Convullex, 300 mg 50 pcs

Pharmgroup:

antiepileptic drug

Pharmic action:

Convulex is an antiepileptic drug.

It also has central myorelaxant and sedative effects.

The mechanism of action is caused mainly by increase of GABA content in CNS due to inhibition of GABA-transferase enzyme. GABA decreases excitability and seizure readiness of motor areas of the brain. In addition, a significant role in the mechanism of action of the drug is played by the effect of valproic acid on GABA receptors (activation of GABA-ergic transmission) as well as the effect on potential-dependent sodium channels.

Another hypothesis is that it acts on post-synaptic receptor sites to mimic or enhance 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:

Absorption
Valproic acid is almost completely absorbed from the GI tract, bioavailability when ingested is 100%. Food intake does not reduce the absorption rate. Cmax in blood plasma after taking tablets of prolonged action is reached after 4 hours, Cmax in blood plasma after oral drops – after 1-3 hours. The therapeutic plasma concentration of valproic acid is 50-150 mg/l.

The prolonged form is characterized by slow absorption, lower (by 25%) but more stable plasma concentrations between 4 and 14 h.

Distribution
Css is reached on days 2-4 of treatment, depending on dosage intervals.
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 are excreted in the feces and exhaled air. T1/2 of valproic acid 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 is reduced.
In combination with other medicinal agents T1/2 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 T1/2 is possible.

Indications

– epilepsy of different etiology (idiopathic, cryptogenic and symptomatic);
– generalized epileptic seizures in adults and children (clonic, tonic-clonic, tonic-clonic, absences, myoclonic, atonic);
– partial seizures in adults and children (with or without secondary generalization);
– specific syndromes (West, Lennox-Gasto);
– behavioral disorders caused by epilepsy;
– febrile seizures in children, childhood tics;
– treatment and prevention of bipolar affective disorders (for oral drops);
– treatment and prevention of bipolar affective disorders that are resistant to treatment with lithium or other drugs (for prolonged action tablets).

Active ingredient

Composition

1 tablet:

– sodium valproate 300 mg.

Auxiliary substances:

citric acid,

ethylcellulose,

copolymer of methyl methacrylate,

trimethylammonioethyl methacrylate chloride and ethyl acrylate (1:2:0.1) (eudragit RS30D),

Purified talc,

Silica colloidal anhydrous,

Magnesium stearate.

How to take, the dosage

Long-acting tablets are taken orally, without chewing, 1-2 times a day, during or immediately after meals, with a small amount of water.

The drops for oral administration are taken orally 2-3 times a day, regardless of meals, with a small amount of water.
Adults are prescribed in initial dose of 600 mg/day with gradual increase every 3 days until clinical effect (disappearance of seizures) is achieved.

The initial dose in monotherapy is 5-15 mg/kg/day, then the dose is gradually increased by 5-10 mg/kg/week.
The recommended daily dose is about 1-2 g, i.e. 20-30 mg/kg. If necessary, the dose can be increased to 2.5 g/day. (30 mg/kg/day).
The maximum dose is 30 mg/kg/day. (in patients with accelerated valproic acid metabolism, the maximum dose may be increased to 60 mg/kg/day under monitoring of plasma valproic acid concentrations).

In case of combined therapy the dose is 10-30 mg/kg/day with subsequent increase by 5-10 mg/kg/week.
Children with body weight over 25 kg are prescribed in initial dose of 300 mg/day. (5-15 mg/kg/day) with a gradual increase by 5-10 mg/kg/week until clinical effect is achieved (seizures disappear), and the dose is usually 1-1.5 g/day (20-30 mg/kg/day). (20-30 mg/kg/day).

The maximum dose is 30 mg/kg/day. (in patients with accelerated valproic acid metabolism, the maximum dose may be increased to 60 mg/kg/day with monitoring of plasma valproic acid concentrations).

In children with body weight of 7.5-25 kg in 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. It should be taken into account that children with body weight less than 20 kg are not recommended to use the drug in the form of sustained-release tablets; they should use other forms of the drug.

Interaction

– Contraindicated combinations
Mefloquine: risk of epileptic seizures due to increased metabolism of valproic acid and decreased plasma concentrations and, on the other hand, the convulsant effect of mefloquine.

Wort: risk of decreased plasma concentrations of valproic acid.
– Unrecommended combinations

Lamotrigine: increased risk of severe skin reactions (toxic epidermal necrolysis). Valproic acid inhibits hepatic microsomal enzymes that metabolize lamotrigine, which slows its T1/2 to 70 h in adults and to 45-55 h in children and increases plasma concentrations. If the combination is necessary, close clinical and laboratory monitoring is required.
– Combinations requiring special precautions

Carbamazepine: valproic acid increases the plasma concentration of the active metabolite carbamazepine to signs of overdose. In addition, carbamazepine increases hepatic metabolism of valproic acid and decreases its concentration. These circumstances require the attention of the physician and determination of plasma concentrations of the drugs and possible revision of their doses.

Phenobarbital, primidone: Valproic acid increases plasma concentrations of phenobarbital or primidone to signs of overdose, more often in children. In turn, phenobarbital or primidone increase hepatic metabolism of valproic acid and decrease its concentration. It is recommended clinical observation during first 2 weeks of combined treatment with immediate decrease of phenobarbital or primidone dose if there are signs of sedation, determination of anticonvulsant blood levels.

Phenytoin: changes in plasma concentrations of phenytoin are possible; phenytoin increases hepatic metabolism of valproic acid and decreases its concentration. Clinical monitoring, determination of blood levels of anticonvulsants, change of dosages if necessary are recommended.

Clonazepam: The addition of valproic acid to clonazepam in single cases may increase the severity of absences.

Ethosuximide: Valproic acid may both increase and decrease the serum concentration of ethosuximide due to changes in its metabolism. Clinical monitoring, determination of anticonvulsant blood levels, and dosage changes if necessary are recommended.

Topiramate: increased risk of hyperammonemia and encephalopathy.

Felbamate: increases plasma concentrations of valproic acid by 35-50%, with risk of overdose. Clinical monitoring, determination of valproic acid levels in blood, and changes in valproic acid dosage when combined with felbamate and after discontinuation are recommended.

Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines: Neuroleptics, tricyclic antidepressants, MAO inhibitors that reduce seizure threshold decrease 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 plasma concentration.

Zidovudine: valproic acid increases the plasma concentration of zidovudine, which leads to increased toxicity.
Carbapenems, monobactams: meropenem, panipenem, and aztreonam and imipenem decrease the plasma concentration of valproic acid, which may lead to decreased anticonvulsant effect.

– Combinations to be considered

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

Indirect anticoagulants: Valproic acid increases the effect of indirect anticoagulants, close monitoring of prothrombin index is required when combined with vitamin K-dependent anticoagulants.

Nimodipine: enhancement of hypotensive effect of nimodipine due to increase of its concentration in plasma due to inhibition of its metabolism by valproic acid.

Myelotoxic drugs: increased risk of suppression of medullary hematopoiesis.
Ethanol and hepatotoxic drugs: increased likelihood of liver damage.

– Other combinations

Peroral contraceptives: valproic acid does not cause induction of microsomal liver enzymes and does not reduce the effectiveness of hormonal oral contraceptives.

Special Instructions

With regard to reports of severe and fatal cases of hepatic failure and pancreatitis when using valproic acid preparations, the following should be kept 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 patient age and duration of treatment, although the risk of pancreatitis decreased with patient age;
– insufficiency of liver function in pancreatitis increases the risk of death;
– early diagnosis (before the ictal stage) is based mainly on clinical observation – detection of early symptoms such as asthenia, anorexia, extreme fatigue, somnolence, sometimes accompanied by vomiting and abdominal pain; and there may be recurrence of epileptic seizures against unchanged antiepileptic therapy.

In such cases, a physician should be seen immediately for clinical examination and liver function tests.

. During treatment, especially during the first 6 months, liver function should be periodically checked – liver transaminase activity, prothrombin levels, fibrinogen, clotting factors, bilirubin concentration, and amylase activity (every 3 months, especially when combined with other antiepileptic drugs) and peripheral blood counts, particularly blood platelets.
Patients who receive other antiepileptic agents should be transferred to valproic acid administration gradually, reaching clinically effective dose in 2 weeks, after which gradual withdrawal of other antiepileptic agents is possible. In patients who have not been treated with other antiepileptic agents, a clinically effective dose should be achieved after 1 week.

The risk of liver side effects is increased with combined anticonvulsant therapy and in children. Consumption of beverages containing ethanol is not allowed.

Before surgical intervention, a complete blood count (including platelet count), determination of bleeding time, coagulogram values are necessary.

If symptoms of “acute” abdomen occur against the background of treatment before surgical intervention, it is recommended to determine blood amylase activity to rule out acute pancreatitis.

In the course of treatment, the possible distortion of urinalysis results in diabetes mellitus (due to increased ketone bodies) and thyroid function parameters should be considered.

If any acute serious side effects develop, the appropriateness of continuing or discontinuing treatment should be discussed with the physician immediately.

In order to reduce the risk of dyspeptic disorders, antispasmodics and sedatives may be used.
Abrupt discontinuation of Convulex may lead to increased frequency of epileptic seizures.

Impact on driving and operating machinery

At the time of treatment, care must be taken when driving vehicles and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions.

Contraindications

– hepatic insufficiency;
– acute and chronic hepatitis;
– pancreatic function disorders;
– porphyria;
– hemorrhagic diathesis;
– expressed thrombocytopenia;
– urea metabolism disorders (including in family history).Combination with Mefloquine, St. John’s Wort, Lamotrigine;
– Lactation;
– Children with body mass less than 7.Children with body weight less than 20 kg (for prolonged action tablets);
– children under 3 years of age (for prolonged action tablets);
– hypersensitivity to valproic acid and its salts or to the components of Convulex.
With caution:
– with anamnestic data on liver and pancreatic diseases (including Family history);
– Inhibition of medullary hematopoiesis (leukopenia, thrombocytopenia, anemia);
– In renal insufficiency;
– In congenital enzymopathies;
– In case of organic brain diseases;
– In hypoproteinemia;
– In pregnancy (especially during the 1st trimester);
– In children with mental retardation;
– In children with body mass over 7.5 kg (for oral drops).

Side effects

On the whole, Convulex® is well tolerated by patients. Side effects are mainly possible with plasma concentrations of the drug above 100 mg/l or with combined therapy.

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

CNS side: Tremor, diplopia, nystagmus, flickering “flies” before the eyes, changes in behavior, mood or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactive state, psychosis, unusual agitation, motor anxiety or irritability), ataxia, dizziness, somnolence, headache, encephalopathy, dysarthria, enuresis, stupor, impaired consciousness, coma.

Hematopoietic system disorders: anemia, leukopenia, thrombocytopenia, decrease of fibrinogen and platelet aggregation, leading to hypocoagulation (accompanied by prolongation of bleeding time, petechial hemorrhages, bruises, hematomas, bleeding).

Metabolic side: decrease or increase in body weight.

Endocrine system disorders: dysmenorrhea, secondary amenorrhea, breast enlargement, galactorrhea.

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

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

Other: peripheral edema, hair loss (usually recovered after discontinuation of the drug).
Overdose: Symptoms: nausea, vomiting, dizziness, diarrhea, respiratory depression, muscle hypotonia, hyporeflexia, miosis, coma.

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

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