Depakin Chronosphere: reviews, instructions for use, price

Pharmacodynamics and pharmacokinetics

Depakine Chronosphere is an antiepileptic drug that has a sedative as well as a central muscle relaxant effect . The active substance of the drug affects the GABAergic system . It increases the concentration of GABA (gamma-aminobutyric acid) in the central nervous system and activates GABAergic transmission .

The bioavailability of the drug in the blood after oral administration is approximately 100%. It enters the brain and cerebrospinal fluid . To achieve a therapeutic effect, the minimum concentration of the drug in the blood serum is 40–50 mg/l. At a concentration of 200 mg/l, the dosage should be reduced. The maximum content in blood plasma is after approximately 7 hours.

A stable concentration in plasma is formed by 3-4 days of use. High degree of binding to plasma proteins. The drug is mainly excreted in the urine. Food intake does not affect pharmacokinetics.

Depakine® Chronosphere

Before starting to use the drug and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed.

As with the use of most antiepileptic drugs, when using valproic acid, a slight increase in the activity of “liver” transaminases is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In such patients, it is necessary to conduct a more thorough study of biological parameters, including the prothrombin index. It may be necessary to adjust the dose of the drug, and, if necessary, repeat clinical and laboratory examination.

Before starting therapy or before surgery, as well as in the event of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to determine the bleeding time and the number of formed elements in the peripheral blood, including platelets.

Severe liver damage

Predisposing factors

Isolated cases of severe liver damage, sometimes with fatal outcome, have been described. Clinical experience shows that those at risk include patients taking multiple antiepileptic drugs at the same time, children under 3 years of age with severe seizures, especially against the background of brain damage, mental retardation and/or congenital metabolic or degenerative diseases; patients concomitantly taking salicylates (since salicylates are metabolized through the same metabolic pathway as valproic acid).

After 3 years, the risk of liver damage decreases significantly and decreases progressively as the patient ages. In most cases, such liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually when valproic acid was used as part of combination antiepileptic therapy.

Suspicion of liver damage

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

- nonspecific symptoms, especially those that began suddenly, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;

- resumption of seizures in patients with epilepsy.

Patients or their family members (when using the drug in pediatric patients) should be warned that they should immediately report the occurrence of any of these symptoms to their doctor. Patients should immediately undergo clinical examination and laboratory testing of liver function tests.

Revealing

Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative are studies reflecting the state of the protein-synthetic function of the liver, especially the determination of the prothrombin index. Confirmation of deviation from the norm of the prothrombin index in the direction of its decrease, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood clotting factors, an increase in the concentration of bilirubin and an increase in the activity of “liver” transaminases), as well as the appearance of other symptoms indicating for liver damage, requires discontinuation of the drug. As a precaution, if patients were taking salicylates concomitantly, their use should also be discontinued.

Pancreatitis

There are rare reported cases of severe forms of pancreatitis in children and adults, which developed regardless of age and duration of treatment. Several cases of hemorrhagic pancreatitis have been observed with rapid progression of the disease from the first symptoms to death.

Children are at increased risk of developing pancreatitis, and this risk decreases with increasing age of the child. Risk factors for developing pancreatitis may include severe seizures, neurological disorders, or anticonvulsant therapy. Liver failure combined with pancreatitis increases the risk of death.

If severe abdominal pain, nausea, vomiting and/or anorexia occur, patients should be evaluated immediately. If pancreatitis is confirmed, in particular, with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment should be started.

Suicidal thoughts and attempts

Suicidal ideation and suicide attempts have been reported in patients taking antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a 0.19% increase in the risk of suicidal ideation and suicide attempts in all patients taking antiepileptic drugs (including a 0.24% increase in this risk in patients taking antiepileptic drugs for epilepsy), compared with their frequency in patients taking placebo. The mechanism of this effect is unknown.

Therefore, patients taking the drug should be constantly monitored for suicidal thoughts and suicide attempts, and if they occur, appropriate treatment should be provided. Patients and their caregivers are advised to immediately consult a physician if they experience suicidal thoughts or suicide attempts.

Carbapenems

The simultaneous use of carbapenems is not recommended (see section “Interaction with other drugs”, “With caution”).

Patients with known or suspected mitochondrial diseases

Valproic acid can initiate or aggravate the manifestations of mitochondrial diseases in the patient, caused by mutations in mitochondrial DNA, as well as in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG). In particular, in patients with congenital neurometabolic syndromes caused by mutations in the gene encoding γ-polymerase (POLG), such as patients with Alpers-Huttenlocher syndrome, a higher incidence of acute liver failure and liver-related deaths was associated with the use of valproic acid. outcomes. The presence of diseases caused by defects in γ-polymerase can be assumed in patients with a family history or symptoms of such diseases, including encephalopathy of unknown origin, refractory epilepsy (focal, myoclonic), status epilepticus, mental and physical retardation, psychomotor regression, axonal sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine with visual (occipital) aura. In accordance with current clinical practice, testing for mutations in the polymerase γ gene (POLG) should be performed to diagnose such diseases (see section "Contraindications").

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

As with other antiepileptic drugs, when taking valproic acid, instead of improvement, some patients experienced a reversible increase in the frequency and severity of seizures (including the development of status epilepticus) or the appearance of new types of seizures. If seizures worsen, patients should immediately consult their doctor (see section "Side effects").

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

Pregnancy Prevention Program

Valproic acid has a high teratogenic effect; the use of valproic acid leads to a high risk of congenital malformations and developmental disorders of the central nervous system in the fetus.

The use of valproic acid is contraindicated:

- during pregnancy for epilepsy, except in cases of absence of alternative treatment methods (see sections “Special instructions”, “Use during pregnancy and breastfeeding”);

— during pregnancy in the treatment and prevention of bipolar affective disorders;

- in women of childbearing potential, unless all the conditions of the Pregnancy Prevention Program are met (see sections “Special Instructions”, “Use during Pregnancy and Breastfeeding”).

When prescribing drugs containing valproic acid, you must:

— conduct an individual assessment of the circumstances of prescribing the drug in each individual case, discuss possible methods of therapy and make sure that the patient understands the potential risks and the need for measures taken to minimize them;

— make sure that the patient has childbearing potential;

— make sure that the patient understands the nature and magnitude of the risks of using valproic acid during pregnancy, in particular, the risks of teratogenic effects, as well as the risks of disorders of the mental and physical development of the child;

— make sure that the patient understands the need to conduct a pregnancy test before starting and during treatment;

- explain the necessary methods of contraception, make sure that the patient uses reliable methods of contraception continuously during treatment with drugs containing valproic acid;

— make sure that the patient understands the need to regularly contact a specialist in the treatment of epilepsy and bipolar affective disorders (at least once a year) to re-analyze the prescribed therapy;

- make sure that the patient understands the need to contact her doctor if she is planning a pregnancy in order to promptly assess the possibility of switching to alternative therapy before stopping the use of contraception;

- inform about the need for immediate consultation with your doctor if you suspect pregnancy;

— ensure that the patient has received all the necessary explanations about the risks and necessary precautions.

The above information is also relevant for women who are not currently sexually active, unless the attending physician is satisfied that there is no childbearing potential.

Female pediatric patients

When prescribing drugs containing valproic acid, you must:

— make sure that female pediatric patients/their legal representatives understand the need to consult with their doctor upon the onset of menarche;

— ensure that female pediatric patients who have reached menarche, or their legal representatives, receive detailed information about the risks of congenital malformations and disorders of the central nervous system in the fetus.

The treating physician should annually re-evaluate the prescribed valproic acid therapy and evaluate the possibility of prescribing alternative therapy. If medications containing valproic acid are the treatment of choice, ensure that reliable methods of contraception are used and that the Pregnancy Prevention Program is followed. Before puberty, the possibility of switching patients to alternative treatment methods should be constantly considered.

Pregnancy test

Before starting treatment with drugs containing valproic acid, it is necessary to exclude pregnancy. Therapy with drugs containing valproic acid cannot be prescribed to women of childbearing potential unless a negative pregnancy test (pregnancy blood test) has been confirmed by a health care professional to prevent the drug from being prescribed during pregnancy.

Contraception methods

Female patients of childbearing potential who are prescribed therapy with drugs containing valproic acid should use reliable methods of contraception continuously throughout the entire treatment period.

Female patients of childbearing potential should be provided with detailed information about methods of preventing pregnancy, and such patients may also seek advice from their physician if they are not using a reliable method of contraception.

You must use at least one reliable method of contraception (preferably simultaneously with methods such as an intrauterine system or implant) or two complementary methods of contraception, including barrier methods. When prescribing a contraceptive method to a patient, it is necessary to take an individualized approach and discuss all possible contraceptive options with the patient to ensure that the patient adheres to and adheres to the regimen. In case of amenorrhea, the patient should also be warned about the use of effective methods of contraception.

Annual analysis of prescribed therapy

At least once a year, the treating physician should evaluate whether medications containing valproic acid are the treatment of choice. The risks associated with therapy should be discussed when prescribing the drug and at each annual review of the prescribed therapy, and ensure that the patient understands all risks.

Planning a pregnancy

If a patient is planning a pregnancy, a specialist in the treatment of epilepsy and bipolar affective disorder should evaluate therapy with drugs containing valproic acid and consider alternative therapy. Every effort should be made to switch the patient from therapy with drugs containing valproic acid before conception and until contraception is discontinued (see section “Use during pregnancy and breastfeeding”). If alternative therapy is not available, the patient should be advised of the risks associated with the use of drugs containing valproic acid for the unborn child to help make an informed decision about family planning.

What to do if you become pregnant?

If you become pregnant, you should contact your healthcare provider immediately to evaluate your treatment and consider alternative therapy.

The health worker must ensure that:

— patients understand all the risks described above;

— patients received recommendations not to stop therapy with valproic acid and to immediately contact their doctor when planning pregnancy.

Concomitant use with estrogen-containing drugs

Valproic acid does not reduce the therapeutic effectiveness of hormonal contraceptives. However, drugs containing estrogen, including estrogen-containing hormonal contraceptives, may increase the clearance of valproic acid, which may lead to a decrease in its serum concentration and, consequently, a decrease in its effectiveness. It is necessary to monitor the concentration of valproic acid in the blood serum and clinical effectiveness (seizure control and mood control) when prescribing or discontinuing estrogen-containing drugs (see section "Interaction with other drugs").

Children (information refers to dosage forms of the drug that can be taken by children under 3 years of age)

In children under 3 years of age, if it is necessary to use the drug, it is recommended to use it in monotherapy and in the dosage form recommended for children. In this case, before starting treatment, the ratio of the potential benefit from the use of valproic acid and the risk of liver damage and the development of pancreatitis when using it should be assessed.

In children under 3 years of age, the simultaneous use of valproic acid and salicylates should be avoided due to the risk of liver toxicity.

Kidney failure

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. If it is impossible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Enzyme deficiency of the carbamide cycle (urea cycle)

If an enzymatic deficiency of the carbamide cycle is suspected, the use of valproic acid is contraindicated. In such patients, several cases of hyperammonemia with the development of stupor or coma have been described. In these cases, metabolic studies should be carried out before starting treatment with valproic acid (see section "Contraindications").

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or child, metabolic studies should be performed before initiating treatment with valproic acid, in particular, determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after meals (see section “Contraindications”).

Patients with systemic lupus erythematosus

Although immune system dysfunction is extremely rare during treatment with valproic acid, the potential benefits of their use must be weighed against the potential risks when using the drug in patients with systemic lupus erythematosus.

Weight gain

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

Patients with diabetes mellitus

Given the possibility of adverse effects of valproic acid on the pancreas, when using the drug in patients with diabetes mellitus, blood glucose concentrations should be carefully monitored. When testing urine for the presence of ketone bodies in patients with diabetes, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partly in the form of ketone bodies.

Patients infected with human immunodeficiency virus (HIV)

in vitro studies

Valproic acid has been found to stimulate HIV replication under certain experimental conditions.
The clinical significance of this fact is unknown. In addition, the significance of data obtained from in vitro
for patients receiving maximally suppressive antiretroviral therapy. However, these data should be taken into account when interpreting the results of continuous viral load monitoring in HIV-infected patients taking valproic acid.

Patients with existing carnitane palmitoyltransferase (CPT) type II deficiency

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

Ethanol

During treatment with valproic acid, ethanol consumption is not recommended.

Other special instructions

The inert matrix of the drug (extended release drug), due to the nature of its excipients, is not absorbed in the gastrointestinal tract; after the release of the active substances, the inert matrix is excreted by the intestines.

Indications for use

Adults are recommended to take Depakine Chronosphere for treatment of:

bipolar affective disorders;
generalized epileptic seizures;
partial epileptic seizures.

For children, the drug is prescribed for the treatment of partial and generalized epileptic seizures .

In addition, it is used as a prophylactic in case of high fever to prevent seizures, if necessary.

Depakine Chronosphere gran prolong peror pack 250 mg N 30

ATX code: N03AG01 (Valproic acid)

Active substance:

valproic acid

Rec.INN registered by WHO

Extended-release granules are almost white or slightly yellowish in color, waxy, free-flowing, without the formation of agglomerates.

sodium valproate - 166.76 mg

valproic acid - 72.61 mg

in terms of sodium valproate - 250 mg

Excipients: solid paraffin - 253.32 mg, glycerol dibehenate - 265.3 mg, colloidal aqueous silicon dioxide*.

Three-layer bags (30) - cardboard packs.

pharmachologic effect

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

Shows antiepileptic activity in various types of epilepsy. The main mechanism of action appears to be related to the effect of valproic acid on the GABAergic system: it increases the content of GABA in the central nervous system and activates GABAergic transmission.

Indications of the drug Depakine Chronosphere:

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.

Children, incl. 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.

Dosage regimen

Depakine® Chronosphere is a dosage form that is particularly suitable for treating children (if they are able to swallow soft foods) or adults with difficulty swallowing.

Depakine® Chronosphere is a long-acting granule that provides more uniform concentrations of valproic acid in the blood and, accordingly, a more uniform distribution in tissues throughout the day.

Bipolar affective disorders

The dose should be selected and monitored individually by the attending physician. The daily dose should be set taking into account the age and body weight of the patient.

The recommended starting dose is 20 mg (in terms of sodium valproate) per kg of body weight. The dose should be increased as quickly as possible to the minimum dose that provides the required therapeutic effect.

The recommended maintenance dose for the treatment of bipolar disorder is between 1000 mg and 2000 mg (in terms of sodium valproate) per day. The dose should be adjusted according to the individual clinical response of the patient. To prevent manic states, an individually selected minimum clinically effective dose should be used.

Epilepsy

In monotherapy, the initial daily dose is usually 5-10 mg (in terms of sodium valproate) per kg of body weight, then it is increased by 5 mg/kg every 4-7 until the optimal dose is reached to prevent the occurrence of epileptic attacks.

Average daily dose:

for children under 14 years of age - 30 mg/kg body weight;

for adolescents 14-18 years old - 25 mg/kg body weight;

for adults and elderly patients (body weight 60 kg and above) - 20 mg/kg body weight.

Contraindications for use

hypersensitivity to sodium valproate, valproic acid, semisodium valproate, valpromide or any of the auxiliary components of the drug;
acute hepatitis;
chronic hepatitis;
a history of severe liver disease (especially drug-induced hepatitis) in the patient and his close blood relatives;
severe liver damage with a fatal outcome when using valproic acid in close blood relatives of the patient;
severe liver dysfunction;
severe pancreatic dysfunction;
hepatic porphyria;
established mitochondrial diseases caused by mutations in the nuclear gene encoding the mitochondrial enzyme γ-polymerase (POLG), for example, Alpers-Huttenlocher syndrome, and suspected diseases caused by defects in γ-polymerase in children under 2 years of age;
patients with established disorders of the carbamide cycle (urea cycle);
hemorrhagic diathesis, thrombocytopenia;
combination with mefloquine;
combination with St. John's wort preparations;
children up to 6 months of age.
Carefully
history of liver and pancreas diseases;
pregnancy;
congenital enzymopathies;
inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
renal failure (dose adjustment required);
hypoproteinemia;
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, selective serotonin reuptake inhibitors, 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 interaction at the level of metabolism or binding to plasma proteins may change the plasma concentrations of either these drugs and/or valproic acid);
simultaneous use with carbamazepine (risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid);
simultaneous use with topiramate or acetazolamide (risk of developing encephalopathy);
in patients with existing carnitine palmitoyltransferase (CPT) type II deficiency (higher risk of developing rhabdomyolysis when taking valproic acid).

Side effects

When using Depakine Chronosphere, the following side effects may occur:

genetic disorders: teratogenic risk ;
from the central nervous system: tremor of the limbs, drowsiness , ataxia ;
from the hearing organs: reversible and irreversible deafness;
from the gastrointestinal tract: epigastric , nausea, vomiting, diarrhea ;
from the skin: transient or dose-dependent alopecia ;
from the immune system: allergic reactions , angioedema , drug rash syndrome with eosinophilia ;
from the psyche: irritability, confusion, hyperactive state, hallucinations ;
from the blood and lymphatic system: thrombocytopenia , agranulocytosis , decreased concentration of fibrinogen in the blood;
from the organs of vision: diplopia , nystagmus ;
from the genital organs: male infertility;
Metabolism: isolated and moderate hyperammonemia ;
general disorders: weight gain.

In addition, in rare cases, when taking the drug, the following are possible:

pancytopenia;
leukopenia;
anemia;
disorders of bone marrow hematopoiesis;
pancreatitis;
toxic epidermal necrolysis ;
Stevens-Johnson syndrome;
erythema multiforme;
rash;
vasculitis;
amenorrhea;
dysmenorrhea;
extrapyramidal disorders;
dementia;
enuresis;
syndrome of impaired secretion of antidiuretic hormone;
hyponatremia;
minor peripheral edema;
liver damage;
changes in behavior, mood;
feeling tired;
psychoses;
motor restlessness;
depression;
aggressiveness;
unusual agitation;
dysarthria.

DEPAKINE CHRONO extended-release film-coated tablets 300 mg No. 100

Severe liver damage Clinical experience shows that patients at risk include those receiving multiple antiepileptic drugs simultaneously, children under 3 years of age with severe seizures, especially in the presence of brain damage, mental retardation and/or congenital metabolic or degenerative diseases. In children over 3 years of age, the risk of liver damage is significantly reduced and decreases progressively as the patient ages. In most cases, liver damage occurs within the first 6 months of treatment. For early diagnosis of liver damage, clinical observation of patients is mandatory. In particular, you should pay attention to the appearance of the following symptoms that may precede the onset of jaundice, especially in patients at risk: nonspecific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain; resumption of seizures in patients with epilepsy. Patients or their family members (when using the drug in children) should be warned that they should immediately report the occurrence of any of these symptoms to their doctor. If these symptoms occur, patients should immediately undergo clinical examination and laboratory testing of liver function tests. Liver function tests should be performed before starting treatment and then periodically during the first 6 months of treatment. Among conventional studies, the most informative are studies reflecting the state of the protein-synthetic function of the liver, especially the prothrombin index. Confirmation of deviations from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the content of fibrinogen and blood coagulation factors, an increase in the concentration of bilirubin and an increase in transaminase activity) requires discontinuation of the use of the drug Depakin® Chrono. As a precaution, if patients were receiving salicylates concomitantly, their use should also be discontinued, because they are metabolized through the same metabolic pathway as valproic acid. Pancreatitis Children are at increased risk of developing pancreatitis, and the risk decreases as the child gets older. Severe seizures, neurological disorders, or anticonvulsant therapy may be risk factors for developing pancreatitis. Liver failure combined with pancreatitis increases the risk of death. Patients who experience severe abdominal pain, nausea, vomiting and/or anorexia should be evaluated immediately. If the diagnosis of pancreatitis is confirmed, in particular with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment initiated. Suicidal thoughts and attempts Suicidal thoughts or attempts have been reported in patients receiving antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a small increase in the risk of suicidal ideation and attempts. The mechanism of this effect is unknown. Therefore, patients receiving Depakine® Chrono should be constantly monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be provided. Patients and caregivers are advised to seek immediate medical attention if a patient experiences suicidal thoughts or attempts. Renal failure A dose reduction of valproic acid may be required due to an increase in the concentration of its free fraction in the blood serum. If it is impossible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient. Insufficiency of carbamide cycle enzymes If a deficiency of carbamide cycle enzymes is suspected, the use of valproic acid is not recommended. Several cases of hyperammonemia with stupor or coma have been described in such patients. In these cases, metabolic studies should be performed before starting treatment with valproic acid. In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cases of cytolysis), a history of lethargy or coma, with mental retardation, or a family history of death of a newborn or child, metabolic studies, in particular the determination of ammonemia (presence of ammonia and its compounds in the blood) on an empty stomach and after meals. Patients with systemic lupus erythematosus Although it has been shown that during treatment with Depakin® Chrono, immune system dysfunction is extremely rare, the potential benefits of its use must be compared with the potential risks when prescribing the drug to patients with systemic lupus erythematosus. Weight gain Patients should be warned of the risk of weight gain at the start of treatment and measures, mainly dietary adjustments, should be taken to minimize this phenomenon. Monitoring laboratory parameters Before starting the use of Depakine® chrono and periodically during the first 6 months of treatment, especially in patients at risk of developing liver damage, liver function tests should be performed. As with most antiepileptic drugs, a slight increase in liver enzyme activity is possible, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. In these patients, a more detailed study of laboratory parameters, including the prothrombin index, is necessary, and dose adjustment of the drug may be required, and, if necessary, repeated clinical and laboratory examinations. Before starting therapy or, if surgery is necessary, in case of spontaneous occurrence of subcutaneous hematomas or bleeding, it is recommended to conduct a hematological blood test (determine the leukocyte formula of the blood, including the number of platelets; bleeding time and coagulogram). Use in pediatrics In children under 3 years of age, if it is necessary to use valproic acid, it is recommended to use the drug Depakine® as monotherapy and in a special dosage form intended for children. In this case, before starting treatment, the ratio of the potential benefit from the use of valproic acid and the risk of liver damage and the development of pancreatitis when using it should be assessed. In children under 3 years of age, concomitant use of salicylates should be avoided due to the risk of hepatotoxicity and bleeding. Ethanol During treatment, alcohol consumption is not recommended. Effect on the ability to drive vehicles and operate machinery Patients should be warned about the risk of drowsiness, especially when undergoing combination anticonvulsant therapy or when combining valproic acid with benzodiazepines. During the treatment period, you must be careful and discuss with your doctor the possibility of driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

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 .

Depakine Chronosphere 1000 mg n30 powder

Dosage form:

drops for oral administration, syrup, enteric-coated tablets, lyophilisate for the preparation of solution for intravenous administration, syrup [for children], tablets, extended-release film-coated tablets, extended-release granules

Pharmachologic effect:

An antiepileptic drug that has a central muscle relaxant and sedative effect. The mechanism of action is associated with an increase in the content of GABA in the central nervous system (due to inhibition of GABA transferase, as well as a decrease in the reuptake of GABA in the brain), resulting in a decrease in the excitability and convulsive readiness of the motor areas of the brain. According to another hypothesis, it acts on sites of postsynaptic receptors, simulating or enhancing the inhibitory effect of GABA. A possible direct effect on membrane activity is associated with changes in K+ conductance. Improves the mental state and mood of patients, has antiarrhythmic activity.

Indications:

Epilepsy of various origins. Epileptic seizures (including generalized and partial seizures, as well as against the background of organic brain diseases). Changes in character and behavior (due to epilepsy). Febrile convulsions (in children), childhood tics. Manic-depressive psychosis with a bipolar course, not amenable to treatment with Li+ drugs or other drugs. Specific syndromes (Vest, Lennox-Gastaut).

Contraindications:

Hypersensitivity, liver failure, acute and chronic hepatitis, pancreatic dysfunction, porphyria, hemorrhagic diathesis, severe thrombocytopenia, lactation.

Side effects:

From the side of the central nervous system: tremor; rarely - changes in behavior, mood or mental state (depression, feeling tired, hallucinations, aggressiveness, hyperactive state, psychosis, unusual agitation, restlessness or irritability), ataxia, dizziness, drowsiness, headache, encephalopathy, dysarthria, enuresis, stupor, disturbance of consciousness, coma. From the sensory organs: diplopia, nystagmus, flashing “spots” before the eyes. From the digestive system: nausea, vomiting, gastralgia, decreased or increased appetite, diarrhea, hepatitis; rarely - constipation, pancreatitis, up to severe injuries with a fatal outcome (in the first 6 months of treatment, more often at 2-12 weeks). From the hematopoietic organs and hemostasis system: inhibition of bone marrow hematopoiesis (anemia, leukopenia); thrombocytopenia, decreased fibrinogen content and platelet aggregation, leading to the development of hypocoagulation (accompanied by prolongation of bleeding time, petechial hemorrhages, bruises, hematomas, bleeding, etc.). Metabolism: loss or increase in body weight. Allergic reactions: skin rash, urticaria, angioedema, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome). Laboratory indicators: hypercreatininemia, hyperammonemia, hyperglycinemia, hyperbilirubinemia, slight increase in the activity of “liver” transaminases, LDH (dose-dependent). From the endocrine system: dysmenorrhea, secondary amenorrhea, breast enlargement, galactorrhea. Other: peripheral edema, alopecia.

Directions for use and dosage:

Orally, during meals or immediately after meals, without chewing, with a small amount of water, 2-3 times a day. The syrup can be mixed with any liquid or added to small amounts of food. The initial dose for monotherapy for adults and children weighing more than 25 kg is 5-15 mg/kg/day, then this dose is gradually increased by 5-10 mg/kg/week. The maximum dose is 30 mg/kg/day (can be increased if it is possible to monitor plasma concentrations to 60 mg/kg/day). With combination therapy in adults - 10-30 mg/kg/day, followed by increasing the dose by 5-10 mg/kg/week. For children weighing less than 25 kg, the average daily dose for monotherapy is 15-45 mg/kg, the maximum is 50 mg/kg. Depending on age: newborns - 30 mg/kg, from 3 to 10 years - 30-40 mg/kg/day, up to 1 year - in 2 doses, in older people - in 3 doses. With combination therapy - 30-100 mg/kg/day. Children weighing less than 20 kg should not use controlled-release tablets. IV stream, 400-800 mg or IV drip, at a rate of 25 mg/kg for 24, 36, 48 hours. If you decide to switch to IV administration after oral administration, the first administration is carried out at a dose of 0.5-1 mg/kg/hour 4-6 hours after the last oral dose.

Special instructions:

During treatment, it is advisable to monitor the activity of “liver” transaminases, bilirubin concentration, peripheral blood patterns, blood platelets, the state of the blood coagulation system, amylase activity (every 3 months, especially when combined with other antiepileptic drugs). For patients receiving other antiepileptic drugs, transfer to valproic acid should be carried out gradually, reaching a clinically effective dose after 2 weeks, after which gradual withdrawal of other antiepileptic drugs is possible. In patients who have not received treatment with other antiepileptic drugs, a clinically effective dose should be achieved after 1 week. The risk of side effects from the liver is increased during combination anticonvulsant therapy, as well as in children. Drinks containing ethanol are not allowed. Before surgery, a general blood test (including platelet count), determination of bleeding time, and coagulogram parameters are required. If symptoms of an “acute” abdomen occur during treatment, before surgery, it is recommended to determine the activity of amylase in the blood to exclude acute pancreatitis. During treatment, one should take into account the possible distortion of the results of urine tests in diabetes mellitus (due to an increase in the content of ketone bodies) and indicators of thyroid function. If any acute serious side effects develop, you should immediately discuss with your doctor the advisability of continuing or stopping treatment. To reduce the risk of developing dyspeptic disorders, it is possible to take antispasmodics and enveloping drugs. Abruptly stopping valproic acid may lead to an increase in epileptic seizures. During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Interaction:

Valproic acid enhances the effects, incl. side effects, other antiepileptic drugs (phenytoin, lamotrigine), antidepressants, antipsychotic drugs (neuroleptics), anxiolytics, barbiturates, MAO inhibitors, thymoleptics, ethanol. The addition of valproic acid to clonazepam in isolated cases can lead to increased severity of absence status. With simultaneous use of valproic acid with barbiturates or primidone, an increase in the concentration of the latter in plasma is observed. Increases T1/2 of lamotrigine (suppresses liver enzymes, causes a slowdown in the metabolism of lamotrigine, as a result of which T1/2 is extended to 70 hours in adults and up to 45-55 hours in children). Reduces the clearance of zidovudine by 38%, while its T1/2 does not change. Tricyclic antidepressants, MAO inhibitors, antipsychotic drugs (neuroleptics), and other drugs that lower the seizure threshold reduce the effectiveness of valproic acid. When combined with salicylates, an increase in the effects of valproic acid is observed (displacement from the connection with plasma proteins), enhances the effect of antiplatelet agents (ASA) and indirect anticoagulants. When combined with phenobarbital, phenytoin, carbamazepine, mefloquine, the content of valproic acid in the blood serum decreases (acceleration of metabolism). Felbamate increases the concentration of valproic acid in plasma by 35-50% (dose adjustment is necessary). With simultaneous use of valproic acid with ethanol and other drugs that depress the central nervous system (tricyclic antidepressants, MAO inhibitors and antipsychotic drugs), increased depression of the central nervous system is possible. Ethanol and other hepatotoxic drugs increase the likelihood of developing liver damage. Valproic acid does not induce liver microsomal enzymes and does not reduce the effectiveness of oral contraceptives. Myelotoxic drugs increase the risk of suppression of bone marrow hematopoiesis.

Interaction

The active substance Depakine Chronosphere activates other psychotropic drugs when used simultaneously, so doses need to be adjusted if necessary.

In addition, Depakine Chronosphere increases plasma concentrations of Phenobarbital , Primidone , Zidovudine , enhancing some of their effects, including the sedative effect of Phenobarbital . The drug also reduces total plasma concentrations of phenytoin .

Valproic acid activates the toxicity of Carbamazepine and Amotrigine . Drugs should be taken together only under the strict supervision of a specialist. In addition, Depakine Chronosphere complicates the metabolism of Lamotrigine in the liver and increases its half-life by almost 2 times.

Valproic acid reduces the average clearance of Felbamate and enhances the hypotensive effect of Nimodipine .

Antiepileptic drugs that induce microsomal liver enzymes reduce the content of the active component Depakine Chronosphere in plasma. Felbamate has the same effect when combined with this drug.

It is not advisable to combine mefloquine and valproic acid , otherwise there is a high risk of an epileptic seizure. The effectiveness of Depakine Chronosphere is also reduced with simultaneous use of St. John's wort and rifampicin . Its concentration, on the contrary, increases when combined with drugs that are known to have a high degree of binding to plasma proteins. The serum concentration of the drug also increases with the use of cimetidine or erythromycin .

It is not recommended to combine Depakine Chronosphere with Carbapenems and Topiramate . If this cannot be avoided, medications should be taken under the strict supervision of a physician.

Ethanol and other potentially hepatotoxic drugs combined with valproic acid enhance the hepatotoxic effect of the latter. And in combination with Clonazepam, it is possible to increase the severity of absence status .

Myelotoxic drugs when used simultaneously with Depakine Chronosphere increase the risk of suppression of bone marrow hematopoiesis.

Instructions for use DEPAKINE CHRONOSPHERE

During treatment with an anticonvulsant drug, resumption or development of new seizures is occasionally possible, regardless of the spontaneous changes in the course of the disease observed in some epileptic conditions. With regard to valproate, this primarily concerns the combination regimen for the treatment of epilepsy, pharmacokinetic interactions, toxicity (hepato- or encephalopathy) and overdose.

Since sodium valproate is converted into valproic acid in the body, it should not be combined with other drugs that share common metabolic pathways (for example, divalproate, valpromide) in order to prevent an overdose of valproic acid.

Before starting treatment and during the first 6 months of treatment, liver function should be periodically monitored, especially in patients at risk.

It should be emphasized that during treatment with Depakine Chronosphere, as with other antiepileptic drugs, a slight, isolated and temporary increase in transaminase levels may be observed, especially at the beginning of treatment, in the absence of any clinical symptoms. In this case, it is recommended to conduct a more complete laboratory examination (including, in particular, determination of the prothrombin index) in order to revise the dose, if necessary, and repeat the tests depending on changes in parameters.

There are extremely rare reports of severe and fatal cases of liver disease.

At increased risk are infants and children under 3 years of age with severe epilepsy, especially epilepsy associated with brain damage, mental retardation, and/or congenital metabolic or degenerative diseases. In children over 3 years of age, the frequency of such complications decreases significantly and gradually decreases with age. In most cases, liver dysfunction was observed during the first 6 months of treatment, usually between 2 and 12 weeks, and most often with combined antiepileptic treatment.

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. On the one hand, there are nonspecific general symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain. On the other hand, there is a relapse of epileptic seizures.

It is recommended to inform the patient, and if it is a child, then his family, that if such clinical symptoms develop, you should immediately consult a doctor. In addition to clinical examination, liver function testing should be performed immediately.

Among the standard parameters, the most important are tests that reflect liver protein synthesis, and especially the prothrombin index. If an abnormally low level of prothrombin, a significant decrease in the level of fibrinogen and coagulation factors, an increase in the level of bilirubin and the activity of liver transaminases are detected, treatment with Depakine Chronosphere should be suspended. It is also necessary to interrupt treatment with salicylates if they were included in the treatment regimen, since their metabolism uses common pathways with valproate.

In extremely rare cases, severe forms of pancreatitis, sometimes fatal, have been reported. These cases were observed regardless of the patient's age or duration of treatment, although the risk was particularly increased for young children. Pancreatitis with an unfavorable outcome was usually observed in children of a younger age group, or in patients with severe epilepsy, brain damage, or when using complex anticonvulsant therapy.

Liver failure due to pancreatitis increases the risk of death.

Before starting therapy or surgery, in the case of hematomas or spontaneous bleeding, it is recommended to conduct a blood test (including determining the blood count, including platelet count, bleeding time and coagulation tests).

In patients with renal failure, it is recommended to take into account the increased concentration of free form of valproic acid in the serum and reduce the dose.

In case of acute abdominal pain and gastrointestinal symptoms such as nausea, vomiting and/or anorexia, it is necessary to keep in mind the risk of developing pancreatitis and, if the level of pancreatic enzymes is elevated, discontinue the drug, taking alternative therapeutic measures.

Sodium valproate is not recommended for use in patients with carbamide cycle enzyme deficiency. In such patients, several cases of hyperammonemia accompanied by stupor and/or coma have been described.

Although it has been shown that during treatment with Depakine Chronosphere, dysfunction of the immune system is extremely rare, the potential benefits of therapy and the risks should be assessed if it is necessary to use the drug in patients suffering from SLE.

Patients should be warned about the risk of weight gain early in treatment; To minimize this effect, the patient should follow an appropriate diet.

Use in pediatrics

In children under 3 years of age

The use of valproate (in the recommended dosage form) as monotherapy is recommended, but before starting treatment, the potential benefits of treatment with the drug should be assessed in relation to the risk of developing liver disease or pancreatitis.

Combined use with salicylates should be avoided in children under 3 years of age.

due to the risk of hepatotoxicity.

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, episodes of cytolysis), a history of lethargy or coma, mental retardation, or a family history of death of a newborn or young child, metabolic studies, especially ammonemia, should be performed before initiating treatment with sodium valproate. on an empty stomach and after meals.

Impact on the ability to drive vehicles and operate machinery

During treatment, patients should be warned about the possible occurrence of temporary drowsiness and the need to be careful when driving vehicles and other activities that require high concentration and speed of psychomotor reactions (especially when using combined anticonvulsant therapy).

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.