Composition, form of production and packaging
Capsules enteric-soluble soft gelatinous pink color, covered with enteric coating, labeled with gray ink "150"; the contents of the capsules are colorless or colorless with a slightly yellowish tinge, with a weak characteristic odor.
1 caps.
valproic acid 150 mg
Excipients:
The composition of the capsule body: Caryon 83 (mannitol 2-4%, sorbitol 27-32%, hydrogenated starch 61-71%) 15.14 mg, glycerol 85% 21.63 mg, gelatin 71.56 mg, titanium dioxide 0.67 mg, iron oxide red (E172) - 0.17 mg, hydrochloric acid 25% - 0.57 mg.
Ingredients of the enteric coating: 30% dispersion of the methacrylic acid-ethyl acrylate copolymer (1: 1) dry (0.7% sodium lauryl sulfate, polysorbate 80% 2.3%) 17.55 mg, triethyl citrate 2.81 mg, macrogol 6000 0.88 mg, glyceryl monostearate 45-55 type II - 0.53 mg.
Ingredients of ink capsule marking: shellac 47.5%, titanium dioxide, iron oxide black dye, butanol, water, propylene glycol, ethanol denatured (methyl alcohol), isopropanol.
10 pieces. - blisters (10) - packs of cardboard.
Capsules enteric-soluble soft gelatinous pink color, covered with enteric coating, labeled with gray ink "300"; the contents of the capsules are colorless or colorless with a slightly yellowish tinge, with a weak characteristic odor.
1 caps.
valproic acid 300 mg
Excipients:
The composition of the capsule body: Caryon 83 (mannitol 2-4%, sorbitol 27-32%, hydrogenated starch 61-71%) 24.94 mg, glycerol 85% 35.63 mg, gelatin 117.86 mg, titanium dioxide 1.1 mg, iron oxide red (E172) - 0.28 mg, hydrochloric acid 25% - 0.94 mg.
Ingredients of the enteric coating: 30% dispersion of methacrylic acid-ethyl acrylate copolymer (1: 1) dry (sodium lauryl sulfate 0.7%, polysorbate 80 2.3%) 28.83 mg, triethyl citrate 4.61 mg, macrogol 6000-1.44 mg, glyceryl monostearate 45-55 type II - 0.86 mg.
The ink composition of the capsule marking: shellac 47.5%, titanium dioxide, iron dye oxide black, butanol, water, propylene glycol, ethanol denatured (methylated alcohol), isopropanol.
20 pcs. - blisters (5) - packs of cardboard.
Capsules enteric-soluble soft gelatinous pink color, covered with enteric coating, labeled with gray ink "500"; the contents of the capsules are colorless or colorless with a slightly yellowish tinge, with a weak characteristic odor.
1 caps.
valproic acid 500 mg
Excipients:
The composition of the capsule body: Caryon 83 (mannitol 2-4%, sorbitol 27-32%, hydrogenated starch 61-71%) 40.97 mg, glycerol 85% 58.53 mg, gelatin 193.64 mg, titanium dioxide 1.81 mg, iron oxide red (E172) - 0.46 mg, hydrochloric acid 25% - 1.54 mg.
Ingredients of the enteric coating: 30% dispersion of the methacrylic acid-ethyl acrylate copolymer (1: 1) dry (sodium lauryl sulfate 0.7%, polysorbate 80 2.3%) 47.62 mg, triethyl citrate 7.62 mg, macrogol 6000-2.38 mg, glyceryl monostearate 45-55 type II - 1.43 mg.
The ink composition of the capsule marking: shellac 47.5%, titanium dioxide, iron dye oxide black, butanol, water, propylene glycol, ethanol denatured (methylated alcohol), isopropanol.
10 pieces. - blisters (10) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Antiepileptic drug. It also has a central muscle relaxant and sedative effect.
The mechanism of action is mainly due to an increase in GABA in the CNS due to inhibition of the enzyme GABA-transferase. GABA reduces the excitability and convulsive readiness of the motor zones of the brain. In addition, the action of valproic acid on the GABA A receptors (activation of GABA-ergic transmission), as well as the influence on the potential-dependent sodium channels, plays an important role in the mechanism of action of the drug. According to another hypothesis, it acts on the sites of postsynaptic receptors, imitating or enhancing the inhibitory effect of GABA. A possible direct effect on membrane activity is associated with changes in conductivity for potassium ions. It improves the mental state and mood of patients, has antiarrhythmic activity.
PHARMACOKINETICS
Suction
Valproic acid is almost completely absorbed from the digestive tract, the bioavailability when ingested is 100%. Eating does not reduce the absorption rate. C max in plasma is observed after 2-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-150 mg / l.
Distribution
C ss is achieved on the 2nd-4th day of treatment, depending on the intervals between doses.
At a plasma concentration of up to 50 mg / l, the binding of valproic acid with plasma proteins is 90-95%, with a concentration of 50-100 mg / l, 80-85%.
Values ​​of concentration in the cerebrospinal fluid correlate with the value of the fraction of the active substance not associated with proteins. Valproic acid penetrates the placental barrier, excreted in breast milk. Concentration in breast milk is 1-10% concentration in the blood plasma of the mother.
Metabolism
Valproic acid is subjected to glucuronidation and oxidation in the liver.
Excretion
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 for monotherapy and for healthy volunteers is 8-20 hours.
Pharmacokinetics in special clinical cases
With uremia, hypoproteinemia and cirrhosis, the binding of valproic acid with 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 the age of 18 months, 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, absences, myoclonic, atonic);
- partial epileptic seizures in adults and children (with or without secondary generalization);
- Specific syndromes (Vesta, Lennox-Gastaut);
- Behavioral disorders due to epilepsy;
- febrile convulsions in children, children's teak;
- treatment and prevention of bipolar affective disorders.
DOSING MODE
Capsules are taken orally, without chewing, 2-3 times / day, during or immediately after a meal, with a small amount of water.
Adults are prescribed in an initial dose of 600 mg / day with a gradual increase in the dose of 150-250 mg every 3 days until the clinical effect (disappearance of seizures).
The initial dose for monotherapy is 5-15 mg / kg / day, then gradually increase the dose by 5-10 mg / kg per week.
The recommended daily dose is about 1-2 g, i.Рµ. 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 metabolism of valproic acid, the maximum dose can be increased to 60 mg / kg / day under the control of the concentration of valproic acid in blood plasma).
When combined 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 in 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), while the dose , as a rule, is 1-1.5 g / day (20-30 mg / kg / day).
The maximum dose is 30 mg / kg / day (in patients with accelerated metabolism of valproic acid, the maximum dose can be increased to 60 mg / kg / day under the control of the concentration of valproic acid in blood plasma).
For children weighing 7.5-25 kg with monotherapy, the average dose is 15-45 mg / kg / day, the maximum - 50 mg / kg / day. When combined therapy - 30-100 mg / kg / day.
Average daily doses of Convulex
Body weight of the patient (kg) Dose (mg / day) Number of capsules 150 mg Number of capsules 300 mg Number of capsules 500 mg
7.5-14 150-450 1-3 - -
14-21 300-600 2-4 1-2 -
21-32 600-900 4-6 2-3 -
32-50 900-1500 - 3-5 2-3
50-90 1500-2500 - - 3-5
Although the pharmacokinetics of valproic acid in the elderly may have its own peculiarities, this is of limited clinical importance, and the dose should be determined by the clinical effect. Due to a decrease in binding to serum albumin, the proportion of unbound preparation in plasma increases. This causes the expediency of a more careful selection of the dose of the drug in the elderly, with the possible use of smaller doses of the drug.
Patients with renal insufficiency may find it necessary to reduce the dose of the drug. The dose should be selected by monitoring the clinical state, since plasma concentrations may not be sufficiently informative.
SIDE EFFECT
In general, Convulex В® is well tolerated by patients. Side effects are possible mainly at a drug concentration in the plasma above 100 mg / l or with combined therapy.
On the part of the digestive system: nausea, vomiting, gastralgia, decreased or increased appetite, diarrhea, hepatitis, constipation, pancreatitis, up to severe lesions with a lethal outcome (in the first 6 months of treatment, usually 2-12 weeks).
From the side of the central nervous system: tremor, diplopia, nystagmus, flashing of the flies before the eyes, changes in behavior, mood or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactive state, psychoses, unusual agitation, motor anxiety or irritability), ataxia, dizziness, drowsiness, headache, encephalopathy, dysarthria, enuresis, stupor, impaired consciousness, coma.
On the part of the hematopoiesis system: anemia, leukopenia, thrombocytopenia, reduction of fibrinogen and platelet aggregation, leading to the development of hypocoagulation (accompanied by prolonged bleeding time, petechial hemorrhages, bruises, bruises, bleeding).
From the side of metabolism: decrease or increase in body weight.
On the part of the endocrine system: dysmenorrhea, secondary amenorrhea, breast enlargement, galactorrhea.
On the part of laboratory indicators: hypercreatininaemia, hyperammonemia, hyperbilirubinemia, a slight increase in the activity of hepatic transaminases, LDH (dose-dependent).
Allergic reactions: skin rash, hives, angioedema, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).
Other: peripheral edema, hair loss (usually recovers after drug discontinuation).
CONTRAINDICATIONS
- liver failure;
acute and chronic hepatitis;
- impaired pancreatic function;
- porphyria;
- hemorrhagic diathesis;
- severe thrombocytopenia;
- Disorders of urea metabolism (including in family history);
- combination with mefloquine, St. John's wort, perforated, lamotrigine;
- lactation period;
- Children's age up to 3 years;
- Hypersensitivity to valproic acid and its salts or components of the drug.
With caution:
- with anamnestic data on liver and pancreas diseases (including family history);
- with oppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, anemia);
- with renal insufficiency;
- with congenital fermentopathy;
- with organic diseases of the brain;
- with hypoproteinemia;
- during pregnancy (especially I trimester);
- children with mental retardation.
PREGNANCY AND LACTATION
During treatment should be protected from pregnancy. In animal experiments, the teratogenic effect of valproic acid has been revealed. The incidence of neural tube defects in children born to women taking valproate in the first trimester of pregnancy is 1-2%. It is advisable in this regard, the use of folic acid preparations. In the first trimester of pregnancy, do not begin treatment with Convex. If the pregnant woman is already receiving the drug, then due to the risk of more seizures, treatment should not be interrupted. The drug should be used in the lowest effective doses, avoiding the combination with other anticonvulsants and, if possible, regularly monitoring the concentration of valproic acid in the plasma.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with renal insufficiency may need to reduce the dose of the drug. The dose is set by monitoring the clinical state of the patient, tk. Valence concentrations of valproic acid in the blood plasma may not be enough informative.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated in severe violations of liver function. With extreme caution, you should prescribe the drug with a history of liver disease.
APPLICATION FOR CHILDREN
Contraindication: children under 3 years (for tablets with prolonged action).
APPLICATION IN ELDERLY PATIENTS
Although the pharmacokinetics of valproic acid in the elderly may have its own peculiarities, this is of limited clinical importance, and the dose should be determined by the clinical effect. Due to a decrease in binding to serum albumin, the proportion of unbound preparation in plasma increases. This causes the expediency of a more careful selection of the dose of the drug in the elderly, with the possible use of smaller doses of the drug.
SPECIAL INSTRUCTIONS
In connection with the available reports of severe and lethal cases of hepatic insufficiency and pancreatitis with the use of valproic acid preparations, it is necessary to bear in mind the following:
- At-risk groups are infants and children under 3 years old, 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, 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 age of the patient;
- Lack of liver function in pancreatitis increases the risk of death;
- early diagnosis (before the icteric stage) is based mainly on clinical observation - the detection of early symptoms such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by vomiting and abdominal pain; with the recurrence of epileptic seizures against a background of unchanged antiepileptic therapy.
In such cases, you should immediately consult a doctor for 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 level of prothrombin, fibrinogen, coagulation factors, bilirubin concentration, and amylase activity (every 3 months, especially when combined with other antiepileptic drugs) and a picture of peripheral blood, in particular, blood platelets.
Patients who receive other antiepileptic drugs, transfer to admission valproic acid should be carried out gradually, reaching a clinically effective dose after 2 weeks, after which a gradual cancellation of other antiepileptic drugs is possible. In patients who were not treated 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 when combined anticonvulsant therapy, as well as in children. Do not drink drinks containing ethanol.
Before the surgical intervention, a general blood test (including platelet numbers), bleeding time, coagulogram indices is required.
If there is a "acute abdomen" symptom complex before treatment, it is recommended to determine the activity of amylase in the blood to exclude acute pancreatitis.
During treatment it is necessary to take into account the possible distortion of the results of urinalysis in diabetes mellitus (due to an increase in the content of ketone bodies), thyroid function indices.
With the development of any acute serious side effects, it is necessary to immediately discuss with the doctor the advisability of continuing or discontinuing treatment.
To reduce the risk of developing dyspeptic disorders, it is possible to take antispasmodics and enveloping agents.
A sharp discontinuation of the use of Convulex can lead to an increase in epileptic seizures.
Impact on the ability to drive vehicles and manage mechanisms
During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.
OVERDOSE
Symptoms: nausea, vomiting, dizziness, diarrhea, impaired breathing function, muscle hypotension, hyporeflexia, miosis, coma.
Treatment: gastric lavage (not later than 10-12 hours) followed by the appointment of activated charcoal, hemodialysis. Forced diuresis, maintenance of function.
DRUG INTERACTION
Contraindications
Mefloquine: risk of epileptic seizures due to increased metabolism of valproic acid and a decrease in its plasma concentration and, on the other hand, a convulsant effect of mefloquine.
St. John's wort: the risk of a decrease in the concentration of valproic acid in the blood plasma.
Unrecommended combinations
Lamotrigine: an increased risk of severe skin reactions (toxic epidermal necrolysis). Valproic acid inhibits microsomal liver enzymes that provide lamotrigine metabolism, which slows down its T 1/2 to 70 hours in adults and up to 45-55 hours in children and increases the concentration in the blood plasma. If a combination is necessary, careful clinical and laboratory testing is required.
Combinations that require special precautions
Carbamazepine: valproic acid increases the concentration of the active metabolite of carbamazepine in plasma to signs of overdose. In addition, carbamazepine increases the hepatic metabolism of valproic acid and reduces its concentration. These circumstances require medical attention and determination of drug concentrations in plasma and possible revision of their doses.
Phenobarbital, primidone: valproic acid increases the concentration of phenobarbital or primidone plasma to signs of overdose, mostly in children. In turn, phenobarbital or primidone enhance hepatic metabolism of valproic acid and reduces its concentration. Recommended clinical observation during the first 2 weeks of combined treatment with immediate reduction of the dose of phenobarbital or primidone when the signs of sedation, anticonvulsant determination level in the blood.
phenytoin:to changes in the plasma concentration of phenytoin, phenytoin increases hepatic metabolism of valproic acid and reduces its concentration. It recommended clinical observation, to determine the level of anticonvulsants in the blood, changing the dosage if necessary.
Clonazepam: adding valproic acid to clonazepam in rare cases can lead to increased severity of absence status.
Ethosuximide: valproic acid can either increase or reduce the concentration of serum ethosuximide due to changes in its metabolism. It recommended clinical observation, to determine the level of anticonvulsants in the blood, changing the dosage if necessary.
Topiramate: increased risk of hyperammonemia and encephalopathy.
felbamate:increasing valproic acid plasma concentration by 35-50%, with the danger of overdose. Recommended clinical observation, determination of valproic acid in blood, changes of valproic acid in combination with a dosage felbamate and after cancellation.
Neuroleptics, MAO inhibitors, antidepressants, benzodiazepines: antipsychotics, tricyclic antidepressants, MAO inhibitors, lowering seizure threshold, reduce the effectiveness of the drug. In turn, valproic acid potentiates the psychotropic effects of these drugs, and benzodiazepines.
Cimetidine, erythromycin: inhibit hepatic metabolism of valproic acid and increase its concentration in plasma.
zidovudine:valproic acid increases the concentration of AZT in the plasma, which leads to an increase its toxicity.
Carbapenems, monobactams: meropenem, panipenem, and aztreonam and imipenem reduce the concentration of valproic acid in plasma, which could lead to a decrease in the anticonvulsant effect.
Combinations to be taken into account
Acetylsalicylic acid: amplification of valproic acid due to the displacement effects of its association with plasma proteins. Valproic acid enhances the effect of acetylsalicylic acid.
Indirect anticoagulants: valproic acid increases the effect of anticoagulants, should be carefully monitored prothrombin index with a joint appointment with the vitamin K-dependent anticoagulant.
nimodipine:nimodipine amplification hypotensive effect due to the increase of its concentration in plasma due to suppression of its metabolism valproic acid.
Myelotoxicity drugs: increased risk of suppression of bone marrow hematopoiesis.
Ethanol and hepatotoxic drugs: increase the likelihood of developing liver disease.
Other combination
oral contraceptives: valproic acid causes no induction of liver microsomal enzymes, and does not reduce the effectiveness of oral hormonal contraception.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 5 years.
