Convullex, drops 300 mg/ml 100 ml

Convulex^® is an antiepileptic drug; it also has central myorelaxant and sedative effects. The mechanism of action is mainly due to inhibition of the enzyme GABA-transferase and increased content of GABA in CNS. GABA prevents pre- and postsynaptic discharges and thereby prevents the spread of seizure activity into the CNS.

In addition, the effects of valproic acid on the GABA_A receptors as well as the effects on voltage-dependent sodium channels play a significant role in the drug’s mechanism of action. According to another hypothesis, it acts on post-synaptic receptor sites, mimicking or enhancing the inhibitory effect of GABA. Possible direct effect on membrane activity is due to changes in potassium conductance. Improves the mental state and mood of patients, has antiarrhythmic activity.

Pharmacokinetics

The equilibrium concentration at injection is reached within minutes and can be maintained by slow infusion. Therapeutic plasma concentrations of the drug range from 50-150 mg/L. Valproic acid is bound to plasma proteins by 90-95% at plasma concentrations up to 50 mg/L and by 80-85% at 50-100 mg/L; in uremia, hypoproteinemia and cirrhosis, protein binding is reduced.

Concentration levels in cerebrospinal fluid correlate with the non-protein-bound fraction of the drug, being about 10% of serum levels. 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.

The drug undergoes glucuronidation and oxidation in the liver; metabolites and unchanged valproic acid (1-3% of dose) are excreted by the kidneys; small amounts are taken out with the feces and exhaled air. T_1/2 of the drug is 8 to 20 h in healthy subjects and in monotherapy; 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 and elderly patients – may be significantly longer.

Indications

Epileptic status; treatment of epileptic seizures (generalized – absences, myoclonic seizures, tonic-clonic, atonic, mixed; partial – simple, complex, secondary generalized seizures; specific syndromes (West, Lennox-Gasto).

Active ingredient

Valproic acid

Composition

Associates:

Sodium saccharinate – 8.5 mg,

orange flavoring – 2 mg,

Hydrochloric acid 37% – q.s. to pH 9.0,

sodium hydroxide – q.s. to pH 9.0,

purified water – to 1 ml.

How to take, the dosage

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

The frequency of administration is 2-3 times a day with meals.

V/v (as sodium valproate) is administered in a dose of 400-800 mg or by drip at a rate of 25 mg/kg for 24, 36 and 48 hours. If concomitant use of oral and IV is necessary, the first administration is by IV infusion at a dose of 0.5-1 mg/kg/h, 4-6 hours after the last oral dose.

Maximum doses: when administered orally for adults and children weighing more than 25 kg, 50 mg/kg/day. Administration at a dose higher than 50 mg/kg/day is possible with monitoring of plasma concentrations of valproate. If plasma concentrations exceed 200 mg/l, the valproic acid dose should be reduced.

The capsules are taken orally, without chewing, 2-3 times daily, during or immediately after a meal, with a small amount of water.

Adults are prescribed in an initial dose of 600 mg/day with gradual increase of the dose by 150-250 mg 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., 20-25 mg/kg. If necessary, the dose may 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 may be increased to 60 mg/kg/day with monitoring of plasma valproic acid concentrations).

In combination therapy the dose is 10-30 mg/kg/day with a subsequent increase of 5-10 mg/kg/week.

In children with a body weight greater than 25 kg, the initial dose is 300 mg/day (5-15 mg/kg/day), with gradual increases of 5-10 mg/kg/week until clinical effect (disappearance of seizures) is achieved, with the dose usually being 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 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, maximum – 50 mg/kg/day. In combined therapy it is 30-100 mg/kg/day.

The average daily dose of Convulex

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Although the pharmacokinetics of valproic acid in the elderly may be different, this is of limited clinical significance, and the dose should be determined by clinical effect. Due to decreased binding to serum albumin, the proportion of unbound drug in plasma increases. This makes it advisable to choose the drug dose more carefully in the elderly, with the possible use of lower doses of the drug.

Patients with renal insufficiency may find it necessary to reduce the drug dose. The dose should be adjusted according to clinical monitoring, since plasma concentrations may be insufficiently informative.

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 T_1/2 to 70 h in adults and 45-55 h in children and increases plasma concentrations. Careful clinical and laboratory monitoring is required if the combination is necessary.

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. Clinical observation during first 2 weeks of combined treatment with immediate decrease of phenobarbital or primidone dose in case of signs of sedative effect is recommended, determination of blood levels of anticonvulsants.

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 a decrease in anticonvulsant effect.

Combinations to be considered

Acetylsalicylic acid: Increase the 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: increase the 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 disease;
• cases of pancreatitis were observed regardless of patient age and duration of treatment, although the risk of pancreatitis decreased with patient age;
• insufficient liver function in pancreatitis increases the risk of death;
• early diagnosis (before the icteric 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 relapse of epileptic seizures on unchanged antiepileptic therapy may occur.

In such cases, consult a physician immediately for clinical examination and liver function tests.

With treatment, especially during the first 6 months, liver function – hepatic 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, should be checked periodically.

Patients who receive other antiepileptic agents should be switched to valproic acid gradually, reaching clinically effective dose after 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, blood amylase activity should be determined prior to surgical intervention 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 taken into account.

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 quick psychomotor reactions.

Contraindications

• high sensitivity to valproic acid;
• explicit hepatic and/or pancreatic dysfunction;
• porphyria;
• hemorrhagic diathesis;
• expressed thrombocytopenia.

With caution:

• in children when treated with several antiepileptic drugs;
• in children and adolescents with multiple comorbidities and severe seizures;
• in impaired renal function;
• in patients with a history of liver and pancreatic disease;
• in inhibition of medullary hematopoiesis: Leukopenia, anemia, thrombocytopenia;
• in congenital enzymopathies;
• in organic brain lesions;
• in hypoproteinemia.

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Side effects

In general, Convullex^® is well tolerated by patients. Side effects are mainly possible at plasma concentrations of the drug above 100 mg/l or during combination 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).

Others: peripheral edema, hair loss (usually recovered after discontinuation of the drug).

Overdose

Symptoms: nausea, vomiting, dizziness, diarrhea, respiratory dysfunction, 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 function.

Pregnancy use

Pregnancy should be prevented during treatment.

The teratogenic effect of valproic acid was found in animal experiments. Frequency of neural tube defects in children born to women who took valproate in the first trimester of pregnancy is 1-2%. It is reasonable to use folic acid preparations for this purpose.

The treatment with Convulex should not be started in the first trimester of pregnancy. If a pregnant woman is already receiving the drug, 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 plasma concentration of valproic acid.

Pediatric use

Pediatric contraindication: children under 3 years of age (for prolonged-acting tablets).

Similarities

Depakine, Depakine 300 Enteric, Valparin XP, Encorat Chrono, Depakine Chronosphere