Convullex, 50 mg/ml syrup 100 ml

Antioepileptic drug.

It also has sedative and central myorelaxant effects.

The mechanism of action is mainly due to an increase of GABA in the CNS due to inhibition of the enzyme GABA-transferase. GABA decreases excitability and seizure readiness of motor areas of the brain. In addition, the effects of valproic acid on GABA_A receptors (activation of GABA-ergic transmission) and the effect on potential-dependent sodium channels play a major role in the mechanism of action of the drug.

According to other speculations, it acts on areas of postsynaptic receptors, mimicking or enhancing the inhibitory effect of GABA. Possible direct effects on membrane activity are related to changes in conductance for potassium ions. Improves the mental state and mood of patients, has antiarrhythmic activity.

Pharmacokinetics

Absorption

Valproic acid is almost completely absorbed from the gastrointestinal tract, bioavailability when ingested is 100%. Food intake does not reduce the absorption rate. C_max in plasma is noted after 2-3 hours. The therapeutic plasma concentration of valproic acid is 50-150 mg/l.

Distribution

C_ss is reached on days 2-4 of treatment, depending on the intervals between doses.

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

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 penetrates the placental barrier and is excreted with breast milk. The concentration in breast milk is 1-10% of the concentration in maternal plasma.

Metabolism

Valproic acid undergoes glucuronidation and oxidation in the liver.

Valproic acid (1-3% of dose) and its metabolites are excreted by the kidneys, small amounts in the feces and exhaled air. T_1/2 in monotherapy and in healthy volunteers is 8-20 h.

Pharmacokinetics in special clinical cases

In uremia, hypoproteinemia and cirrhosis, the binding of valproic acid to plasma proteins is decreased.

When combined with other drugs, T_1/2 may be 6-8 h due to induction of metabolic enzymes.

In patients with impaired liver function, elderly patients and children under 18 months of age a significant increase in T_1/2 is possible.

Indications

epilepsy of various etiologies (idiopathic, cryptogenic and symptomatic);
generalized epileptic seizures in adults and children (clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic);
partial epileptic seizures in adults and children (with or without secondary generalization);
specific syndromes (West, Lennox-Gastaut);
behavioral disorders caused by epilepsy;
febrile convulsions in children, childhood tics;
treatment and prevention of bipolar affective disorders.

Pharmacological effect

Antiepileptic drug.

It also has a sedative and central muscle relaxant effect.

The mechanism of action is mainly due to an increase in GABA content in the central nervous system due to inhibition of the GABA transferase enzyme. GABA reduces the excitability and convulsive readiness of the motor areas of the brain. In addition, the effect of valproic acid on GABAA receptors (activation of GABA-ergic transmission) and the effect on voltage-dependent sodium channels plays an important role in the mechanism of action of the drug.

According to other assumptions, it acts on sites of postsynaptic receptors, simulating or enhancing the inhibitory effect of GABA. A possible direct effect on membrane activity is associated with changes in conductivity for 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, bioavailability when taken orally is 100%. Eating does not reduce the rate of absorption. Cmax in plasma is observed after 2-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-150 mg/l.

Distribution

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

At a concentration in blood plasma 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%.

Concentration values ​​in the cerebrospinal fluid correlate with the value of the non-protein-bound fraction of the active substance. Valproic acid penetrates the placental barrier and is excreted in breast milk. The concentration in breast milk is 1-10% of the concentration in maternal plasma.

Metabolism

Valproic acid undergoes glucuronidation and oxidation in the liver.

Removal

Valproic acid (1-3% of the dose) and its metabolites are excreted by the kidneys, small amounts – with feces and exhaled air. T1/2 with monotherapy and in healthy volunteers is 8-20 hours.

Pharmacokinetics in special clinical situations

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

When combined with other drugs, T1/2 can be 6-8 hours due to the induction of metabolic enzymes.

In patients with impaired liver function, elderly patients and children under 18 months of age, a significant increase in T1/2 is possible.

Special instructions

Due to reports of severe and fatal cases of liver failure and pancreatitis when using valproic acid preparations, the following should be kept in mind:

at increased risk are 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 patient’s age and duration of treatment, although the risk of developing pancreatitis decreased with the patient’s age;
insufficiency of liver function with pancreatitis increases the risk of death;
early diagnosis (before the icteric stage) is based mainly on clinical observation – identification of early symptoms such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by vomiting and abdominal pain; in this case, a relapse of epileptic seizures may occur against the background of unchanged antiepileptic therapy.

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

During treatment, especially in the first 6 months, it is necessary to periodically check liver function – the activity of liver transaminases, the level of prothrombin, fibrinogen, coagulation factors, bilirubin concentration, as well as amylase activity (every 3 months, especially when combined with other antiepileptic drugs) and the picture of peripheral blood, in particular, blood platelets.

In patients receiving other antiepileptic drugs, transfer to valproic acid should be carried out gradually, reaching a clinically effective dose after 2 weeks, after which gradual withdrawal of other antiepileptic drugs is possible. In patients not treated with other antiepileptic drugs, a clinically effective dose should be achieved after 1 week.

The risk of side effects from the liver is increased during combination anticonvulsant therapy, as well as in children. Drinks containing ethanol are not allowed.

Before surgery, a general blood test (including platelet count), determination of bleeding time, and coagulogram parameters are required.

If the 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) and indicators of thyroid function.

If any acute serious side effects develop, you should immediately discuss with your doctor the advisability of continuing or stopping treatment.

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

Abruptly stopping taking Convulex may lead to an increase in epileptic seizures.

Impact on the ability to drive vehicles and operate machinery

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

Active ingredient

Valproic acid

Composition

1 ml
sodium valproate
50 mg

Excipients:

maltitol liquid (lycasin 80/55) – 800 mcg,

methyl parahydroxybenzoate – 1 mg,

propyl parahydroxybenzoate – 400 mcg,

sodium saccharinate – 1 mg,

sodium cyclamate – 3 mg,

sodium chloride – 400 mcg,

raspberry flavor 9/372710 – 400 mcg,

peach flavor 9/030307 – 1.25 mg,

purified water – up to 1 ml.

Pregnancy

During treatment, pregnancy should be protected.

Experiments on animals revealed the teratogenic effect of valproic acid.

The incidence of neural tube defects in children born to women who took valproate in the first trimester of pregnancy is 1-2%. In this regard, it is advisable to use folic acid preparations.

In the first trimester of pregnancy, treatment with Convulex should not be started. If a pregnant woman is already receiving the drug, treatment should not be interrupted due to the risk of increased seizures.

The drug should be used in the lowest effective doses, avoiding combination with other anticonvulsants and, if possible, regularly monitoring the concentration of valproic acid in plasma.

Use in children

Contraindication: children under 3 years of age (for tablets with prolonged action).

Contraindications

liver failure;
acute and chronic hepatitis;
pancreatic dysfunction;
porphyria;
hemorrhagic diathesis;
severe thrombocytopenia;
disorders of urea metabolism (including family history);
combination with mefloquine, St. John’s wort, lamotrigine;
lactation period;
children under 3 years of age;
hypersensitivity to valproic acid and its salts or components of the drug.

With caution:

with anamnestic data on diseases of the liver and pancreas (including family history);
with suppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
with renal failure;
for congenital enzymopathies;
for organic diseases of the brain;
with hypoproteinemia;
children with mental retardation.

Use for liver dysfunction

Contraindicated in severe liver dysfunction. The drug should be prescribed with extreme caution if there is a history of liver disease.

Use for renal impairment

Patients with renal failure may require a dose reduction. The dose is set by monitoring the patient’s clinical condition, because values ​​of valproic acid concentration in blood plasma may not be sufficiently informative.

Use in elderly patients

Although the pharmacokinetics of valproic acid may vary in the elderly, this is of limited clinical significance and dosing should be based on clinical effect. Due to decreased binding to serum albumin, the proportion of unbound drug in plasma increases. This makes it advisable to more carefully select the dose of the drug in the elderly, with the possible use of smaller doses of the drug.

Side Effects

In general, Konvulex® is well tolerated by patients. Side effects are possible mainly when the drug concentration in plasma is above 100 mg/l or during combination therapy.

From the digestive system: nausea, vomiting, gastralgia, decreased or increased appetite, diarrhea, hepatitis, constipation, pancreatitis, up to severe injuries with a fatal outcome (in the first 6 months of treatment, more often for 2-12 weeks).

From the side of the central nervous system: tremor, diplopia, nystagmus, flashing “floaters” before the eyes, changes in behavior, mood or mental state (depression, feeling tired, hallucinations, aggressiveness, hyperactive state, psychosis, unusual agitation, restlessness or irritability), ataxia, dizziness, drowsiness, headache, encephalopathy, dysarthria, enuresis, stupor, impaired consciousness, coma

From the hematopoietic system: anemia, leukopenia, thrombocytopenia, decreased fibrinogen content and platelet aggregation, leading to the development of hypocoagulation (accompanied by prolongation of bleeding time, petechial hemorrhages, bruises, hematomas, bleeding).

From the metabolic side: decrease or increase in body weight.

From the endocrine system: dysmenorrhea, secondary amenorrhea, breast enlargement, galactorrhea.

Laboratory parameters: hypercreatininemia, hyperammonemia, hyperbilirubinemia, slight increase in the activity of liver transaminases, LDH (dose-dependent).

Allergic reactions: skin rash, urticaria, angioedema, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).

Other: peripheral edema, hair loss (usually restored after discontinuation of the drug).

Interaction

Contraindicated combinations

Mefloquine: risk of epileptic seizures due to increased metabolism of valproic acid and a decrease in its plasma concentration and, on the other hand, the convulsant effect of mefloquine.

St. John’s wort: risk of reducing the concentration of valproic acid in the blood plasma.

Not recommended combinations

Lamotrigine: increased risk of severe skin reactions (toxic epidermal necrolysis). Valproic acid inhibits microsomal liver enzymes that ensure the metabolism of lamotrigine, which slows down its T1/2 to 70 hours in adults and up to 45-55 hours in children and increases plasma concentrations. If the combination is necessary, careful clinical and laboratory monitoring is required.

Combinations requiring special precautions

Carbamazepine: Valproic acid increases the plasma concentration of the active metabolite of carbamazepine to the point of signs of overdose. In addition, carbamazepine enhances the hepatic metabolism of valproic acid and reduces its concentration. These circumstances require the attention of a doctor and determination of drug concentrations in plasma and a possible revision of their doses.

Phenobarbital, primidone: Valproic acid increases plasma concentrations of phenobarbital or primidone to the point of signs of overdose, more often in children. In turn, phenobarbital or primidone enhance the hepatic metabolism of valproic acid and reduce its concentration. Clinical observation is recommended during the first 2 weeks of combined treatment with an immediate reduction in the dose of phenobarbital or primidone if signs of sedation appear, and determination of the level of anticonvulsants in the blood.

Phenytoin: changes in the concentration of phenytoin in plasma are possible; phenytoin increases the hepatic metabolism of valproic acid and reduces its concentration. Clinical observation is recommended, determining the level of anticonvulsants in the blood, changing dosages if necessary.

Clonazepam: The addition of valproic acid to clonazepam in isolated cases may lead to an increase in the severity of absence status.

Ethosuximide: Valproic acid can either increase or decrease the serum concentrations of ethosuximide due to changes in its metabolism. Clinical observation is recommended, determining the level of anticonvulsants in the blood, changing dosages if necessary.

Topiramate: Increases the risk of hyperammonemia and encephalopathy.

Felbamate: increased plasma concentrations of valproic acid by 35-50%, with risk of overdose. Clinical observation, determination of the level of valproic acid in the blood, and changes in the dosage of valproic acid when combined with felbamate and after its discontinuation are recommended.

Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines: neuroleptics, tricyclic antidepressants, MAO inhibitors that lower the seizure threshold reduce the effectiveness of the drug. In turn, valproic acid potentiates the effect of these psychotropic drugs, as well as benzodiazepines.

Cimetidine, erythromycin: suppress the hepatic metabolism of valproic acid and increase its plasma concentration.

Zidovudine: Valproic acid increases the plasma concentration of zidovudine, leading to increased toxicity.

Carbapenems, monobactams: meropenem, panipenem, as well as aztreonam and imipenem reduce the concentration of valproic acid in plasma, which may lead to a decrease in the anticonvulsant effect.

Combinations to consider

Acetylsalicylic acid: increased effects of valproic acid due to its displacement from plasma proteins. Valproic acid enhances the effect of acetylsalicylic acid.

Indirect anticoagulants: valproic acid enhances the effect of indirect anticoagulants; careful monitoring of the prothrombin index is necessary when administered together with vitamin K-dependent anticoagulants.

Nimodipine: increased 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 suppression of bone marrow hematopoiesis.

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

Other combinations

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

Overdose

Symptoms: nausea, vomiting, dizziness, diarrhea, respiratory dysfunction, muscle hypotonia, hyporeflexia, miosis, coma.

Treatment: gastric lavage (no later than 10-12 hours) followed by the administration of activated charcoal, hemodialysis. Forced diuresis, maintenance of function.

Storage conditions

In a dry place, protected from light, at a temperature of 15–21 °C

Shelf life

5 years

Manufacturer

Geroth Pharmaceuticals GmbH, Germany