Convulsofin-retard - instructions for use, dose, side effects, contraindications

active substances: valproate sodium 199.80 mg / 333.00 mg, valproic acid 87.00 mg / 145.00 mg (equivalent to sodium valproate 100.20 mg / 167.00 mg);

Excipients: hypromellose-2910 57.00 / 95.00 mg, hypromellose-2208 57.00 / 95.00 mg, silicon dioxide colloidal water 27.60 / 46.00 mg, acesulfame potassium 3.60 / 6.00 mg;

shell: butyl methacrylate copolymer 11.55 / 15.20 mg, magnesium stearate 2.89 / 3.80 mg, titanium dioxide 1.97 / 2.60 mg, dibutyl sebacate 1.75 / 2.30 mg, sodium lauryl sulfate 0.84 / 1 , 10 mg.

Description:

Oblong biconvex tablets, covered with a film shell of white color, with a risk on both sides. Almost odorless.

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.G.01 Valproic acid

Pharmacodynamics:

Antiepileptic drug, which has central muscle relaxant and sedative effect.

It shows antiepileptic activity in various types of epilepsy. The main mechanism of action, apparently, is associated with the action of valproic acid on the GABA -ergic system: an increase in the content of gamma-aminobutyric acid (GABA) in central nervous system and activation of GABA-ergic transmission.

Pharmacokinetics:

Absorption.

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

When taking valproic acid, prolonged-release tablets, 500 mg at a dose of 1000 mg / day, the minimum plasma concentration is 44.7 ± 9.8 μg / ml, and the maximum plasma concentration (C_max) is 81.6 ± 15.8 μg / ml. The time to reach the maximum concentration is 6.58 ± 2.23 hours. Equilibrium concentration is achieved within 3-4 days of regular intake of the drug.

The average therapeutic range of serum concentrations of valproic acid is 50-100 mg / l. With the justified need to achieve higher concentrations and blood plasma, the ratio of expected benefit to the potential risk of unwanted adverse reactions, especially dose-dependent ones, should be carefully weighed. For example, at concentrations of more than 100 mg / l, an increase in unwanted adverse reactions is expected until the development of intoxication. At a plasma concentration of more than 150 mg / l, a dose reduction is required.

Distribution

The volume of distribution depends on age and is usually 0.13-0.23 l / kg, in young people - 0.13-0.19 l / kg.

Cligation of blood plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, the association with plasma proteins decreases. In severe renal failure, the concentration of the free fraction (therapeutically active) of valproic acid can be increased by 8.5-20%.

When hypoproteinemia total concentration of valproic acid (free fraction (unbound to plasma proteins) + bound fraction (bound to plasma proteins)) may not be changed, but may decline because of increased metabolism of free fraction (unbound to plasma proteins) valproic acid. Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in CSF is 10% of the corresponding serum concentration.

Valproic acid penetrates into breast milk during lactation. In the equilibrium state, the concentration of valproic acid in breast milk is 1 to 10% of its serum concentration.

Metabolism

Metabolised in the liver by glucuronation, as well as beta, omega, and omega₁-oxidation.More than 20 metabolites have been identified, metabolites after omega-oxidation have a hepatotoxic effect.

Valproic acid does not induce microsomal liver enzymes: unlike most other antiepileptic drugs, valproic acid does not affect the degree of both its own metabolism and the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Excretion

Valproic acid is mainly excreted by the kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted by the kidneys unchanged.

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

The half-life (T_1/2) is 15-17 hours. When combined with antiepileptic drugs that induce microsomal liver enzymes, the plasma clearance of valproic acid increases, and T_1/2decreases, the degree of their change depends on the degree of induction of microsomal liver enzymes by other antiepileptic drugs.

T_1/2in children older than 2 months is close to that in adults.

In patients with liver disease T_1/2 valproic acid is increased.

When an overdose was observed, an increase in T_1/2to 30 hours. Hemodialysis exposed only the free fraction of valproic acid in blood plasma (10%).

Peculiarities of pharmacokinetics in pregnancy

With an increase in the distribution of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. In this case, despite taking the drug in a constant dose, it is possible to reduce the serum concentrations of valproic acid. In pregnancy may vary bond valproic acid plasma proteins, which may lead to an increase in the concentration of the free fraction (therapeutically active) valproic acid. In comparison with the form covered with enteric-coated shell, the form of prolonged action in equivalent doses is characterized by the following:

- Absence of a delay of a suction after reception;

- prolonged absorption; identical bioavailability;

- less C_max (decrease in C_maxby about 25%), but with a more stable plateau phase from 4 to 14 hours after administration;

- more linear correlation between dose and concentration of valproic acid in blood plasma.

Indications:

In adults: treatment of generalized epileptic seizures: clinical, topical, tonic-clinical, absence, myoclonic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs).

Treatment of partial epileptic seizures: partial seizures with secondary generalization or without it (in monotherapy or in combination with other antiepileptic drugs).

Treatment and prevention of bipolar affective disorders.

Children: treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs).

Treatment of partial epileptic seizures: partial seizures with secondary generalization or without it (in monotherapy or in combination with other antiepidemic drugs).

Contraindications:

Hypersensitivity to sodium valproate, valproic acid, semiotria valproate, valpromide or to any of the components of the drug; acute hepatitis; chronic hepatitis; severe diseasesliver (especially drug-induced hepatitis) in the history of the patient and his close blood relatives; severe liver damage with lethal when using valproic acid in close blood relatives of the patient; severe violations of the liver or pancreas; hepatic porphyria; simultaneous application with mefloquine; simultaneous application with preparations of St. John's wort; Children under 6 years of age (risk of falling into the airway during swallowing).

Carefully:

Diseases of the liver and pancreas in history; congenital fermentopathy; oppression of bone marrow function (leukopenia, thrombocytopenia, anemia); renal failure (dose adjustment required); hypoproteinemia (see sections "Pharmacokinetics", "Method of administration and dose"); in patients receiving several anticonvulsants because of an increased risk of liver damage; in patients with insufficiency carnitine palmitoyltransferazy type II there is a higher risk of rhabdomyolysis with valproic acid.

Simultaneous use of drugs,provoking convulsive attacks or reducing the threshold of convulsive readiness, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of seizures).

Simultaneous use of neuroleptics, monoamine oxidase (MAO) inhibitors, antidepressants, benzodiazepine (the possibility of potentiating their effects).

Simultaneous use of phenobarbital, primidon, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine (due to pharmacokinetic interactions at the level of metabolism or communication with blood plasma proteins, the plasma concentrations of these drugs may change and / or valproic acid, see the section on "Interaction with other medicinal products" for more details).

Simultaneous use of carbamazepine (the risk of potentiating the toxic effects of carbamazepine and reducing the plasma concentration of valproic acid).

Simultaneous application of topiramate (risk of encephalopathy).

Pregnancy and lactation:

Fertility

In men valproic acid can reduce sperm motility and cause male infertility. In addition, in connection with the possibility of developing unwanted effects on the part of the endocrine system and genital organs in women (such as dysmenorrhea, amenorrhea, polycystic ovaries, hyperandrogenia), fertility in women may be reduced.

Pregnancy

The risk associated with the development of epileptic seizures during pregnancy

During pregnancy, the development of generalized tonic-clonic epileptic seizures, epileptic status with the development of hypoxia may pose a particular risk to the mother and fetus in connection with the possibility of a lethal outcome.

The risk associated with the use of valproic acid during pregnancy

Experimental studies of reproductive toxicity, conducted in mice, rats and rabbits, demonstrated the presence of teratogenic action in valproic acid. The available clinical data confirm that in children born to mothers with epilepsy who received valproic acid,there is an increased frequency of intra-uterine development disorders of varying severity (neural tube developmental defects, craniofacial deformities, developmental limbs, cardiovascular system, hypospadias, and multiple intrauterine malformations affecting different organ systems) compared with the frequency of pregnancy women of some other antiepileptic drugs.

The meta-analysis data, including register and cohort studies, showed that the incidence of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during pregnancy was 10.73% (95% confidence interval 8.16% 13.29%). The available data indicate the dose-dependent nature of these unwanted effects.

The risk of congenital malformations in children born to mothers with epilepsy who received valproic acid monotherapy during monotherapy in pregnancy was 1.5 times higher compared to phenytoin alone, approximately 2.3 times higher than monotherapy with carbamazepine or phenobarbital, and approximately 3.7 times higher than lamotrigine monotherapy.

The available data suggest a relationship between the intrauterine exposure of valproic acid and the risk of delayed development (especially speech development, as well as a decline in the verbal IQ) in children born to mothers with epilepsy taking valproic acid. The delay in development is often combined with malformations and phenomena of dysmorphism. However, in cases of developmental delay in these children, it is difficult to pinpoint the causal relationship with valproic acid because of the possibility of simultaneous exposure to other factors such as a low level of intelligence of the mother or both parents; genetic, social factors, environmental factors; Inadequate treatment effectiveness aimed at preventing epileptic seizures in the mother during pregnancy.

Also reported on the development of various autistic disorders in children exposed to intrauterine effects of valproic acid. Both monotherapy with valproic acid and combination therapy with the inclusion of valproic acid. are associated with an unfavorable outcome of pregnancy,but according to available data, combined antiepileptic therapy, including valproic acid, is associated with a higher risk of adverse pregnancy outcome compared with valproic acid monotherapy.

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

In connection with the foregoing, valproic acide should be used in pregnancy and in women of reproductive age without extreme necessity.

Women of reproductive age or planning pregnancy should be informed about the need not to use valproic acid drugs in the therapy of epilepsy and bipolar disorders in pregnant women and pregnant women planning, with the exception of patients with intolerance or ineffectiveness of other drugs. If valproic acid is the only drug of choice, then patients should use effective methods of contraception, especially during puberty and during pregnancy planning should be carefully monitored by the attending physician.Women taking the drug at this time should not independently discontinue treatment without consulting a doctor.

If a woman with epilepsy plans to become pregnant or becomes pregnant, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the relationship of benefit and risk. If, after a reassessment of the relationship of benefit and risk, treatment with valproic acid should still be continued during pregnancy, it is recommended that it be applied in a minimally effective daily dose divided into several doses. It should be noted that during pregnancy, the use of long-acting drug dosage forms is preferable. When bipolar disorder is indicated, consideration should be given to stopping treatment with valproic acid.

One month before conception and within 2 months after it, folic acid (at a dose of 5 mg / day) should be added to antiepileptic treatment, since this can minimize the risk of neural tube malformations.

A permanent special prenatal control should be performed to identify possible malformations of the neural tube or other fetal malformations, including ultrasound.

Risk for newborns

There have been reports of the development of single cases of hemorrhagic syndrome in newborns whose mothers were taking valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia and, possibly, due to a decrease in the activity of coagulation factors. It was also reported on the development of fetal anaphyrnogenemia. This hemorrhagic syndrome should be distinguished from a decrease in the concentration of vitamin K-dependent factors caused by phenobarbital and other inducers of microsomal liver enzymes. Therefore, in newborns born to mothers who received valproic acid, it is necessary to determine the number of platelets in the blood, the plasma concentration of fibrinogen, clotting factors and coagulogram. Reported cases of hypoglycemia in newborns, whose mothers during the third trimester of pregnancy were valproic acid.

Hypothyroidism was reported in newborns whose mothers received valproic acid during pregnancy.

In newborns, whose mothers were taking valproic acid in the last trimester of pregnancy,can lead to withdrawal syndrome (in particular, the appearance of agitation, irritability, hyperreflexia, tremor, hyperkinesia, muscle tone disorders, tremors, seizures and difficulty in feeding).

Breastfeeding period

Isolation of valproic acid in breast milk is low, its concentration in milk is 1-10% of its serum concentration.

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

Based on literature data and a small clinical experience, mothers may plan breastfeeding with valproic acid monotherapy, but one should keep in mind the possibility of developing unwanted adverse reactions, especially hematologic disorders.

Dosing and Administration:

The drug Convulsofin retard is intended only for adults and children over 6 years old with a body weight of more than 17 kg.

Tablets of prolonged action are a form of delayed release of valproic acid, which avoids abrupt increases in the concentration of valproic acid in blood plasmaafter taking the drug Convulsofin-retard and for a longer time maintain a constant concentration of valproic acid in the blood plasma during the day.

To facilitate the reception of an individually selected dose of the drug Convulsofin-retard tablets may be divided in half. Tablets are taken without crushing or chewing them.

Dosing regimen with epilepsy

The daily dose is selected individually by the attending physician.

It is necessary to select a minimally effective dose to prevent the development of epileptic seizures (especially in pregnancy). The daily dose should be adjusted according to age and body weight. A stepwise (gradual) increase in the dose is recommended until the minimum effective dose is reached. He a clear connection was established between the daily dose, the concentration in the blood plasma, and the therapeutic effect. Therefore, the optimal dose should be determined mainly by the clinical response. Determination of the concentration of valproic acid in blood plasma can serve as a supplement to clinical observation if epilepsy is not controlled or there is a suspicion of developing unwanted reactions.The range of therapeutic concentration in blood plasma is usually 40-100 mg / l (300-700 μmol / l).

With monotherapy, the initial dose is usually 5-10 mg / kg. The dose is then gradually increased every 4-7 days at a dose of 5 mg / kg to the dose necessary to achieve control of epileptic seizures.

Medium daily doses (with prolonged use):

- for children 6-14 years (body weight 20-30 kg) - 30 mg / kg / day (600-900 mg / day);

- for children 14-18 years (body weight 40-60 kg) - 25 mg / kg / day (1000-1500 mg / day);

- for adults, including elderly patients (body weight not less than 60 kg) - at an average of 20 mg / kg / day (1200-2100 mg / day).

Despite the fact that the daily dose is determined depending on the age and body weight of the patient, a wide range of individual sensitivity to the Convulsofin retard preparation should be taken into account.

If epilepsy is not amenable to control at such doses, they can be increased by monitoring the patient's condition and the concentration of valproic acid in the blood plasma. In some cases, the full therapeutic effect of the drug Convulsofin retard appears not immediately, but develops within 4-6 weeks. Therefore, do not increase the daily dose above the recommended average daily dose before this time.The daily dose can be divided into 1-2 administrations, preferably during meals. Use in one dose is possible with well-controlled epilepsy. Most patients who are already taking immediate-release valproic acid can be transferred to a sustained-release dosage form immediately or for several days, and patients should continue to take the previously selected daily dose.

For patients who have previously taken antiepileptic drugs, a transfer to the use of the drug Convulsofin-retard in the dosage form of a sustained-release tablet should be carried out gradually, reaching the optimal dose for about 2 weeks. At the same time, the dose of an antiepileptic drug taken earlier, in par- ticular, phenobarbital, should be reduced. If previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, it should be within 4-6 weeks after taking the last dose of these antiepileptic drugsmonitor the concentration of valproic acid in the blood plasma and, if necessary (as the effect of inducing the metabolism of microsomal liver enzymes decreases), reduce the daily dose of valproic acid.

If necessary, the combination of the drug Convulsofin-retard with other antiepileptic drugs should be administered gradually (see "interaction with other drugs").

Dosing regimen for manic episodes of bipolar disorder

Adults

The daily dose of Convulsofin-retard is selected individually by the attending physician.

The recommended initial daily dose is 750 mg / day or 20 mg / kg / day.

Medicinal forms with prolonged release can be taken once or twice a day. The dose should be increased as soon as possible to achieve the minimum therapeutic dose, which causes the desired clinical effect. The average daily dose is 1000-2000 mg / day. Patients receiving a daily dose of more than 45 mg / kg / day should be under close medical supervision.

When treating manic episodes with bipolar disorders, it is necessary to apply an individually selected minimum effective dose.

Children and teens

The efficacy and safety of using Convulsofin-retard in the treatment of manic episodes in bipolar disorders in patients younger than 18 years of age have not been evaluated.

Application preparation the patients of special groups

In patients with renal insufficiency and / or hypoproteinemia should take into account the possibility of increasing the concentration of the free fraction (therapeutically active) valproic acid in the blood serum and, if necessary, reduce the dose of the drug Convulsofin retard, focusing on the selection of the dose mainly on the clinical picture, rather than the total concentration of valproic acid in the blood plasma (free fraction fraction) to avoid possible errors in the selection of a dose.

Side effects:

Side effects are classified according to the following frequency: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - less than 0.01%, including single messages; unknown frequency (there is no possibility to estimate the frequency of development).

Congenital, hereditary and genetic disorders: teratogenic risk (see section "Application during pregnancy and during breastfeeding").

Co side of the blood and lymphatic system: often - anemia, thrombocytopenia; infrequently - pancytopenia, leukopenia, neutropenia.

Leukopenia and pancytopenia can be with or without bone marrow depression. After the drug is stopped, the blood picture returns to normal. Rarely - a violation of bone marrow hematopoiesis, including isolated aplasia / hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis; reduction in the content of clotting factors (at least one), deviation from the norm of blood clotting parameters (such as an increase in prothrombin time, an increase in activated partial thromboplastin time, an increase in thrombin time, an increase in INR [international normalized ratio]). (See the sections on "Use during pregnancy and during breastfeeding" and "Special instructions").

The emergence of spontaneous ecchymosis and bleeding indicates the need to discontinue the drug and conduct a survey.

Laboratory and instrumental data: often - an increase in body weight (weight gain should be carefully monitored, since weight gain is a factor contributing to the development of the polycystic ovary syndrome); rarely - biotin deficiency / biotinidase deficiency.

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

* Stupor and lethargy sometimes lead to transient coma / encephalopathy and were either isolated, or combined with increased frequency of convulsive attacks against the background of treatment, and also decreased with withdrawal of the drug or with a decrease in its dose. These cases were mainly observed during combined therapy (in particular with phenobarbital or topiramate) or after a sharp increase in the dose of valproic acid.

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

From the side of the organ of vision: the unknown frequency is diplopia.

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

Co side of the gastrointestinal tract: very often - nausea; often vomiting, gum changes (mainly gum hyperplasia), stomatitis, epigastric pain, diarrhea, which often occur in patients at the beginning of treatment, but with continued use of the drug usually disappear after a few days and do not require discontinuation of therapy; infrequently - pancreatitis, sometimes with a fatal outcome (development of pancreatitis is possible during the first 6 months of treatment); in the case of acute pain in the abdomen, it is necessary to control the activity of serum amylase; unknown frequency - abdominal cramps, anorexia, increased appetite.

Frequent reactions from the digestive system can be reduced by taking the drug during or after a meal.

Co side of the kidneys and urinary tract: infrequent - renal insufficiency; rarely - enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (complex of biochemical and clinical manifestations of affection of proximal renal tubules with violation of tubular reabsorption of phosphate, glucose,amino acids and bicarbonate), the development mechanism of which is still unclear.

From the skin and subcutaneous tissues: often - hypersensitivity reactions, such as urticaria, pruritus; transient (reversible) or dose-dependent alopecia (hair loss), including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary, and also alopecia against the background of developed hypothyroidism; infrequent - angioedema, rash, hair disorders (such as abnormal hair structure, hair color changes, abnormal hair growth, disappearance of waviness and curly hair, or vice versa, appearance of curly hair in persons with initially straight hair), hirsutism, acne ; rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

FROMabout the side of the musculoskeletal system and connective tissue: infrequently - decrease bone mineral density, osteopenia, osteoporosis and fractures in patients taking valproic acid for a long time, the mechanism of influence on the metabolism of bone tissue is not established; rarely - systemic lupus erythematosus, rhabdomyolysis.

Disorders from the endocrine system: syndrome of inadequate secretion of antidiuretic hormone (SNSADG), hyperandrogenism (hirsutism, virilization, acne, alopecia in masculine type and / or increase in androgen concentrations in the blood); rarely - hypothyroidism.

From the side of metabolism and nutrition: often - hyponatremia; rarely - hyperammonemia *.

* There may be cases of isolated and moderate hyperammonemia without changing liver function indicators that do not require discontinuation of treatment. There was also reported the occurrence of hyperammonemia, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and other neurologic symptoms), which required the cessation of valproic acid intake and additional examination.

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

Co the sides of the vessels: often bleeding and hemorrhage; infrequently - vasculitis.

General disorders: infrequently - hypothermia, moderate peripheral edema.

From the liver and bile ducts: often - liver damage: deviation from the norm of indicators of the functional state of the liver, such as a decrease in the prothrombin index,especially in combination with a significant reduction in fibrinogen and clotting factors, an increase in the concentration of bilirubin and an increase in the activity of "hepatic" transaminases in the blood; hepatic insufficiency, in exceptional cases - with a fatal outcome. It is necessary to monitor patients for possible violations of liver function.

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

OnDisintegration of the psyche: often - a state of confusion, hallucinations, aggressiveness *, agitation *, attention violation *; depression (when combining valproic acid with other anticonvulsants); rarely - behavioral disorders *, psychomotor hyperactivity *, impaired ability to learn *; depression (with monotherapy with valproic acid).

* Undesirable reactions, mainly observed in patients of childhood.

Overdose:

Clinical manifestations of acute massive overdose usually occur in the form of coma with hypotonia of the muscles, hyporeflexia, miosis, respiratory depression, metabolic acidosis,excessive decrease in arterial pressure and vascular collapse / shock. Cases of intracranial hypertension due to edema of the brain are described.

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

With a massive overdose, a lethal outcome is possible, but usually the prognosis is favorable when overdosed.

Symptoms of overdose may vary. The development of convulsive seizures with very high plasma concentrations of valproic acid has been reported.

Treatment: gastric lavage, which is effective for 10-12 hours after taking the drug. To reduce the absorption of valproic acid, it may be effective to receive activated charcoal, including its administration through a nasogastric tube. It is necessary to monitor the state of the cardiovascular and respiratory systems and maintain an effective diuresis. It is necessary to monitor the liver and pancreas. If breathing is depressed, artificial ventilation may be necessary. In some cases, naloxone. In very severe cases of massive overdose, hemodialysis and hemoperfusion were effective.

Interaction:

Effect of valproic acid or other drugs

Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines

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

Lithium preparations

Valproic acid does not affect serum lithium concentrations.

Phenobarbital

Valproic acid increases the plasma concentration of phenobarbital (due to a decrease in its hepatic metabolism), in connection with which the development of sedative action of the latter, especially in children, is possible. Therefore, careful medical observation of the patient during the first 15 days of combination therapy with immediate reduction of the dose of phenobarbital in case of development of sedative action and, if necessary, determination of plasma concentrations of phenobarbital is recommended.

Primidone

Valproic acid increases plasma concentrations of primidone with an increase in its undesirable reactions (such as sedation); with long-term treatment, these symptoms disappear. A thorough clinical observation of the patient is recommended, especially at the onset of a combination therapy with a primidone dose adjustment if necessary.

Phenytoin

Valproic acid reduces the total plasma concentrations of phenytoin. Besides, valproic acid increases the concentration of the free fraction of phenytoin with the possibility of developing symptoms of an overdose (valproic acid expels phenytoin from the connection with the proteins of the blood plasma and slows down its hepatic metabolism). Therefore, careful clinical observation of the patient and the determination of the concentrations of phenytoin and its free fraction in blood plasma are recommended.

Carbamazepine

With the simultaneous use of valproic acid and carbamazepine, the occurrence of clinical manifestations of the toxicity of carbamazepine has been reported, since valproic acid can potentiate the toxic effects of carbamazepine. It is recommended to closely monitor such patients,especially at the beginning of the combination therapy, with correction, if necessary, a dose of carbamazepine.

Lamotrigine

Valproic acid slows the metabolism of lamotrigine in the liver and increases T_1/2lamotrigine almost 2 times. This interaction can lead to an increase in lamotrigine toxicity, in particular to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical observation and, if necessary, correction (reduction) of the dose of lamotrigine is recommended.

Zidovudine

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

Felbamat

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

Nimodipine (for oral administration and, by extrapolation, solution for parenteral administration)

Strengthening the hypotensive effect of nimodipine due to an increase in its plasma concentration (inhibition of the metabolism of nimodipine by valproic acid).

The effect of other drugs on valproic acid

Antiepileptic drugs that induce microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine)

These drugs reduce the plasma concentrations of valproic acid. In the case of combination therapy, it is necessary to adjust the dose of valproic acid depending on the clinical response and the concentration of valproic acid in the blood plasma.

Felbamat

With the simultaneous use of felbamate and valproic acid, the clearance of valproic acid is reduced by 22-50% and the plasma concentrations of valproic acid are accordingly increased. Plasma concentrations of valproic acid should be monitored.

Meflokhin

With the simultaneous use of mefloquine and valproic acid, it is possible to develop an epileptic fit due to the fact that mefloquine can cause seizures and accelerate the metabolism of valproic acid.

The preparationyou St. John's wort

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

Drugs that have a high and strong bond with blood plasma proteins (acetylsalicylic acid)

In the case of concomitant use of valproic acid and drugs that have a high and strong association with plasma proteins (acetylsalicylic acid), an increase in the concentration of the free fraction of valproic acid is possible.

Indirect anticoagulants

With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of the prothrombin index is required.

Cimetidine, erythromycin

Serum concentrations of valproic acid may increase in the case of simultaneous use of cimetidine or erythromycin (as a result of slowing the hepatic metabolism of valproic acid).

Carbapenems (panipenem, meropenem, imipenem)

Reducing the concentration of valproic acid in blood plasma with its simultaneous use with carbapenems, resulting in a 60-100% reduction in the concentration of valproic acid in blood plasma for two days of simultaneous therapy, which was sometimes combined with the occurrence of seizures.

Carbapenems should not be used concomitantly in patients with a selected dose of valproic acid because of their ability to rapidly and rapidly reduce the concentration of valproic acid in the blood plasma. If carbapenem treatment can not be avoided, careful monitoring of valproic acid concentrations in blood plasma should be carried out.

Rifampicin

Rifampicin can reduce the concentration of valproic acid in the blood plasma and lead to a loss of its therapeutic effect. Therefore, it may be necessary to increase the dose of valproic acid with simultaneous application of rifampicin.

Other interactions

Topiramate

The simultaneous use of valproic acid and topiramate was associated with encephalopathy and / or hyperammonemia. Patients taking these two drugs at the same time should be under close medical supervision for the development of symptoms of hyperammonemic encephalopathy.

Estrogen-progestogen preparations

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

FROM etanol and other potentially hepatotoxic drugsand

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

Clonazepam

The simultaneous use of clonazepam with valproic acid can lead in a few cases tostrengthening the expression of absences status.

Myelotoxic drugs

With simultaneous application with valproic acid, the risk of oppression of bone marrow function increases.

Special instructions:

Severe liver damage

Predisposing factors

Clinical experience shows that patients at high risk for developing severe hepatitis are patients who receive several antiepileptic drugs at the same time, children under the age of three with severe seizures, especially in the presence of brain damage, mental retardation and / or congenital metabolic or degenerative diseases; patients taking salicylates at the same time (since salicylates are metabolized along the same metabolic pathway as valproic acid).

After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the patient's age increases. In most cases, liver damage occurred during the first 6 months of treatment, usually between 2 and 12 weeks of treatment and usually with the use of valproic acid in combination antiepileptic therapy.

Simpvolumes suspicious of liver damage

For early diagnosis of liver damage, clinical monitoring of patients is mandatory. In particular, attention should be paid to the appearance of the following symptoms that may precede the onset of jaundice, especially in patients at risk (see above):

- specific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and bOlive in the abdomen;

- resumption of convulsive seizures in patients with epilepsy.

It is necessary to warn patients or their families (when using the drug in children) that they should immediately report the occurrence of any of these symptoms to the treating doctor. Patients should immediately carry out a clinical examination and a laboratory study of liver function indicators.

Identify

Determination of functional liver samples should be performed before starting treatment and why periodically during the first 6 months of treatment. Among the usual studies, the most informative studies reflect the state of protein-synthetic liver function, especially the prothrombin index.Confirmation of the deviation from the norm of the prothrombin index, especially in combination with deviations from the norm of other laboratory parameters (a significant decrease in the concentration of fibrinogen and clotting factors, an increase in bilirubin concentration and an increase in the activity of transaminases) requires the discontinuation of valproic acid. For the purpose of precaution, if patients receive salicylates concomitantly, their administration should also be discontinued, as they are metabolized along the same metabolic pathway as valproic acid.

Pancreatitis

There are reported cases of severe forms of pancreatitis, including hemorrhagic pancreatitis with a fatal outcome. Young children are at increased risk of developing pancreatitis, with an increase in the child's age, the risk is reduced. Severe convulsions, neurologic disorders, or anticonvulsant therapy may be risk factors for the development of pancreatitis. Hepatic insufficiency, combined with pancreatitis, increases the risk of death.

Immediately follow patients who experience severe abdominal pain, nausea, vomiting, and / or anorexia.In case of confirmation of the diagnosis of pancreatitis, 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

There have been reports of suicidal thoughts and attempts in patients receiving antiepileptic drugs for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a slight increase in the risk of suicidal thoughts and attempts. The mechanism of this effect is unknown.

Therefore, patients receiving valproic acid should be constantly monitored for suicidal thoughts or attempts, and if they occur, appropriate treatment should be provided. Patients and caregivers are advised when suicidal thoughts or attempts are made to seek immediate medical attention.

Karbapenems

Simultaneous use of carbapenems is not recommended (see the section "Interaction with other drugs").

Women of reproductive age

In pregnant women and pregnant women planning the use of valproic acid in the treatment of epilepsy and bipolar disorders is unacceptable, except for patients with intolerance or ineffectiveness of other drugs. If valproic acid is the only drug of choice, then patients should use effective methods of contraception, especially during puberty and during pregnancy planning should be carefully monitored by the attending physician. Women taking the drug at this time should not independently discontinue treatment without consulting a doctor.

When using the drug in women of reproductive age, it is necessary to exclude pregnancy and make sure that the woman uses effective methods of contraception.

Methods for monitoring the safety of valproic acid

Before starting valproic acid and periodically during the first 6 months of treatment, especially in patients at risk of developing liver disease, liver function tests should be performed.As with the majority of antiepileptic drugs, there may be a slight increase in the activity of "hepatic" enzymes (especially at the beginning of treatment), which occurs without clinical manifestations and is transient. These patients need a more detailed study of laboratory indicators, including a prothrombin index, and may require dose adjustment, and, if necessary, repeated clinical and laboratory examination.

Before the start of therapy, or if it is necessary to perform a surgical operation, in case of spontaneous subcutaneous hematoma or bleeding, a hematological blood test is recommended (determine the leukocyte blood count, including platelet count, bleeding time and coagulogram).

Renal insufficiency

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum. If it is not possible to monitor plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Insufficiency of urea enzymes

If suspicion of enzyme deficiency in the urea cycle is advisable, the use of valproic acid is not recommended. Such patients described several cases of hyperammonemia accompanied by a stupor or coma. In these cases, metabolic studies should be performed prior to treatment with valproic acid. In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cytolysis cases), a history of lethargy or coma, a mental retardation or a family history of neonatal or child death, metabolic studies should be performed prior to treatment with valproic acid, ammonia (the presence of ammonia and its compounds in blood plasma) on an empty stomach and after eating.

Patients with systemic lupus erythematosus

Despite the fact that in the process of treatment with valproic acid, immune system abnormalities are extremely rare, before using the drug in patents with systemic lupus erythematosus it is necessary to evaluate the ratio of the expected benefit and the possible risk of its use.

Weight gain

Patients should be warned about the risk of weight gain at the beginning of treatment, and take measures, mainly dietary ones, to minimize this risk.

Ethanol

During treatment with valproic acid, ethanol is not recommended.

Patients with diabetes mellitus

Given the potential for adverse effects of valproic acid on the pancreas, the use of the drug in patients with diabetes should carefully monitor the concentration of glucose in the blood. In the study of urine for the presence of ketone bodies in patients with diabetes mellitus, it is possible to obtain false-positive results, since valproic acid is excreted by the kidneys, partially in the form of ketone bodies.

Patients infected with the human immunodeficiency virus (HIV)

AT in vitro it was found that valproic acid stimulates HIV replication under certain experimental conditions. The clinical significance of this fact, if any, is unknown. In addition, the value of these data obtained in the studies in vitro, for patients receiving maximum suppressive antiretroviral therapy.However, these data should be taken into account when interpreting the results of continuous monitoring of viral load in HIV-infected patients taking valproic acid.

Patients with existing insufficiency carnitine palmitoyltransferase (CBT) type II

Patients with existing type II CPT deficiency should be warned about a higher risk of developing rhabdomyolysis with valproic acid.

Effect on the ability to drive transp. cf. and fur:

Patients should be warned about the risk of drowsiness, especially if combined anticonvulsant therapy is used or when valproic acid is used with benzodiazepines.

During the treatment period, care must be taken to discuss with the attending physician the ability to drive vehicles and engage in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Form release / dosage:Tablets of prolonged action, film-coated, 300 mg and 500 mg.

Packaging:

Dosage of 300 mg: 10 tablets in a blister of aluminum foil, glued together with aluminum foil. By 2, 3, 5, 6, 9, 10, 20 or 50 blisters together with instructions for use in cardboard pack.

Dosage 500 mg: 10 tablets in a blister of aluminum foil, glued together with aluminum foil. By 2, 3, 5, 6, 9, 10, 12, 20 or 50 blisters together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003108

Date of registration:21.07.2015

Date of cancellation:2020-07-21

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

MERCKLE, GmbH Germany

Representation: & nbspTeva Teva Israel

Information update date: & nbsp09.12.2015

Illustrated instructions

Instructions

Convulsofin retard (CONVULSOFIN-RETARD)