Convulex, ampoules 100mg/ml, 5ml, 5pcs

Composition

Auxiliary substances:

sodium hydroxide-117 mg,

disodium hydrophosphate dodecahydrate-71.8 mg,

d/i water-up to 5 ml

Pharmacological action

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

The mechanism of action is mainly due to an increase in the content of GABA in the central nervous system due to inhibition of the enzyme GABA-transferase. GABA reduces excitability and convulsive readiness of motor areas of the brain.

In addition, the effect of valproic acid on GABA_{A receptors} (activation of gabaergic transmission)and the effect on potential-dependent sodium channels play an important role in the mechanism of action of the drug. According to other hypotheses, it acts on areas of postsynaptic receptors, mimicking or enhancing the inhibitory effect of GABA. A possible direct effect on membrane activity is related to 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, bioavailability when taken orally is 100%. Food intake does not reduce the rate of absorption. _Cmax in plasma is noted after 2-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-150 mg/l.

Distribution

of_csss is achieved on day 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%.

The values of the concentration in the cerebrospinal fluid correlate with the value of the non-protein fraction of the Active ingredient. Valproic acid penetrates 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.

Deduction

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

Pharmacokinetics in special clinical cases

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

When combined with other drugs, T_1/2 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 T_{1/2 is possible}.

Indications

• epilepsy of different etiologies (idiopathic, cryptogenic, and symptomatic);
• generalized epileptic seizures in adults and children (clonic, tonic, tonic-clonic, absence seizures, myoclonic, atonic);
• partial seizures in adults and children (with secondary generalization or without);
• specific syndromes (Vesta, Lennox-gastaux);
• behavioural disorders due to epilepsy;
• febrile convulsions in children, child tick;
• treatment and prophylaxis of bipolar affective disorders.

Use during pregnancy and lactation

During treatment, you should be protected from pregnancy. In animal experiments, the teratogenic effect of valproic acid was revealed. The incidence of neural tube defects in children born to women who took valproates 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, you should not start treatment with Convulex. If the pregnant woman is already receiving the drug, then due to the risk of increased seizures, treatment should not be interrupted.

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

• hepatic impairment;
• acute and chronic hepatitis,
• dysfunction of the pancreas;
• porphyria;
• bleeding diathesis;
• severe thrombocytopenia;
• metabolic disorders of urea (including family history);
• the combination with mefloquine, the St. John’s wort, the lamotrigine;
• lactation;
• children’s age up to 3 years;
• increased sensitivity to valproic acid and its salts or components of the drug.

With caution:

• with anamnestic data on liver and pancreatic diseases (including in the family history);
• with inhibition of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
• with renal failure;
• with congenital fermentopathies;
• with organic brain diseases;
• with hypoproteinemia;
• children with mental retardation.

Use in patients with liver function disorders

Contraindicated in severe hepatic impairment. With extreme caution, the drug should be prescribed if there is a history of liver disease.

Use in patients with impaired renal function

Patients with renal insufficiency may need to reduce the dose of the drug. The dose is set by monitoring the patient’s clinical condition, since the values of valproic acid concentration in blood plasma may not be sufficiently informative.

Use in elderly patients

Although the pharmacokinetics of valproic acid in the elderly may have their own characteristics, this is of limited clinical significance, and the dose should be determined by the clinical effect. Due to a decrease in binding to serum albumin, the proportion of unbound drug in plasma increases. This makes it advisable to select the dose of the drug more carefully in the elderly, with the possible use of smaller doses of the drug.

Side effects

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

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

From the central nervous system:  tremor, diplopia, nystagmus, flickering of “flies” in front of the eyes, changes in behavior, mood or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactivity, psychosis, unusual agitation, motor 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 prolonged bleeding time, petechial hemorrhages, bruising, hematomas, bleeding).

From the side of metabolism:  decrease or increase in body weight.

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

From the side of laboratory parameters:  hypercreatininemia, hyperammonemia, hyperbilirubinemia, slight increase in hepatic transaminase activity, LDH (dose-dependent).

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

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

Interaction

Contraindicated combinations of

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

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

Not recommended combinations

Lamotrigine:  increased risk of severe skin reactions (toxic epidermal necrolysis). Valproic acid inhibits microsomal liver enzymes responsible for lamotrigine metabolism, which slows down its T_1/2 to 70 hours in adults and 45-55 hours in children and increases the concentration in blood plasma. If a combination is necessary, careful clinical and laboratory monitoring is required.

Combinations that require special precautions

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

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

Phenytoin: there may be changes in the concentration of phenytoin in plasma, phenytoin increases the hepatic metabolism of valproic acid and reduces its concentration. It is recommended to conduct clinical monitoring, determine the level of anticonvulsants in the blood, and change the dosage if necessary.

Clonazepam: the addition of valproic acid to clonazepam in isolated cases can lead to an increase in the severity of the absent status.

Ethosuximide: valproic acid can both increase or decrease the concentration of ethosuximide in the blood serum due to changes in its metabolism. It is recommended to conduct clinical monitoring, determine the level of anticonvulsants in the blood, and change the dosage if necessary.

Topiramate: the risk of hyperammonemia and encephalopathy increases.

Felbamat: an increase in the concentration of valproic acid in plasma by 35-50%, with the risk of overdose. It is recommended to conduct clinical monitoring, determine the level of valproic acid in the blood, and change the dosage of valproic acid when combined with felbamate and after its withdrawal.

Antipsychotics, MAO inhibitors, antidepressants, benzodiazepines:neuroleptics, tricyclic antidepressants, and MAO inhibitors, which reduce the threshold of convulsive readiness, reduce the effectiveness of the drug. In turn, valproic acid potentiates the effect of these psychotropic drugs, as well as benzodiazepines.

Cimetidine, erythromycin: inhibit hepatic metabolism of valproic acid and increase its concentration in plasma.

Zidovudine: valproic acid increases the concentration of zidovudine in plasma, which leads to an increase in its 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 for

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

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

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

Myelotoxic drugs: increased risk of bone marrow hematopoiesis suppression.

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.

How to take, course of use and dosage

Individual approach. For oral use in adults and children with a body weight of more than 25 kg, the initial dose is 10-15 mg/kg/day. Then the dose is gradually increased by 200 mg / day with an interval of 3-4 days until the clinical effect is achieved. The average daily dose is 20-30 mg / kg. For children weighing less than 25 kg and newborns, the average daily dose is 20-30 mg / kg

. The frequency of use is 2-3 times / day with meals.

IV (in the form of sodium valproate) is administered at a dose of 400-800 mg or dropwise at the rate of 25 mg / kg for 24,36 and 48 hours. If simultaneous oral and intravenous use is necessary, the first use is carried out by intravenous infusion at a dose of 0.5-1 mg/kg/h 4-6 hours after the last oral use.

Maximum doses: when taken orally for adults and children with a body weight of more than 25 kg-50 mg / kg / day. Use at a dose of more than 50 mg / kg / day is possible if the concentration of valproate in blood plasma is controlled. If the blood plasma concentration exceeds 200 mg / l, the dose of valproic acid should be reduced.

Capsules are taken orally, without chewing,2-3 times / day, during or immediately after meals, with a small amount of water.

Adults are prescribed an initial dose of 600 mg / day with a gradual increase in the dose by 150-250 mg every 3 days until the clinical effect (disappearance of seizures) is achieved.

The initial dose for monotherapy is 5-15 mg / kg / day, then the dose is gradually increased by 5-10 mg / kg per week.

The recommended daily dose is about 1-2 g, i. e. 20-25 mg/kg. If necessary, the dose can be increased to a maximum dose of 2.5 g / day (30 mg / kg).

The maximum dose is 30 mg / kg / day (in patients with accelerated valproic acid metabolism, the maximum dose can be increased to 60 mg/kg / day under the control of valproic acid concentration in blood plasma).

In combination therapy, the dose is 10-30 mg / kg / day, followed by an increase of 5-10 mg / kg per week.

Children with a body weight of more than 25 kg are prescribed an initial dose of 300 mg / day (5-15 mg / kg/day), with a gradual increase of 5-10 mg/kg per week until the clinical effect (disappearance of seizures) is achieved, while the dose is usually 1-1.5 g/day (20-30 mg/kg/day).

The maximum dose is 30 mg / kg / day (in patients with accelerated valproic acid metabolism, the maximum dose can be increased to 60 mg/kg / day under the control of valproic acid concentration in blood plasma).

For children with a body weight of 7.5-25 kg with monotherapy, the average dose is 15-45 mg/kg/day, the maximum is 50 mg/kg/day. In combination therapy – 30-100 mg / kg / day.

Average daily doses of Convulex

Although the pharmacokinetics of valproic acid in the elderly may have their own characteristics, this is of limited clinical significance, and the dose should be determined by the clinical effect. Due to a decrease in binding to serum albumin, the proportion of unbound drug in plasma increases. This makes it advisable to select the dose of the drug more carefully in the elderly, with the possible use of smaller doses of the drug.

Patients with renal insufficiency may need to reduce the dose of the drug. The dose should be selected based on monitoring the clinical condition, since plasma concentrations may not be sufficiently informative.

Overdose

Symptoms: nausea, vomiting, dizziness, diarrhea, respiratory failure, muscle hypotension, hyporeflexia, miosis, coma.

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

Special instructions

Due to reports of severe and fatal cases of hepatic insufficiency and pancreatitis, the following should be taken into account when using valproic acid preparations::

• high-risk group includes infants and children up to 3 years, with severe epilepsy, often associated with brain damage and congenital metabolic or degenerative diseases;
• in most cases, liver function abnormalities developed in the first 6 months (usually between 2 and 12 weeks) of treatment, often combined with 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 age of the patient;
• the impairment of liver function in pancreatitis increases the risk of death;
• early diagnosis (before icteric stage) is mainly based on clinical observation, the detection of early symptoms, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by vomiting and abdominal pain; this may be a recurrence of epileptic seizures on the background of unchanged antiepileptic therapy.

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

During treatment, especially in the first 6 months, it is necessary to periodically check liver function – the activity of hepatic transaminases, the level of prothrombin, fibrinogen, clotting 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, the transition to valproic acid should be carried out gradually, reaching a clinically effective dose after 2 weeks, after which the gradual withdrawal of other antiepileptic drugs is possible. In patients who have not been treated with other antiepileptic drugs, the clinically effective dose should be reached after 1 week.

The risk of liver side effects is increased during combined 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 acute stomach symptom complex occurs during treatment, it is recommended to determine the amylase activity in the blood before surgery to exclude acute pancreatitis.

During treatment, possible distortion of the results of urine tests in diabetes mellitus (due to an increase in the content of ketone bodies), thyroid function indicators should be taken into account.

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

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

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

Influence on the ability to drive motor vehicles and manage mechanisms

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

Form of production

Ampoules

Storage conditions

In a dark place, at a temperature not exceeding 25 °C

Shelf life

3 years

Active ingredient

Valproic Acid

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution