Convulsofin retard pills 500mg №50

Active ingredient - Valproic acid
 
Dosage form: film-coated, prolonged action tablets

Composition:

1 pill contains:
active ingredients: sodium valproate 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;
sheath: 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. Oblong biconvex tablets, film-coated white color, with a risk on both sides. Almost odorless.
Pharmacotherapeutic group: antiepileptic drug
Pharmacodynamics:
Antiepileptic drug that has a central muscle relaxant and sedative effect.
It shows antiepileptic activity in various types of epilepsy. The main mechanism of action seems to be related to the effects of valproic acid on the GABAergic system: an increase in the content of gamma-aminobutyric acid (GABA) in the central nervous system and the activation of GABAergic transmission. Absorption.
The bioavailability of sodium valproate and valproic acid when administered orally is close to 100%.
When taking valproic acid, pills of prolonged action, 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 mcg / ml. The time to reach the maximum concentration is 6.58 ± 2.23 hours. Equilibrium concentration is reached 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. If there is a reasonable need to achieve higher concentrations and blood plasma, the ratio of the expected benefit to the possible risk of unwanted adverse reactions, especially dose-dependent ones, should be carefully weighed. For example, at concentrations greater than 100 mg / l, an increase in undesirable side reactions is expected, up to the development of intoxication. With a plasma concentration of more than 150 mg / l, a dose reduction of the drug is required.

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

Communication with plasma proteins (mainly with albumin) is high (90-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, communication with plasma proteins is reduced. In severe renal failure, the concentration of the free fraction (therapeutically active) of valproic acid may increase by 8.5–20%.

In hypoproteinemia, the total concentration of valproic acid (free fraction (unbound to plasma proteins) + bound fraction (bound to plasma proteins)) may not change, but may also decrease due to an increase in metabolism of the free fraction (unbound to plasma proteins) valproic acid acid. Valproic acid penetrates into the cerebrospinal fluid and into the brain. The concentration of valproic acid in the cerebrospinal fluid is 10% of the corresponding concentration in serum.
Valproic acid penetrates into breast milk during lactation. In equilibrium, the concentration of valproic acid in breast milk is from 1 to 10% of its concentration in blood serum.

Metabolism
Metabolized in the liver by glucuronidation, as well as beta, omega-, and omega.₁-oxidation Revealed more than 20 metabolites, metabolites after omega-oxidation have a hepatotoxic effect.
Valproic acid does not induce liver microsomal enzymes: unlike most other antiepileptic drugs, valproic acid does not affect the extent of its own metabolism, or the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Removal
Valproic acid is preferentially 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, 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 increases.
Overdose, an increase in T was observed._1/2up to 30 h. Only the free fraction of valproic acid in the blood plasma (10%) is subjected to hemodialysis.

Features of pharmacokinetics during pregnancy
With an increase in the distribution of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. At the same time, despite taking the drug in a constant dose, a decrease in serum concentrations of valproic acid is possible. During pregnancy, the association of valproic acid with plasma proteins may change, which may lead to an increase in the concentration of the free fraction (therapeutically active) of valproic acid. Compared with the enteric-coated form, the form of prolonged action in equivalent doses is characterized by the following:
- no suction delay after taking;
- prolonged absorption; identical bioavailability;
- less C_max (decrease C_maxabout 25%), but with a more stable plateau phase from 4 to 14 hours after ingestion;
- a more linear correlation between the dose and the concentration of valproic acid in the blood plasma.

Indications and usage

In adults: treatment of generalized epileptic seizures: clinical, topical, tonic-clinical, absences, myoclonic, atopic; Lennox-Gasto syndrome (in monotherapy or in combination with other anti-epileptic 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.
In children: treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gasto syndrome (in monotherapy or in combination with other anti-epileptic drugs).
Treatment of partial epileptic seizures: partial seizures with secondary generalization or without it (in monotherapy or in combination with other anti-epidemic drugs). Hypersensitivity to sodium valproate, valproic acid, seminarium valproate, valpromidum, or to any of the components of the drug; acute hepatitis; chronic hepatitis; heavyliver disease (especially drug-induced hepatitis) in a history of the patient and his close blood relatives; severe lesions of the liver with a fatal outcome when using valproic acid in close relatives of the patient; severe violations of the liver or pancreas; hepatic porphyria; simultaneous use with mefloquine; simultaneous use with the preparations Hypericum perforatum; children's age up to 6 years (the risk of pills in the respiratory tract when swallowing).
Carefully:
History of the liver and pancreas; congenital fermentopathies; inhibition of bone marrow function (leukopenia, thrombocytopenia, anemia); renal failure (dose adjustment is required); hypoproteinemia (see sections "Pharmacokinetics", "Dosage and administration"); in patients receiving multiple anticonvulsants because of the increased risk of liver damage; in patients with existing Carnitine palmitoyltransferase type II deficiency, there is a higher risk of developing rhabdomyolysis when taking valproic acid.

The simultaneous use of drugs that provoke seizures or reduce the threshold of convulsive readiness, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, butyrophenone derivatives, chloroquine, bupropion, tramadol (risk of convulsions).

The simultaneous use of neuroleptics, monoamine oxidase inhibitors (MAO), antidepressants, benzodiazepine (the possibility of potentiation of their effects).
The simultaneous use of phenobarbital, primidone, phenytoin, lamotrigine, zidovudine, felbamate, Acetylsalicylic acid , indirect anticoagulants, cimetidine, Erythromycin , carbapenems, rifampicin, nimodipine (in relation to the level of the subjects at the same level at the level of the level of the level of the level of the level of the level of the level of the subject, and the level of the subject at the level of the subject of the subjects of the subjects who apply to the level of the subject of the subjects of the subject of the same and / or valproic acid, for details, see the section "Interaction with other drugs").
The simultaneous use of Carbamazepine (the risk of potentiation of the toxic effects of carbamazepine and a decrease in plasma concentration of valproic acid).
Simultaneous use of topiramate (risk of encephalopathy). Fertility
In men, valproic acid can reduce sperm motility and cause male infertility. In addition, due to the possibility of the development of undesirable effects on the part of the endocrine system and genital organs in women (such as dysmenorrhea, amenorrhea, polycystic ovaries, hyperandrogeny), fertility may be reduced in women.

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

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 valproic acid teratogenic action. Available clinical data confirm that children born to mothers with epilepsy who received valproic acid have an increased frequency of intrauterine developmental disorders of varying degrees of severity (neural tube defects, craniofacial deformities, developmental disorders of the extremities, cardiovascular system, hypospadias; as well as multiple intrauterine malformations affecting various organ systems) as compared with the frequency when some other antiepileptic drugs are taken by pregnant women 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 monotherapy with valproic acid during pregnancy was 10.73% (95% confidence interval 8.16% - 13.29%). Available data indicate the dose-dependent nature of these undesirable effects.

The risk of congenital malformations in children born to mothers with epilepsy,who received during pregnancy monotherapy with valproic acid monotherapy, was 1.5 times higher than phenytoin monotherapy, about 2.3 times higher than carbamazepine or phenobarbital monotherapy, and about 3.7 times higher than lamotrigine monotherapy.
Available data suggest a relationship between intrauterine exposure to valproic acid and the risk of developmental delay (especially speech development, as well as a decrease in verbal IQ) in children born to mothers with epilepsy who took valproic acid. The developmental delay is often combined with developmental defects and dysmorphism. However, in cases of developmental delay in such children, it is difficult to establish a causal relationship with the use of valproic acid because of the simultaneous effects of other factors, such as low intelligence of the mother or both parents; genetic, social factors, environmental factors; lack of effectiveness of treatment aimed at preventing epileptic seizures in the mother during pregnancy.

It was also reported on the development of various autistic disorders in children exposed to prenatal valproic acid. As monotherapy with valproic acid, and combination therapy with the inclusion of valproic acid. associated with adverse outcomes of pregnancybut according to the available data, combined antiepileptic therapy, including valproic acid, is associated with a higher risk of adverse outcome of pregnancy compared with valproic acid monotherapy.
Risk factors for fetal malformations are: a dose of more than 1000 mg / day (but a lower dose does not exclude this risk) and the combination of valproic acid with other anticonvulsants.
In connection with the above, valproic acid should not be used during pregnancy and in women of reproductive age without extreme necessity.
Women of reproductive age or those planning pregnancy should be informed about the need not to use valproic acid in the treatment of epilepsy and bipolar disorders in pregnant women and women planning pregnancy, with the exception of patients with intolerance or ineffectiveness of other drugs. In the event that valproic acid drugs are the only drugs of choice, patients should use effective methods of contraception, especially during puberty and during pregnancy planning, should be under the careful supervision of the attending physician. Women who are currently taking the drug should not stop the treatment themselves without consulting a doctor.
If a woman with epilepsy plans to become pregnant or has become pregnant, the question of continuing treatment with valproic acid or its cancellation is decided after a reassessment of the relationship between benefits and risks.If, after reassessing the relationship of benefits and risks, treatment with valproic acid should still be continued during pregnancy, then it is recommended to use it in the minimum effective daily dose divided into several doses. It should be noted that during pregnancy it is preferable to use dosage forms of the drug with prolonged action. When showing bipolar disorders, discontinuation of treatment with valproic acid should be considered.
A month before conception and for 2 months after it, folic acid should be added to antiepileptic treatment (at a dose of 5 mg / day), as this can minimize the risk of neural tube developmental defects.
Constant special prenatal monitoring should be carried out to identify possible malformations of the neural tube or other fetal malformations, including ultrasound.

Risk for newborns
It was reported on the development of isolated cases of hemorrhagic syndrome in newborns whose mothers took valproic acid during pregnancy. This hemorrhagic syndrome is associated with thrombocytopenia, hypofibrinogenemia, and may be due to a decrease in the activity of coagulation factors. The development of afibrinogenemia with a fatal outcome has also been reported. This hemorrhagic syndrome should be distinguished from a decrease in the concentration of vitamin K-dependent factors caused by phenobarbital and other inducers of liver microsomal enzymes.Therefore, in newborns born to mothers who received valproic acid, it is necessary to determine the number of platelets in the blood, plasma fibrinogen concentration, blood coagulation factors and coagulogram. Cases of hypoglycemia have been reported in newborns whose mothers took valproic acid during the third trimester of pregnancy.
It was reported about the development of hypothyroidism in newborns whose mothers took valproic acid during pregnancy.
Newborns whose mothers took valproic acid in the last trimester of pregnancy may experience withdrawal syndrome (in particular, agitation, irritability, hyperreflexia, trembling, hyperkinesia, muscle tone disorders, tremor, convulsions, and feeding difficulties).

Breastfeeding period
The release of valproic acid into breast milk is low, its concentration in milk is 1-10% of its concentration in blood serum.
There are limited clinical data on the use of valproic acid during breastfeeding, and therefore the use of the drug during this period is not recommended.
Based on literature data and little clinical experience, mothers can plan breastfeeding with monotherapy with valproic acid, but it should be remembered that the development of unwanted adverse reactions, especially hematological disorders, is possible. The drug Konvulsofin-retard is intended only for adults and children over 6 years old with a body weight of more than 17 kg.
Long-acting pills are a form of delayed release of valproic acid, which allows you to avoid sudden increases in the concentration of valproic acid in the blood plasma after taking the drug Konulsofin-retard and longer maintain a constant concentration of valproic acid in the blood plasma during the day.
To facilitate the administration of an individually selected dose of the drug Convulsofine retard, pills can be divided in half. pills are taken without crushing or chewing them.

Dosing regimen for epilepsy
The daily dose is selected by the attending physician individually.
A minimum effective dose should be selected to prevent the development of epilepsy attacks (especially during pregnancy). The daily dose should be set in accordance with age and body weight. Recommended stepwise (gradual) increase in dose to achieve the minimum effective dose. It was not established a clear relationship between the daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined mainly by clinical response. Determining the concentration of valproic acid in the blood plasma can serve as an adjunct to clinical observation if epilepsy is uncontrollable or if undesirable reactions are suspected.The therapeutic plasma concentration range is usually 40–100 mg / l (300–700 µmol / l).

With monotherapy, the initial dose is usually 5-10 mg / kg. Then the dose is gradually increased every 4-7 days at the rate of 5 mg / kg to the dose necessary to achieve control over the attacks of epilepsy.

Average daily doses (with long-term use):
- for children 6-14 years old (body weight 20-30 kg) - 30 mg / kg / day (600-900 mg / day);
- for children of 14-18 years old (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) - 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 drug Konulsofin-retard should be taken into account.
If epilepsy is not controlled 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 does not appear immediately, but develops within 4-6 weeks. Therefore, one should not increase the daily dose above the recommended average daily dose earlier than this period. The daily dose can be divided into 1-2 doses, preferably with meals. Use at one time is possible with well controlled epilepsy. Most patients who are already taking immediate release valproic acid can be transferred to a long-acting dosage form immediately or within a few days, while patients should continue to take the previously selected daily dose.
For patients who have previously taken antiepileptic drugs, the transfer to the use of the drug Konulsofin-retard in the dosage form of a pill of prolonged action should be carried out gradually, reaching the optimal dose in about 2 weeks. At the same time, the dose of a previously taken antiepileptic drug, especially phenobarbital, should be reduced. If a previously taken antiepileptic drug is canceled, it should be discontinued gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, it should be 4-6 weeks after taking the last dose of these antiepileptic drugs to control plasma plasma valproic acid and, if necessary (as the effect of metabolizing microsomal liver enzymes decreases), reduce the daily dose valproic acid.
If necessary, the combination of the drug Konvulsofin-retard with other antiepileptic drugs should be administered gradually (see "interaction with other drugs").

Dosing regimen for manic episodes in bipolar disorders
Adults
The daily dose of the drug Konvulsofin-retard is selected by the attending physician individually.
The recommended initial daily dose is 750 mg / day or 20 mg / kg / day.
Sustained release dosage forms can be taken once or twice a day.The dose should be increased as quickly as possible until the minimum therapeutic dose is reached, which causes the desired clinical effect. The average daily dose of 1000-2000 mg / day. Patients receiving a daily dose above 45 mg / kg / day should be under close medical supervision.
When treating manic episodes in bipolar disorders, an individually selected minimum effective dose should be used.

Kids and teens
The efficacy and safety of the use of the drug Konvulsofin-retard in the treatment of manic episodes in bipolar disorders in patients younger than 18 years of age have not been evaluated.

Use of the drug in patients of special groups
In patients with renal insufficiency and / or hypoproteinemia, one should consider the possibility of increasing the concentration of the free fraction (therapeutically active) valproic acid in the serum and, if necessary, reduce the dose of the drug Konulsofin-retard, focusing on the selection of the dose mainly on the clinical picture, and not on total plasma valproic acid concentration (free fraction bound fraction) to avoid possible errors in dose selection. Side effects are classified according to the following frequency: very often - at least 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 way to estimate the frequency of development).
Congenital, hereditary and genetic disorders: teratogenic risk (seesection "Use during pregnancy and during breastfeeding").
From the side of blood and lymphatic system: often - anemia, thrombocytopenia; infrequently - pancytopenia, leukopenia, neutropenia.
Leukopenia and pancytopenia can be with or without bone marrow depression. After discontinuation of the drug, the blood picture returns to normal. Rarely - a violation of bone marrow hematopoiesis, including isolated aplasia / hypoplasia of erythrocytes, agranulocytosis, macrocytic anemia, macrocytosis; a decrease in coagulation factors (at least one), a deviation from the norm in blood clotting indicators (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 sections “Use during pregnancy and during breastfeeding” and “Special Instructions”).

The appearance of spontaneous ecchymosis and bleeding indicates the need to cancel the drug and the survey.

Laboratory and instrumental data: often - an increase in body weight (weight gain should be carefully monitored, since an increase in body weight is a factor contributing to the development of polycystic ovary syndrome); rarely, biotin deficiency / biotinidase deficiency.
From the nervous system: very often - tremor; often extrapyramidal disorders, stupor *, drowsiness, convulsions *,memory impairment, headache, nystagmus, dizziness, which may occur several 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 atrophy of the brain, cognitive impairment; unknown frequency - sedation.
* Stupor and lethargy sometimes led to transient coma / encephalopathy and were either isolated or combined with an increase in convulsive seizures during treatment, and also decreased when the drug was withdrawn or the dose was reduced. These cases were mainly observed during combination therapy (in particular with phenobarbital or topiramate) or after a sharp increase in valproic acid dose.
On the part of the organ of hearing and labyrinth disorders: often - reversible and irreversible deafness.
On the part of the organ of vision: unknown frequency - diplopia.
On the part of the respiratory system, organs of the chest and mediastinum: infrequently - pleural effusion.
On the part of the gastrointestinal tract: very often - nausea; often - vomiting, gum changes (mainly gingival 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 cessation of therapy; infrequently - pancreatitis,sometimes fatal (the development of pancreatitis is possible during the first 6 months of treatment); in case of acute abdominal pain, it is necessary to 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.
On the part of the kidneys and urinary tract: infrequently - renal failure; rarely, enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a complex of biochemical and clinical manifestations of the proximal renal tubules with impaired tubular reabsorption of phosphate, glucose, amino acids and bicarbonate), the mechanism of development of which is still unclear.
On the part of the skin and subcutaneous tissues: often - hypersensitivity reactions, such as urticaria, itching; transient (reversible) or dose-dependent alopecia (hair loss), including androgenic alopecia on the background of developed hyperandrogenism, polycystic ovary, as well as alopecia on the background of developed hypothyroidism; infrequently - angioedema, rash, irregularities in the hair (such as disruption of normal hair structure, change in hair color, abnormal hair growth, disappearance of waviness and curly hair, or, conversely, hair curliness in people with initially straight hair), hirsutism, acne; rarely, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, drug rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).
On the part of the musculoskeletal system and connective tissue: infrequently - a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients who take valproic acid for a long time, the mechanism of influence on bone metabolism has not been established; rarely, systemic lupus erythematosus, rhabdomyolysis.
Endocrine disruption: inadequate antidiuretic hormone secretion syndrome (SSSADG), hyperandrogenism (hirsutism, virilization, acne, male type alopecia and / or increased concentrations of androgens in the blood); rarely - hypothyroidism.
Metabolism and nutrition: often - hyponatremia; rarely, hyperammonemia *.
* There may be cases of isolated and moderate hyperammonemia without changes in liver function indices that do not require cessation of treatment. It was also reported about the occurrence of hyperammonemia, accompanied by the appearance of neurological symptoms (for example, the development of encephalopathy, vomiting, ataxia and other neurological symptoms), which required the discontinuation of valproic acid and additional examination.

Benign, malignant and unspecified tumors (including cysts and polyps): rarely - myelodysplastic syndrome.
From the side of the vessels: often - bleeding and hemorrhage; infrequently - vasculitis.
General p