Konvulex syrup 50mg / ml, 100ml

• epilepsy of various etiologies (idiopathic, cryptogenic and symptomatic);

• generalized epileptic seizures in children (clonic, tonic, tonic-clonic, atonic, myoclonic, absences);

• West syndrome, Lennox-Gastaut syndrome;

• partial epileptic seizures in children (with or without secondary generalization);

• febrile seizures in children;

• children's teak.

The drug is taken orally, regardless of food intake, with a small amount of liquid.

The dosage regimen is selected individually, taking into account the age and body weight of the patient.

The initial daily dose for children weighing less than 20 kg for all recommended conditions is 10-15 mg / kg / day, with a gradual increase in the dose (by 5-10 mg / kg / week) until the optimal clinical effect is achieved (the disappearance of seizures ). For children weighing more than 20 kg, in all recommended conditions, the initial daily dose is 300 mg, with a gradual increase in the dose (by 5-10 mg / kg / week) until the optimal clinical effect is achieved.

The average daily dose of 30 mg / kg can be increased under the control of the concentration of the drug in the blood plasma up to 40-60 mg / kg.

The average daily dose for children with monotherapy is 30 mg / kg, for adolescents - 20-30 mg / kg. It is recommended to divide the daily dose into 2 doses for patients under the age of 1 year, into 3 doses for patients over the age of 1 year.

Patients with renal insufficiency may need to reduce the dose of the drug. The dose is set by monitoring the patient's clinical condition. the values ??of the concentration of valproic acid in blood plasma may be insufficiently informative.

Syrup for children is colorless or slightly yellowish, with a fruity odor.

1 ml

sodium valproate 50 mg

Excipients: liquid maltitol (lycasin 80/55) - 0.8 mg, methyl parahydroxybenzoate - 1 mg, propyl parahydroxybenzoate - 0.4 mg, sodium saccharinate - 1 mg, sodium cyclamate - 3 mg, sodium chloride - 0.4 mg, raspberry flavor 9/372710 - 0.4 mg, peach flavor 9/030307 - 1.25 mg, purified water - up to 1 ml.

• liver failure;

• acute and chronic hepatitis;

• dysfunction of the pancreas;

• porphyria;

• hemorrhagic diathesis;

• severe thrombocytopenia (below 75 109 / l);

• disorders of urea metabolism (including family history);

• combination with mefloquine, St. John's wort, lamotrigine;

• lactation period;

• hypersensitivity to valproic acid and its salts or drug components.

Care should be taken to prescribe the drug to the following categories of patients:

• with anamnestic data about diseases of the liver and pancreas (including family history);

• with inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);

• with renal failure;

• with congenital fermentopathies;

• with organic diseases of the brain;

• with hypoproteinemia;

• children with mental retardation;

• during pregnancy (especially in the first trimester).

pharmachologic effect

Antiepileptic drug. It has a central muscle relaxant and sedative effect.

The mechanism of action is mainly due to an increase in the content of gamma-aminobutyric acid (GABA) in the central nervous system due to inhibition of the enzyme GABA-transferase.

GABA reduces the excitability and seizure readiness of the motor areas of the brain. In addition, in the mechanism of action of the drug, a significant role belongs to the effect of vaproic acid on GABAA receptors (activation of GABA-ergic transmission), as well as the effect on voltage-dependent sodium channels. According to another hypothesis, it acts on the sites of postsynaptic receptors, mimicking or enhancing the inhibitory effect of GABA. A possible direct effect on membrane activity is associated with changes in the conductivity of potassium ions.

Improves the mental state and mood of patients, has antiarrhythmic activity.

Pharmacokinetics

Suction

Valproic acid is almost completely absorbed from the gastrointestinal tract, oral bioavailability is about 100%. Food intake does not decrease the rate of absorption. Cmax in plasma is observed after 1-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-100 mg / l.

Distribution

Css is achieved on days 2-4 of treatment, depending on the intervals between doses.

At a plasma concentration of up to 50 mg / l, the binding of valproic acid to plasma proteins is 90-95%, at a concentration of 50-100 mg / l - 80-85%.

Valproic acid penetrates the BBB. The values ??of the concentration in the cerebrospinal fluid correlate with the value of the non-protein-bound fraction of the active substance. Valproic acid crosses the placental barrier and is excreted in breast milk. The concentration in breast milk is 1-10% of the concentration in the mother's blood plasma.

Metabolism

Valproic acid undergoes glucuronidation and oxidation in the liver.

Withdrawal

Valproic acid (1-3% of the dose) and its metabolites are excreted by the kidneys, in small quantities - with feces and exhaled air. T1 / 2 with monotherapy and in healthy volunteers is 10-15 hours, in children - 6-10 hours.

Pharmacokinetics in special clinical situations

With uremia, hypoproteinemia and cirrhosis, the binding of valproic acid to plasma proteins decreases.

When combined with inducers of liver microsomal enzymes involved in the metabolism of vaproic acid, T1 / 2 can be 6-8 hours.

In patients with impaired liver function and children under 18 months, T1 / 2 can be significantly longer.

Side effect

In general, the drug is well tolerated by patients. Side effects are possible mainly with a plasma concentration of vaproic acid above 100 mg / l or with combination therapy.

From the nervous system: ataxia, cases of cognitive impairment with progression up to the development of a complete picture of dementia syndrome (reversible within a few weeks or months after discontinuation of the drug), states of confusion or convulsions, stupor and lethargy, sometimes leading to transient coma (encephalopathy) , reversible parkinsonism, headache, dizziness, mild postural tremors and drowsiness, changes in behavior, mood, or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactivity, psychosis, unusual agitation, restlessness or irritability), dysarthria.

From the side of the organ of vision: diplopia, nystagmus, flashing 'flies' before the eyes.

From the organ of hearing: reversible or irreversible hearing loss.

From the digestive system: nausea, vomiting, gastralgia, decreased or increased appetite, constipation, diarrhea (which usually disappear within a few days without discontinuing the drug), impaired liver function, hepatitis, pancreatitis up to severe fatal lesions (in the first 6 months of treatment, more often at 2-12 weeks).

On the part of the hematopoietic system: inhibition of bone marrow hematopoiesis (anemia, leukopenia or pancytopinia), thrombocytopenia, decreased fibrinogen content and platelet aggregation, leading to the development of hypocoagulation (accompanied by prolonged bleeding time, petechial hemorrhages, bruising), hemorrhages, hemorrhages.

From the urinary system: enuresis, cases of reversible Fanconi syndrome (of unknown origin).

From the genitals and mammary gland: menstrual irregularities, secondary amenorrhea, breast enlargement, galactorrhea.

Allergic reactions: skin rash, urticaria, vasculitis, angioedema, photosensitivity, cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

On the part of laboratory parameters: isolated and moderate hyperammonemia without changes in liver function tests, especially with polytherapy (drug withdrawal is not required), hyperammonemia associated with neurological symptoms is possible (further examination is required), an increase in the activity of hepatic transaminases, a decrease in fibrinogen content or an increase bleeding time, usually without clinical manifestations and especially at high doses (valproic acid has an inhibitory effect on the second stage of platelet aggregation), hyponatremia.

Others: teratogenic risk, peripheral edema, weight gain, disorders of the immune system, hair loss (as a rule, it recovers after discontinuation of the drug).

Application during pregnancy and lactation

During baking, you should prevent pregnancy. In experiments on animals, the teratogenic effect of vaproic acid was revealed. According to available data, in humans, valproic acid mainly causes a violation of the development of the neural tube: myelomeningocele, spina bifida (1-2%). Cases of facial dysmorphia and malformations of the limbs (especially their shortening), as well as malformations of the cardiovascular system, are described. The risk of malformations is higher with combination therapy than with monotherapy with sodium valproate. Considering the above, the use of the drug during pregnancy is possible only when the intended benefit to the mother outweighs the potential risk to the fetus. In the first trimester of pregnancy, you should not start treatment with KonvulexЃ. If the already ongoing treatment with vaproic acid in a pregnant woman is effective,treatment should not be interrupted. In such cases, monotherapy is recommended, and the minimum effective daily dose should be divided into two doses. In addition to antiepileptic therapy, folic acid supplements (5 mg / day) may be added to minimize the risk of neural tube defects.

Valproic acid can cause hemorrhagic syndrome in newborns, which appears to be associated with hypofibrinogenemia. There have been cases of fatal afibrinogenemia. Perhaps this is due to a decrease in a number of blood coagulation factors.

In newborns, it is imperative to determine the number of platelets, the level of fibrinogen in plasma and blood coagulation factors.

Since valproic acid is excreted in breast milk in concentrations from 1% to 10%, it is recommended to stop breastfeeding while taking the drug.

Application for violations of liver function

Contraindicated in liver failure, acute and chronic hepatitis.

Application for impaired renal function

The drug should be prescribed with caution in case of renal failure.

Application in children

With care: children with mental retardation.

special instructions

There is evidence of the possible occurrence of suicidal thoughts and behavior in patients receiving antiepileptic drugs. A meta-analysis of clinical trials of antiepileptic drugs found a slightly increased risk of suicidal thoughts and behavior. The mechanism of this phenomenon is not fully understood, the possibility of an increase in the risk of suicidal thoughts and behavior when using valproic acid preparations is not excluded. Patients and their families, as well as healthcare professionals caring for such patients, should be informed about the risks of suicidal thoughts and behavior.

In connection with the existing reports of severe and fatal cases of liver failure and pancreatitis, when using valproic acid preparations, the following should be borne in mind:

• the high-risk group is infants and children under 3 years of age with severe epilepsy, often associated with brain damage and congenital metabolic or degenerative diseases;

• in most cases, liver dysfunction developed in the first 6 months (usually between 2 and 12 weeks) of treatment, more often with combined antiepileptic treatment;

• cases of pancreatitis were observed regardless of the age of the patient and the duration of treatment, although the risk of developing pancreatitis decreased with the age of the patient;

• failure of liver function with pancreatitis increases the risk of death;

• early diagnosis (before the icteric stage) is based mainly on clinical observation - the identification of early symptoms such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by vomiting and abdominal pain; at the same time, there may be a relapse of epileptic seizures against the background of unchanged antiepileptic therapy.

In such cases, you should immediately consult a doctor for a clinical examination and liver function analysis.

During treatment, especially in the first 6 months, it is necessary to periodically check the liver function - the activity of hepatic transaminases, the content of prothrombin, fibrinogen, blood coagulation factors, the concentration of bilirubin, as well as the activity of amylase (every 3 months, especially when combined with other antiepileptic drugs) and a picture of peripheral blood, in particular, blood platelets. The development of severe thrombocytopenia (below 75x109 / L) has been described when treated with high doses of valproic acid (with plasma levels above 110 mg / L in women and 135 mg / L in men). The platelet count returned to normal after discontinuation of treatment; in some patients, it returned to normal without discontinuation of treatment.

When treated with valproic acid, hypothermia can be observed, both in combination with hyperammonemia and without it. Hypothermia can be accompanied by lethargy, confusion, coma, cardiovascular and respiratory disorders.

With the use of valproic acid, even with normal liver function indicators, hyperammonemia may be observed. The level of ammonium in the blood should be determined when patients develop drowsiness, vomiting, changes in mental state, as well as hypothermia. If severe hyperammonemia is detected, treatment with valproic acid should be discontinued. Hyperammonemic encephalopathy (in some cases, fatal) with the use of valproic acid can develop in patients with disorders of urea metabolism, in particular with ornithine transcarbamylase deficiency. Before starting treatment with valproic acid, the state of urea metabolism should be investigated in patients with a history of encephalopathy or coma of unknown origin, with periodic vomiting and lethargy, episodes of irritability, ataxia,a family history of urea metabolism disorders. Patients with hyperammonemic encephalopathy developing during therapy with valproic acid should urgently receive appropriate treatment, including the withdrawal of valproic acid.

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 other antiepileptic drugs can be gradually withdrawn. In patients who have not received treatment with other antiepileptic drugs, a clinically effective dose should be achieved after 1 week.

The risk of developing side effects from the liver is increased with combined anticonvulsant therapy, as well as in children.

Before surgery, a general blood test (including the number of platelets), determination of bleeding time, and coagulogram indicators are required.

If a symptom complex 'acute abdomen' occurs during treatment, it is recommended to determine the activity of amylase in the blood before the start of surgery 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), indicators of thyroid function.

If any acute, serious side effect develops, you should immediately discuss with your doctor whether to continue or discontinue treatment.

When using the drug in patients with renal insufficiency, it is recommended to take into account the increased concentration of the free form of valproic acid in the blood plasma and reduce the dose.

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

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

Patients should be warned of the risk of weight gain at the start of treatment and diet should be advised to minimize such exposure.

To reduce the risk of developing dyspeptic disorders, it is possible to take antispasmodics and enveloping agents.

Abrupt discontinuation of the drug can lead to an increase in epileptic seizures.

Drinks containing ethanol are not allowed during treatment.

Influence on the ability to drive vehicles and use mechanisms

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Overdose

Symptoms: nausea, vomiting, dizziness, diarrhea, respiratory failure, muscle hypotension, hyporeflexia, miosis, coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis; Cases of intracranial hypertension associated with cerebral edema have been described.

Treatment: gastric lavage (no later than 10-12 hours), intake of activated charcoal, hemodialysis, forced diuresis, maintenance of vital functions.

Drug interactions

Contraindicated combinations

ћефлохин: риск эпилептических припадков вследствие усилени¤ метаболизма вапьпроевой кислоты и снижени¤ ее концентрации в плазме и, с другой стороны, вследствие судорожного эффекта мефлохина.

«веробой продыр¤вленный: риск снижени¤ концентрации вапьпроевой кислоты в плазме крови.

Ќерекомендуемые сочетани¤

Ћамотриджин: повышенный риск т¤желых кожных реакций (токсический эпидермальный некролиз). ¬альпроева¤ кислота ингибирует микросомальные ферменты печени, обеспечивающие метаболизм ламотриджина, что замедл¤ет его “1/2 до 70 ч у взрослых и до 45-55 ч у детей и повышает концентрацию в плазме крови. ?сли комбинаци¤ необходима, требуетс¤ тщательный клинический и лабораторный контроль.

—очетани¤, требующие особых предосторожностей

 арбамазепин: вальпроева¤ кислота повышает концентрацию активного метаболита карбамазепина в плазме до признаков передозировки.  роме того, карбамазепин усиливает печеночный метаболизм вальпроевой кислоты и снижает ее концентрацию. Ёти обсто¤тельства требуют внимани¤ врача и определени¤ концентраций препаратов в плазме и возможного пересмотра их доз.

‘енобарбитал, примидон: вальпроева¤ кислота повышает концентрацию фенобарбитала и примидона в плазме до признаков передозировки, чаще у детей. ¬ свою очередь, фенобарбитал и примидон усиливают печеночный метаболизм вальпроевой кислоты и снижают ее концентрацию. –екомендуетс¤ клиническое наблюдение в течение первых 2 недель комбинированного лечени¤ с немедленным уменьшением дозы фенобарбитала и примидона при по¤влении признаков седации, определение концентрации противоэпилептических средств в крови.

‘енитоин: возможны изменени¤ концентрации фенитоина в плазме, фенитоин усиливает печеночный метаболизм вальпроевой кислоты и снижает ее концентрацию. –екомендуетс¤ клиническое наблюдение, определение концентрации противоэпилептических средств в крови, изменение доз при необходимости.

 лоназепам: добавление вальпроевой кислоты к клоназепаму в единичных случа¤х может приводить к усилению выраженности абсансного статуса.

Ётосуксимид: вальпроева¤ кислота может как повышать, так и снижать концентрацию этосуксимида в сыворотке крови вследствие изменени¤ его метаболизма. –екомендуетс¤ клиническое наблюдение, определение концентрации противоэпилептических средств в крови, изменение доз при необходимости.

“опирамат: повышаетс¤ риск развити¤ гипераммониемии или энцефалопатии. –екомендуетс¤ клинический и лабораторный контроль в течение первого мес¤ца лечени¤ и в случае возникновени¤ симптомов гипераммониемии.

‘елбамат: повышение концентрации вальпроевой кислоты в плазме на 35-50%, с опасностью передозировки. –екомендуетс¤ клиническое наблюдение, определение концентрации вальпроевой кислоты в крови, изменение доз вальпроевой кислоты при сочетании с фелбаматом и после его отмены.

Ќейролептики, ингибиторы ћјќ, антидепрессанты, бензодиазепины: нейролептики, трициклические антидепрессанты, ингибиторы ћјќ, снижающие порог судорожной готовности, уменьшают эффективность препарата. ¬ свою очередь, вальпроева¤ кислота потенцирует действие данных психотропных препаратов, а также бензодиазепинов; рекомендуетс¤ клинический мониторинг и, при необходимости, корректировка дозы препарата.

?иметидин, эритромицин подавл¤ют печеночный метаболизм вальпроевой кислоты и повышают ее концентрацию в плазме.

«идовудин: вальпроева¤ кислота увеличивает концентрацию зидовудина в плазме, что ведет к повышению его токсичности.

 арбапенемы, монобактам: меропенем, панипенем, а также азтреонам и имипенем снижают концентрацию вальпроевой кислоты в плазме, что может привести к снижению противосудорожного эффекта. –екомендуетс¤ клиническое наблюдение, определение концентрации препаратов в плазме крови; может потребоватьс¤ коррекци¤ дозы вальпроевой кислоты в ходе лечени¤ антибактериальным средством и после его отмены.

—очетани¤, которые следует принимать во внимание

јцетилсалицилова¤ кислота: усиление эффектов вальпроевой кислоты вследствие вытеснени¤ ее из св¤зи с белками плазмы. ¬альпроева¤ кислота усиливает эффект ацетилсалициловой кислоты.

Ќепр¤мые антикоагул¤нты: вальпроева¤ кислота усиливает эффект непр¤мых антикоагул¤нтов, необходим тщательный контроль протромбинового индекса при совместном назначении с витамин  -зависимыми антикоагул¤нтами.

Nimodipine: an increase in the hypotensive effect of nimodipine due to an increase in its concentration in plasma due to the suppression of its metabolism by valproic acid.

Myelotoxic drugs: increased risk of inhibition of bone marrow hematopoiesis.

Ethanol and hepatotoxic drugs increase the likelihood of developing liver damage.

Other combinations

Oral contraceptives: Valproic acid does not induce microsomal liver enzymes and does not reduce the effectiveness of hormonal oral contraceptives.