25 degrees. The shelf life of this medication is two years.

Indications for use

According to the instructions, Depakine Chrono is recommended as a monotherapy drug or in combination with other antiepileptic drugs for the treatment of the following diseases in children and adults:

• 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.

Relative (it is recommended to take Depakine Chrono with extreme caution):

• 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, topiramate , 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.

Recommended average daily doses of valproic acid for long-term use (depending on age and body weight):

• 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.

Instructions:

Clinical and pharmacological group

02.011 (Anticonvulsant)

Release form, composition and packaging

Extended-release tablets, almost white, oblong, scored on both sides, odorless or with a slight odor.

Excipients: hypromellose 4000 mPa.s (methylhydroxypropylcellulose), ethylcellulose (20 mPa.s), sodium saccharin, hydrated colloidal silicon dioxide.

Shell composition: hypromellose 6 mPa.s (methylhydroxypropylcellulose), macrogol 6000, talc, titanium dioxide, 30% polyacrylate dispersion when expressed in dry extract.

50 pcs. — polypropylene bottles (2) — cardboard boxes.

Extended-release tablets, almost white, oblong, scored on both sides, odorless or with a slight odor.

Excipients: hypromellose 4000 mPa.s (methylhydroxypropylcellulose), ethylcellulose (20 mPa.s), sodium saccharin, anhydrous colloidal silicon dioxide, hydrated colloidal silicon dioxide.

Shell composition: hypromellose 6 mPa.s (methylhydroxypropylcellulose), macrogol 6000, talc, titanium dioxide, 30% polyacrylate dispersion when expressed in dry extract.

30 pcs. — polypropylene bottles (1) — cardboard boxes.

pharmachologic effect

An anticonvulsant drug with central muscle relaxant and sedative effects. Shows antiepileptic activity in all types of epilepsy.

The main mechanism of action appears to be related to the effect of valproic acid on the GABAergic system: the drug increases the content of GABA in the central nervous system and activates GABAergic transmission.

Therapeutic effectiveness begins with a minimum concentration of 40-50 mg/l and can reach 100 mg/l. At a concentration of more than 200 mg/l, a dose reduction is necessary.

Pharmacokinetics

Suction

Bioavailability of the drug is about 100%.

Compared with the enteric-coated dosage form, the sustained-release tablet formulation is characterized by no absorption latency, prolonged absorption, identical bioavailability, lower Cmax (approximately 25% reduction in Cmax), but with a more stable plateau phase from 4 to 14 hours after dosing, there is a more linear correlation between dose and drug plasma concentration.

Distribution

Plasma protein binding is high, dose-dependent and saturable. Distributed predominantly into the blood and extracellular fluid. Sodium valproate penetrates the cerebrospinal fluid and the brain.

An equilibrium state is achieved after 3-4 days of regular oral administration of the drug.

The therapeutic effectiveness of the drug is manifested at plasma concentrations from 40 to 100 mg/l. When the concentration of the active substance in plasma exceeds 200 mg/l, a dose reduction is necessary.

Metabolism and excretion

Metabolized by beta-oxidation and conjugation with glucuronic acid. It is excreted mainly in urine in conjugated form. T1/2 is 15-17 hours.

It is not an inducer of cytochrome P450 isoenzymes. Does not affect the degree of both its own biotransformation and the biotransformation of other substances, such as estrogens, progestogens and vitamin K antagonists.

Dosage

Depakine Chrono is a dosage form with a delayed release of the active substance, which leads to a decrease in Cmax values ​​of valproic acid in the blood plasma and provides more uniform concentrations throughout the day compared to conventional dosage forms of Depakine.

The drug is taken orally. The daily dose is recommended to be taken in 1 or 2 doses, preferably with meals.

The dose should be set in accordance with the patient’s age and body weight, as well as taking into account individual sensitivity to the drug.

A good correlation has been established between the daily dose, serum concentration of the drug and the therapeutic effect, so the optimal dose should be determined depending on the clinical response. Determination of plasma valproic acid concentrations may be considered as an adjunct to clinical monitoring when epilepsy is uncontrolled or adverse effects are suspected. The concentration range at which clinical effect is observed is usually 40-100 mg/L (300-700 µmol/L).

For adults and children weighing more than 17 kg, the initial daily dose is usually 10-15 mg/kg body weight, then the dose is increased to the optimal one. The average dose is 20-30 mg/kg/day. In the absence of a therapeutic effect (if the seizures do not stop), the dose can be increased; In this case, careful monitoring of the patient's condition is necessary.

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

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

The tablets are taken without crushing or chewing.

Use in 1 dose is possible for well-controlled epilepsy.

When switching from immediate-release valproate tablets, which provided the necessary control over the disease, to a sustained-release form (Depakine Chrono), the daily dose should be maintained.

Replacement of other antiepileptic drugs with Depakine Chrono should be carried out gradually, reaching the optimal dose of valproate within approximately 2 weeks. In this case, depending on the patient’s condition, the dose of the previous drug is reduced.

For patients not taking other antiepileptic drugs, doses should be increased after 2-3 days in order to reach the optimal dose within about a week.

If combination with other anticonvulsants is necessary while using Depakine Chrono, such drugs should be administered gradually.

Overdose

Symptoms: coma with muscle hypotonia, hyporeflexia, miosis, respiratory depression, metabolic acidosis; Cases of intracranial hypertension associated with cerebral edema have been described.

Treatment: in the hospital - gastric lavage, if no more than 10-12 hours have passed after taking the drug; monitoring and correction of the functional state of the cardiovascular and respiratory systems, maintaining effective diuresis. In very severe cases, dialysis is performed. The prognosis is generally good, but a few cases of death have been described.

Drug interactions

Combinations are contraindicated

When Depakine Chrono and mefloquine are used together, the development of convulsions is possible due to increased biotransformation of valproic acid and the ability of mefloquine to cause convulsions.

When used simultaneously with St. John's wort, there is a risk of reducing the concentration of valproic acid in the blood plasma.

Combinations are not recommended

When used together, Depakine Chrono can slow down the metabolism of lamotrigine in the liver and increase its concentration in the blood plasma, as well as increase the likelihood of severe skin reactions, including the development of toxic epidermal necrolysis (if combination therapy is necessary, careful clinical and laboratory monitoring is required).

Combinations that require special caution when using

When used simultaneously with carbamazepine, the concentration of its active metabolite in the blood plasma increases with signs of overdose. In addition, carbamazepine increases the metabolism of valproic acid in the liver, which leads to a decrease in the concentration of valproic acid in the blood plasma (clinical observation, determination of drug concentrations in the blood plasma, and adjustment of their doses, especially at the beginning of treatment, are recommended).

When using Depakine Chrono in combination with meropenem, panipenem, and also, apparently, with aztreonam and imipenem, a decrease in the concentration of valproic acid in the blood plasma is possible with an increased risk of seizures (clinical observation is recommended, determination of drug concentrations in the blood plasma; correction may be required doses of valproic acid during antibiotic treatment and after its discontinuation).

When felbamate and Depakine Chrono are used together, it is possible to increase the concentration of valproic acid in the blood plasma and the risk of overdose (clinical and laboratory monitoring and, possibly, dose adjustment of valproic acid during treatment with felbamate and after its discontinuation are recommended).

When used together, the drug Depakine Chrono increases the concentration of phenobarbital and primidone in the blood plasma, which leads to overdose symptoms, usually in children. In addition, there is a decrease in the concentration of valproic acid in the blood plasma, associated with an increase in its metabolism in the liver under the influence of phenobarbital or primidone (clinical monitoring is recommended during the first 15 days of combination treatment with an immediate reduction in the dose of phenobarbital or primidone when the first signs of sedation appear, determination plasma concentrations of both anticonvulsants).

With simultaneous use of Depakine Chrono with phenytoin, there is a risk of a decrease in the concentration of valproic acid in the blood plasma, which is associated with increased metabolism of valproic acid in the liver under the influence of phenytoin (clinical monitoring is recommended with determination of the concentrations of both drugs in plasma and, if necessary, correction of their doses).

When used simultaneously with topiramate, the risk of developing hyperammonemia or encephalopathy increases, which is due to the increased effect of valproic acid (intensive clinical and laboratory monitoring is recommended during the first month of treatment and in case of symptoms of ammonemia).

Valproic acid potentiates the effect of neuroleptics, MAO inhibitors, antidepressants, benzodiazepines (clinical monitoring and, if necessary, dose adjustment of the appropriate drug are recommended).

With simultaneous use of Depakine Chrono with cimetidine or erythromycin, it is possible to increase the concentration of valproic acid in the blood plasma due to a decrease in its biotransformation in the liver.

With simultaneous use, Depakine Chrono can increase the concentration of zidovudine in the blood plasma, which leads to increased toxicity of zidovudine.

Combinations to Consider

When used simultaneously with nimodipine for oral administration (and, apparently, parenterally), the hypotensive effect of nimodipine is enhanced due to a decrease in its metabolism under the influence of valproic acid and an increase in plasma concentration.

With the simultaneous use of Depakine Chrono and acetylsalicylic acid, an increase in the effects of valproate is observed due to an increase in its concentration in the blood plasma.

When indirect anticoagulants and vitamin K antagonists are used simultaneously with Depakine Chrono, careful monitoring of the prothrombin index is required.

Valproic acid does not cause enzyme induction, therefore, when used simultaneously, Depakine Chrono does not affect the effectiveness of combined hormonal contraceptives containing estrogens and progesterone.

Use during pregnancy and lactation

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

Experimental studies on mice, rats and rabbits have shown a teratogenic effect.

According to available data, in humans, valproate predominantly causes disturbances in the development of the neural tube: myelomeningocele, spina bifida (1-2%). Cases of facial dysmorphia and malformations of the limbs (especially shortened limbs), as well as malformations of the cardiovascular system, have been described.

The risk of malformations is higher with combination antiepileptic therapy than with sodium valproate monotherapy. However, it is quite difficult to establish a cause-and-effect relationship between fetal malformations and other factors (including genetic, social, environmental factors).

Considering the above, during pregnancy the use of the drug is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.

If a woman is planning a pregnancy, the indications for antiepileptic treatment should be reconsidered.

During pregnancy, antiepileptic treatment with valproate should not be interrupted if it is effective. In such cases, monotherapy is recommended; the minimum effective daily dose should be divided into several doses.

In addition to antiepileptic therapy, folic acid preparations (at a dose of 5 mg/day) can be added, because they help minimize the risk of neural tube malformations. However, regardless of whether the patient receives folates or not, in any case, special antenatal monitoring for the condition of the neural tube or other malformations should be carried out.

Valproate can cause hemorrhagic syndrome in newborns, which appears to be associated with hypofibrinogenemia.

Cases of afibrinogenemia with fatal outcomes have been reported. This may be due to a decrease in a number of blood clotting factors. In newborns, platelet counts, plasma fibrinogen levels, and coagulation factors should be monitored.

Valproate is excreted in breast milk in low concentrations (from 1% to 10% of plasma concentrations). According to the literature and based on little clinical experience, breastfeeding can be planned during treatment with Depakine Chrono as monotherapy, taking into account its safety profile (especially hematological disorders).

Side effects

From the central nervous system and peripheral nervous system: from ≥ 0.01% to < 1% - ataxia; ≤ 0.01% - cases of cognitive impairment with a progressive onset until the development of a full picture of dementia syndrome (reversible within several weeks or months after discontinuation of the drug).

Stupor or lethargy is possible, sometimes leading to transient coma (encephalopathy); these cases were isolated or associated with a paradoxical increase in the frequency of seizures during therapy, their frequency decreased when treatment was suspended or the drug dose was reduced. Most often, such cases are described during complex treatment (especially with phenobarbital) or after a sharp increase in the dose of valproate.

In some cases, reversible parkinsonism.

Possible headaches, mild postural tremor and drowsiness.

From the digestive system: often at the beginning of treatment - nausea, vomiting, gastralgia, diarrhea (usually disappear within a few days without stopping the drug); possible increase in the activity of liver transaminases; from ≥ 0.01% to < 0.1% - liver dysfunction; ≤ 0.01% - pancreatitis (early cessation of treatment is required), sometimes fatal.

From the hematopoietic system: often - dose-dependent thrombocytopenia; from ≥ 0.01% to < 0.1% - inhibition of bone marrow hematopoiesis, including anemia, leukopenia, pancytopenia.

From the urinary system: ≤ 0.01% - enuresis; in some cases, reversible Fanconi syndrome of unknown origin.

From the blood coagulation system: in some cases, more often when used in high doses (sodium valproate has an inhibitory effect on the second stage of platelet aggregation), a decrease in fibrinogen levels or an increase in bleeding time, usually without clinical manifestations.

Metabolism: often - isolated and moderate hyperammonemia without changes in liver function tests, especially with polytherapy (drug discontinuation is not required); hyperammonemia is possible, accompanied by neurological symptoms (examination required); <0.01% - hyponatremia.

Allergic reactions: skin rash, urticaria, vasculitis; <0.01% - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Other: alopecia; ≥ 0.01% to < 0.1% - reversible or irreversible hearing loss; <0.01% - mild peripheral edema; weight gain (since weight gain is a risk factor for polycystic ovary syndrome, careful monitoring of the condition of such patients is recommended); There have been reports of menstrual irregularities and amenorrhea.

Storage conditions and periods

The drug should be stored in protective packaging in a dry place at a temperature below 25°C. Shelf life: 3 years.

Indications

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, 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).

Contraindications

- acute hepatitis;

- chronic hepatitis;

- cases of severe hepatitis in the patient or in his family history, primarily of drug origin;

- porphyria;

- combination with mefloquine;

- combination with St. John's wort preparations;

- not recommended for use in combination with lamotrigine;

- children under 6 years of age (risk of entry into the respiratory tract when swallowing);

- hypersensitivity to the drug.

special instructions

Before starting treatment and during the first 6 months of therapy, periodic monitoring of liver function is necessary, especially in patients at risk.

If a slight increase in the activity of liver enzymes is detected, especially at the beginning of treatment, it is recommended to conduct a more complete laboratory examination (including, in particular, determination of the prothrombin index) in order to correct the regimen if necessary; the examination should be repeated in the future.

Among the classical tests, the most important are those reflecting protein synthesis in the liver and especially the prothrombin index. If there is a significant decrease in the level of prothrombin, a marked decrease in the content of fibrinogen, blood clotting factors, an increase in the level of bilirubin and transaminases, treatment with Depakin Chrono should be suspended. If the patient is receiving salicylates at the same time, they should also be discontinued immediately, since salicylates and valproate have common metabolic pathways.

There are rare reports of severe cases of liver disease with fatal outcome. The high-risk group consists of children of the younger age group. With age, the frequency of such complications decreases.

In most cases, liver dysfunction was observed during the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combination antiepileptic therapy.

Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk:

- nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;

- recurrence of epileptic seizures during antiepileptic therapy.

The patient, and if it is a child, then his family, should be warned about the need to immediately notify the doctor about the occurrence of these symptoms. In addition to clinical examination, liver function testing should be performed immediately in such cases.

In rare cases, severe forms of pancreatitis have been reported, sometimes with death. These cases were observed regardless of the patient's age and duration of treatment, although the risk of developing pancreatitis decreased with increasing age of the patients. Insufficiency of liver function in pancreatitis increases the risk of death.

Before starting therapy, before surgery, if spontaneous hematomas or bleeding occur, it is recommended to monitor the peripheral blood picture (with the number of platelets), determine the bleeding time and conduct coagulation tests.

In case of acute abdominal pain syndrome and symptoms such as nausea, vomiting and/or anorexia, immediate examination of the patient is necessary, and if the diagnosis of pancreatitis is confirmed, the drug should be discontinued.

When using Depakine Chrono in patients with renal failure, it is recommended to take into account the increased concentration of the free fraction of valproic acid in the blood plasma and reduce the dose.

If it is necessary to prescribe the drug to patients with systemic lupus erythematosus and other diseases of the immune system, the expected therapeutic effect and the possible risk of therapy should be assessed, since when using Depakine Chrono, disorders of the immune system were observed in extremely rare cases.

It is not recommended to prescribe the drug to patients with carbamide cycle enzyme deficiency. In such patients, several cases of hyperammonemia accompanied by stupor and/or coma have been described.

In children with unexplained symptoms from the digestive system (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, with mental retardation or a family history of death of a newborn or child, metabolic studies should be carried out before starting treatment with Depakin Chrono, especially ammonemia during fasting and after eating.

Patients should be warned of the risk of weight gain early in treatment and advised to follow a diet to minimize this effect.

Impact on the ability to drive vehicles and operate machinery

During the treatment period, patients must be careful when driving vehicles and other activities that require high concentration and speed of psychomotor reactions.

Use for renal impairment

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

Use for liver dysfunction

The drug is contraindicated in case of liver dysfunction.

Conditions for dispensing from pharmacies

The drug is available with a prescription.

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.

What kind of drug is Depakine?

According to medical statistics, epilepsy occurs in approximately 1% of the world's population.
Among the patients there are many women of childbearing age. If we talk about the types of epilepsy, then we can roughly distinguish 3:

• congenital;
• acquired. For example, after suffering a traumatic brain injury;
• gestational - developing during pregnancy.

Regardless of the cause of the disease, in the presence of convulsive seizures, the attending epileptologist who monitors the patient’s condition prescribes anticonvulsants, in particular Depakine.

For those who are interested in why Depakine is prescribed to pregnant women, the answer is that it contains valproic acid. Used to treat epilepsy of various origins.

Depakine during pregnancy is not recommended in the 1st trimester, because there is a high risk of developing pathology in the fetus.

Depakine is known under such names as apilepsin and depakine enteric.

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 meals).

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.

It is not recommended to drink alcohol while taking the drug.

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.

Results

We reviewed the rules for taking Depakine Chrono 300 and the instructions for using Depakine Chrono 500. Reviews about the drug are very mixed. Patients note that it can improve mood, eliminate feelings of anxiety and fear, but it causes inhibition of reactions and motor functions, memory impairment, and decreased intelligence. For some, the drug caused causeless hysterics, tearfulness, irritability, and aggression, which negatively affected work and relationships with others.

Reviews of the side effects of Depakine in children are also common. Parents note that the drug causes nausea and vomiting in children and delayed reactions. Patients also note hair loss when taking Depakine, disruption of the menstrual cycle, and deterioration in the condition of the facial skin.

However, there are patients who are satisfied with treatment with this drug. Side effects of Depakine Chrono can be avoided by following the recommendations of your doctor and constantly monitoring the condition of your internal organs. The active ingredient in the drug is sodium valproate.

So, what kind of drug is this - “Depakine”? What do patients and doctors say about him? The drug is described as a very effective drug against epilepsy. The medication is valued for its prolonged action and more progressive accumulation of the active substance in human brain tissue. The main disadvantage of the drug is the regular occurrence of side effects.

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 drug 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.

Indications for treating children

Side effects of Depakine Chrono in children occur quite often. An important aspect in therapy is the inability to distinguish extensive attacks from local ones. Epilepsy syndrome in young children can occur in very different ways. It is extremely important that the drug used against epilepsy has a broad spectrum of action. In our country, for a long time, exclusively drugs from the benzodiazepine group (Gidazepam, Diazepam, Clonazepam and others) were used, which did not show their effectiveness in all cases.

Reviews about Depakine are mixed. Parents of young patients report positive and negative effects. A lot of side effects are noted by mothers and fathers of babies who are prescribed this drug. Based on reviews from parents, we can conclude that if your child has not been diagnosed with epilepsy, then it is better to refrain from taking Depakine.

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.

Where to buy Depakine syrup 57.64 mg/ml 150 ml Falkenstein

The drug is delivered throughout Russia and the CIS. The goods are paid for only upon receipt. As a rule, the price for Depakine syrup 57.64 mg/ml 150 ml Falkenstein in pharmacies is much higher than on the Internet. You can consult and get more detailed information about the product by entering contacts on the official website, the operator will call you back within a few minutes.

The discounted price on the official website is 263 rubles.

Go to the official website Depakine syrup 57.64 mg/ml 150 ml

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;
• quetiapine: increased risk of neutropenia/leukopenia;
• estrogen-progestogen drugs: the effectiveness of these drugs is not reduced;
• ethanol, other potentially hepatotoxic drugs: the hepatotoxic effect of valproic acid may worsen;
• drugs that have a myelotoxic effect: the risk of inhibition of bone marrow hematopoiesis increases;
• clonazepam: there is a possibility of increased severity of absence status.