Pharmacological properties of the drug Convulex injection solution
Pharmacodynamics. Sodium valproate increases the content of GABA in the brain, which correspondingly leads to an increase in the content of GABA in postsynaptic neurons. In addition, sodium valproate affects the transport of potassium ions across neuronal membranes. The result of this influence is the suppression of the occurrence and spread of epileptic excitation along neurons. Sodium valproate has anticonvulsant activity in various types of epilepsy. The drug does not have a pronounced hypnotic or sedative effect, as well as a depressant effect on the respiratory center. Does not have a negative effect on blood pressure, heart rate, kidney function and body temperature. Pharmacokinetics. With intravenous administration, the therapeutic concentration of the drug in the blood serum is achieved in the first minutes; if necessary, it can be maintained at the required level using infusion. Approximately 90–95% of valproic acid is bound to plasma proteins, predominantly albumin; the degree of binding decreases when administered at higher doses. In elderly patients and in patients with liver or kidney failure, the degree of binding of the drug to plasma proteins is much lower. Biotransformation occurs through glucuronidation and beta, omega and omega-1 oxidation. Approximately 20% of the dose is excreted by the kidneys as a glucuronide ester, ≤5% is excreted unchanged in the urine.
CONVULEX ORAL DROPS 300MG/ML 100ML COMPLETE WITH DISPENSER
Contraindicated combinations
:
— mefloquine
- the 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 convulsant effect of mefloquine,
— St. John's wort
- the risk of a decrease in 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 the concentration in the blood plasma. If the combination is necessary, careful clinical and laboratory monitoring is required.
Combinations requiring special precautions
:
- carbamazepine
- valproic acid increases the concentration of the active metabolite of carbamazepine in plasma to 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 dosages,
— phenobarbital, primidone
- valproic acid increases the concentration of phenobarbital or primidone in plasma to 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 combination treatment with immediate reduction of the dose of phenobarbital or primidone if signs of sedation appear, 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 can lead to increased severity of absence status,
— ethosuximide
- valproic acid can both increase and decrease the concentration of ethosuximide in the blood serum due to changes in its metabolism. Clinical observation is recommended, determining the level of anticonvulsants in the blood, changing dosages if necessary,
— topiramate
- the risk of developing hyperammonemia and encephalopathy increases,
— felbamate
- an increase in the concentration of valproic acid in plasma by 35-50%, with the risk of overdose. Clinical observation is recommended, determining the level of valproic acid in the blood, changing the dosage of valproic acid when combined with felbamate and after its discontinuation,
— neuroleptics, monoamine oxidase inhibitors (MAOIs), antidepressants, benzodiazepines
- neuroleptics, tricyclic antidepressants, MAO inhibitors, which reduce the threshold for 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
- suppress the hepatic metabolism of valproic acid and increase its concentration in plasma,
— zidovudine
- valproic acid increases the concentration of zidovudine in plasma, which leads to increased toxicity,
— carbapenems, monobactams
- meropenem, panipem, as well as azeonam and imipenem reduce the concentration of valproic acid in plasma, which can 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 co-administered 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 microsomal liver enzymes and does not reduce the effectiveness of hormonal oral contraceptives.
Use of the drug Convulex solution for injection
The daily dose of the drug is selected individually, taking into account age, body weight and sensitivity to sodium valproate. If there is no significant correlation between the daily dose, serum concentration and therapeutic effect, the optimal dose should be adjusted based on the clinical effect. If an adequate therapeutic effect cannot be achieved or side effects of therapy occur, the level of valproate in the blood plasma should be determined and clinical indicators monitored. The effective concentration in blood plasma ranges from 40 to 100 mg/l (300–700 µmol/l). The dose for slow intravenous administration is 5–10 mg/kg body weight. In middle-aged patients weighing 65 kg, this is approximately 500 mg of sodium valproate, or the contents of 1 ampoule. If there is a need to use the drug in the form of an intravenous infusion, the recommended rate of administration is 0.5–1 mg/kg/h. In cases where it is necessary to quickly achieve and maintain a high concentration of the drug in the blood plasma, the following administration regimen is recommended: intravenous administration of sodium valproate at a dose of 15 mg/kg over 5 minutes, after 30 minutes begin an infusion of sodium valproate at a rate of 1 mg/kg. kg/h under the control of plasma concentration (to achieve a level of 75 mcg/ml). For proper dose selection, the clinical condition of the patient should be taken into account. If repeated injection or infusion of sodium valproate is necessary, the maximum daily dose should not exceed 2500 mg. Children, including infants over 2 months of age, should first be prescribed the drug orally (usually at a dose of 20–30 mg/kg/day), and then given intravenous injections or infusion at a rate of 0.8–1.35 mg/day. kg/h. If it is necessary to transfer the patient from oral to injection or infusion administration of the drug, the dose ratio should be 1:1. IV administration should begin 12 hours after the last oral dose. The maximum daily dose for intravenous administration is 2500 mg. Recommended average daily doses of sodium valproate: • for middle-aged and elderly people - 20 mg/kg; • for adolescents - 25 mg/kg; • for children - 30 mg/kg. The solution for infusion is prepared at the rate of: the contents of 1 ampoule (500 mg of sodium valproate) per 500 ml of infusion solution. The prepared solution is administered at a rate of 1 ml/kg/h. To prepare an infusion solution of sodium valproate, it is necessary to use the following solutions: isotonic solution of sodium chloride; 5% glucose solution; Lactated Ringer's solution. The injection solution should be administered slowly (over approximately 3–5 minutes), IV only, or used as an infusion (to continue therapy or for repeated administration). Cannot be administered simultaneously with other solutions for intravenous administration. Only transparent, colorless or slightly yellowish solution is suitable for use.
Side effects of the drug Convulex injection solution
From the blood system: rarely - thrombocytopenia (especially in children), leukopenia, decreased blood clotting, which is accompanied by an increase in bleeding time, petechial hemorrhages, hematomas, bleeding, hypofibrinogenemia, eosinophilia, anemia. From the nervous system and sensory organs: possible headache, drowsiness, paresthesia, impaired consciousness, stupor, depression, feeling of fatigue, weakness, aggressive behavior, tremor, rarely - muscle spasms and ataxia, increased irritability, hyperactivity, hallucinations, tinnitus , encephalopathy. From the urinary system: enuresis. From the gastrointestinal tract: depending on the dose, there may be an increase or decrease in body weight, increased appetite or anorexia, nausea, vomiting, pain in the epigastric region, diarrhea and other dyspeptic disorders, impaired liver function (increased levels of liver transminases and bilirubin levels in the blood serum) and pancreas, pancreatitis. From the skin: photosensitivity, alopecia. Allergic reactions: skin rash, angioedema, necrotizing skin lesions with a fatal outcome (in older children when used for 6 months). Laboratory values: Possible increases in testosterone levels have been reported very rarely. Other: rarely - nonspecific pain and enuresis, mainly in children, the possibility of polycystic ovary syndrome. In addition, amenorrhea and other menstrual irregularities are possible. There are isolated reports of the development of Fanconi syndrome (metabolic acidosis, phosphaturia, aminoaciduria, glycosuria), which resolves after discontinuation of sodium valproate. When using sodium valproate in the form of an injection solution, transient nausea and drowsiness may occur immediately after administration of the drug.
Special instructions for the use of the drug Convulex solution for injection
When using sodium valproate, the level of transaminases, bilirubin, amylases and platelet counts in the blood should be regularly monitored (every 3 months). The drug inhibits platelet aggregation, which can cause prolongation of blood clotting time during bleeding. The possibility of developing hemorrhagic complications in the postoperative period in patients using sodium valproate should be taken into account. With prolonged use of the drug, the development of hematomas and bleeding is possible. In such cases, the drug should be discontinued immediately. Sodium valproate can cause the development of drug-induced pancreatitis and liver dysfunction (especially in the first 6 months of use), therefore, during this period it is necessary to regularly monitor the functional state of the pancreas and liver, and prothrombin levels. Impaired liver function and liver failure during therapy with sodium valproate sometimes develops in children with epilepsy and concomitant metabolic and degenerative diseases, organic brain pathology and delayed mental development. Treatment with sodium valproate should be stopped by gradually reducing the dose, monitoring the EEG, the parameters of which should not deteriorate. When reducing the dose of the drug in children, body weight and age characteristics should be taken into account. Prescribing the drug during pregnancy is possible only if the potential benefit to the mother outweighs the potential risk to the fetus. During pregnancy, the use of sodium valproate should not be interrupted without clear medical indications, since sudden cessation of use or a sharp reduction in the dose of the drug can cause epileptic seizures in a pregnant woman, which can cause significant harm to the mother and fetus. Women of childbearing potential should be informed of the need to use contraceptive measures before initiating valproate therapy. There are reports of the development of hemorrhagic syndrome in newborns whose mothers took valproate during pregnancy. The development of the syndrome is associated with hypofibrinogenemia, which can lead to decreased blood clotting. This syndrome should be differentiated from folic acid deficiency. It is necessary to monitor the platelet index, fibrinogen levels and blood coagulation factors in newborns whose mothers took the drug. Valproate crosses the placental barrier and reaches higher concentrations in fetal blood than in maternal blood. Sodium valproate is excreted into breast milk. At dynamic equilibrium, the concentration of valproate in breast milk is approximately 10% of the serum concentration. It is recommended to discontinue breast-feeding while using sodium valproate. Sodium valproate should be used with caution in children requiring additional antiepileptic drugs; in children and adolescents with concomitant diseases and mental disorders; with bone marrow damage; for enzymopathy: for hypoproteinemia; with systemic lupus erythematosus. Sodium valproate weakens attention and has a slight sedative effect, so you should be careful when working with machinery and refrain from driving during treatment.
Convulex 500 mg No. 100 caps. solution/intestinal
Instructions for medical use of the drug Convulex® Trade name Convulex® International nonproprietary name Valproic acid Dosage form Delayed-release capsules 150 mg, 300 mg, 500 mg Composition One capsule contains the active substance - valproic acid 150, 300 or 500 mg, composition of the capsule shell : hydrogenated hydrolyzed starch (Karion 83), glycerin (glycerol) 85%, gelatin, titanium dioxide (E171), iron oxide red (E172), hydrochloric acid 25%, enteric coating: 30% dispersion of methacrylic acid-ethyl acrylate copolymer ( 1:1) (Eudragit L30D), triethyl citrate, macrogol 6000, glycerol monostearate 44-55 type II, Description Soft gelatin capsules of oval shape, pink color, size 3, length about 9.8 mm and diameter about 7.3 mm (for a dosage of 150 mg). Soft gelatin capsules are oval-shaped, pink, size 6, approximately 13.5 mm long and approximately 8.1 mm in diameter (for a dosage of 300 mg). Soft gelatin capsules are oblong in shape, size 9.5, length about 21.1 mm and diameter about 7.8 mm (for a dosage of 500 mg). The contents of the capsules are a colorless to slightly yellowish liquid with a weak characteristic odor. Pharmacotherapeutic group Antiepileptic drugs. Fatty acid derivatives. Valproic acid. ATC code N03AG01 Pharmacological properties Pharmacokinetics Enteric-coated capsules release the active substance only in the small intestine, where it is absorbed. Valproic acid is quickly and almost completely absorbed from the gastrointestinal tract, bioavailability when taken orally is 100%. Eating does not reduce the rate of absorption. The maximum level of concentration in plasma is observed after 2-3 hours. Equilibrium concentration is achieved on the 2-4th day of treatment, depending on the dosing intervals. The therapeutic concentration of the drug in blood plasma ranges from 40-100 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 concentrations of 50-100 mg/l; with uremia, hypoproteinemia and cirrhosis, protein binding is reduced. The level of concentration in the cerebrospinal fluid correlates with the size of the non-protein-bound fraction of the drug. 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 blood plasma. The drug undergoes glucuronidation and oxidation in the liver, metabolites and unchanged valproic acid (1-3% of the dose) are excreted by the kidneys, small amounts are excreted in feces and exhaled air. The elimination period of the drug is from 10 to 15 hours in healthy people and with monotherapy, in children it is shorter than 6-10 hours, in patients with impaired liver function and elderly patients it can be much longer. Pharmacodynamics Konvulex is an antiepileptic drug that also has a central muscle relaxant and sedative effect. The mechanism of action is primarily due to inhibition of the GABA transferase enzyme and an increase in the content of gamma-aminobutyric acid in the central nervous system. Gamma-aminobutyric acid inhibits pre- and postsynaptic discharges and thereby prevents the spread of seizure activity in the central nervous system. In addition, in the mechanism of action of the drug, a significant role is played by the effect of valproic acid on gamma-aminobutyric acid A receptors, as well as the effect on voltage-dependent Na channels. Acts on areas of postsynaptic receptors, simulating or enhancing the inhibitory effect of gamma-aminobutyric acid. A possible direct effect on membrane activity is associated with changes in potassium conductance. Improves the mental state and mood of patients, has antiarrhythmic activity. Indications for use - epileptic seizures (including generalized and partial, as well as against the background of organic brain diseases) - prevention of migraine attacks - manic-depressive syndrome with bipolar course, when lithium is contraindicated or not tolerated by the patient. Method of administration and dosage The drug is taken orally, without chewing, 1 – 2 times a day, during or after meals, with a small amount of liquid. The duration of use is determined by the doctor. Adults The initial dose for monotherapy is 5-15 mg/kg/day, for combination therapy - 10-30 mg/kg/day, then this dose is gradually increased by 5-10 mg/kg/week. The average daily dose is 20-30 mg/kg body weight. The daily dose can be increased to 60 mg/kg if it is possible to monitor the concentration of the drug in the blood plasma. For use in children under 6 years of age, the following forms of the drug Convulex are recommended: drops for oral administration and syrup for children. The dosage for children 6 years of age and older is 10-20 mg/kg with a gradual increase to 20-35 mg/kg per day. In children requiring doses greater than 40 mg/kg per day, biochemical and hematological parameters should be monitored. Elderly Although the pharmacokinetics of valproate in the elderly is different, it is of limited clinical significance and the dose 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. Patients with renal failure It may be necessary to reduce the dose of the drug. The dose should be selected based on monitoring of the clinical condition, since plasma concentrations may not be sufficiently informative. Average daily doses: Age Body weight (kg) Average dose mg/day 6 years 15-20 kg 450-600 7-11 years 20-40 kg 600-1200 12-17 years 40-60 kg 1000-1500 Adults and elderly More 60 kg 1200-2100 Side effects Convulex is well tolerated by patients. Side effects are possible mainly when the drug level in plasma is above 100 mg/l or with combination therapy. Often (from ³1/100 to <1/10 cases) - nausea, vomiting, anorexia or increased appetite, diarrhea, gastralgia, hepatitis - tremor - diplopia, flashing "floaters" before the eyes - anemia, thrombocytopenia, decreased fibrinogen content, platelet aggregation and blood clotting, accompanied by prolongation of bleeding time, petechial hemorrhages, bruises, hematomas, bleeding, agranulocytosis, lymphocytosis - decrease or increase in body weight - hypercreatininemia, hyperammonemia, hyperglycinemia, hyperbilirubinemia, slight increase in the activity of "liver" transaminases, LDH (dose-dependent) - dysmenorrhea , secondary amenorrhea, enlarged mammary glands, galactorrhea - peripheral edema, hair loss (usually restored after discontinuation of the drug) - vasculitis - hearing loss, paresthesia - polycystic ovary syndrome - enuresis in children Rare (from ³1/10,000 to <1/1,000 cases ) - constipation - 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, stupor, impaired consciousness, coma - leukopenia, pancytopenia, lymphocytosis, erythrocyte hypoplasia - liver dysfunction - systemic lupus erythematosus - lethargy, confusion - headache, nystagmus - skin rash, urticaria, angioedema, photosensitivity Very rare (<1/10,000 cases) - encephalopathy, coma - pancreatitis, up to severe injuries with a fatal outcome (in the first 6 months of treatment, more often for 2-12 weeks) - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme - reversible Fanconi syndrome - bone marrow aplasia - hyponatremia - impaired renal function Contraindications - hypersensitivity to valproate or any of the excipients - severe dysfunction of the liver and/or pancreas - hepatic porphyria - acute and chronic hepatitis - a case of severe hepatitis in the patient’s personal or family history, including those associated with taking medications - thrombocytopenia - hemorrhagic diathesis - combined use with carbapenems - combined use with St. John's wort - combined use with mefloquine - pregnancy and lactation - children under 6 years of age - children under 18 years of age with manic-depressive syndrome with bipolar course Drug interactions With simultaneous use valproic acid with ethanol and other drugs that depress the central nervous system (tricyclic antidepressants, monoamine oxidase inhibitors and antipsychotics), may increase CNS depression. Ethanol and other hepatotoxic drugs increase the likelihood of developing liver damage. Tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), antipsychotics and other drugs that lower the seizure threshold reduce the effectiveness of valproic acid. Convulex, depending on its concentration in plasma, can displace thyroid hormones from their binding sites to plasma protein and cause their metabolism, which can lead to a false diagnosis indicating hypothyroidism. Convulex enhances the effects, incl. side effects, other antiepileptic drugs (phenytoin, lamotrigine), antidepressants, antipsychotics, tranquilizers, barbiturates, MAO inhibitors, thymoleptics, ethanol. The addition of valproate to clonazepam in isolated cases can lead to increased severity of absence status. With the simultaneous use of valproic acid with barbiturates or primidone, an increase in their concentration in the blood plasma is observed. Increases the half-life (T1/2) of lamotrigine (inhibits liver enzymes, causes a slowdown in the metabolism of lamotrigine, as a result of which T1/2 is extended to 70 hours in adults and to 45-55 hours in children). Reduces the clearance of zidovudine by 38%, while its T1/2 does not change. Konvulex increases the toxic effect of zidovudine. When combined with salicylates, an increase in the effects of valproic acid is observed (displacement from plasma proteins). Concomitant use should be avoided, especially in children under 12 years of age. Konvulex enhances the effect of antiplatelet agents (acetylsalicylic acid) and indirect anticoagulants. When combined with phenobarbital, phenytoin, carbamazepine, mefloquine, the content of valproic acid in the blood serum decreases (acceleration of metabolism). Felbamate increases the concentration of valproic acid in plasma by 35-50% (dose adjustment is necessary). Cholestyramine may reduce the absorption of valproic acid. Rifampicin may reduce the level of valproic acid in the blood, which may lead to the disappearance of the therapeutic effect. Therefore, it may be necessary to adjust the dosage of Convulex when used simultaneously with rifampicin. Valproic acid does not induce liver enzymes and does not reduce the effectiveness of oral contraceptives. Special instructions Special caution is required when prescribing Convulex to the following categories of patients: - with anamnestic data on diseases of the liver and pancreas, as well as bone marrow damage - with impaired renal function - with congenital enzymopathies - mentally retarded children - with hypoproteinemia Considering the presence of such forms of Convulex , like syrup and drops, the capsule form is not recommended for use in children under 6 years of age. For liver disorders Before starting treatment and periodically during the first six months of treatment, especially among patients at risk and those with a history of liver disease, liver function parameters should be continuously monitored. Such patients should be under close medical supervision. Liver function tests include prothrombin time, aminoferase and/or bilirubin levels, and/or fibrinogen breakdown products. At the first stage, there may be an increase in aminoferase levels; this is usually a temporary phenomenon that responds to dose reduction. Patients with abnormal biochemical tests should undergo repeat clinical evaluation and liver function (including prothrombin time) should be monitored until normal. However, an excessively prolonged prothrombin time, especially if it is associated with abnormal values of other relevant tests, requires discontinuation of treatment. Hepatic dysfunction, including liver failure leading to death, has been reported in patients treated with valproic acid. Patients most often at risk are children, especially those younger than 3 years of age, and patients with inherited metabolic or degenerative disorders, organic brain dysfunction, or severe seizures associated with mental retardation. Most of these events occurred during the first six months of therapy, predominantly at weeks 2 to 12, and typically included multidrug anticonvulsant therapy. For this group of patients, monotherapy is preferred. In the early stages of liver failure, clinical symptoms can be more helpful in correcting the diagnosis than laboratory tests. Severe or fatal liver disease may be preceded by unusual symptoms, usually of sudden onset, such as loss of seizure control, discomfort, weakness, lethargy, edema, loss of appetite, vomiting, abdominal pain, drowsiness and jaundice. They represent indications for immediate discontinuation of the drug. Patients should be instructed to immediately report any such signs to their healthcare provider for appropriate evaluation. There is still no clear evidence of which tests can be predictive, but tests that measure protein synthesis, such as prothrombin time, are still thought to be the most relevant. In patients with hepatic dysfunction, concomitant use of the salicylic acid salt should be discontinued as it may share the same metabolic pathway and thereby increase the risk of hepatic failure. For hematological disorders Before starting treatment, as well as before surgery, appropriate blood tests (red blood cell count, bleeding time and coagulation test) should be done in order to clarify whether there is an increased risk of complications such as bleeding. Patients with a history of bone marrow involvement should also be closely monitored. For pancreatic disorders In very rare cases, severe pancreatitis has been reported, which could be fatal. The risk of death is observed in young children and decreases with increasing age. Severe seizures or neurological disorders during combination anticonvulsant therapy may be risk factors for serious pancreatitis. If kidney failure occurs along with pancreatitis, the risk of death increases. Patients should be advised that they should contact their physician immediately if they develop symptoms suggestive of pancreatitis (eg, abdominal pain, nausea, vomiting). Such patients should undergo a thorough medical evaluation (including measurement of serum amylase levels); If pancreatitis is diagnosed, valproic acid should be discontinued. Patients with a history of pancreatitis should be under close clinical supervision. Weight gain Valproic acid very often causes weight gain, which can be noticeable and progressive. Patients should be advised of this risk at the start of treatment, as well as appropriate measures to minimize weight gain. Systemic lupus erythematosus Convulex may, although in rare cases, cause systemic lupus erythematosus or aggravate existing lupus erythematosus. Hyperammonemia If there is a suspicion of enzymatic deficiency of the urea cycle, metabolic studies should be carried out before starting treatment, as there is a risk of hyperammonemia with the use of valproate. In patients who develop symptoms such as apathy, somnolence, vomiting, hypotension, or an increased incidence of epileptic seizures, serum ammonia and valproate levels should be monitored. Suicide/suicidal ideation Suicidal ideation and behavior have been reported among patients receiving antiepileptic agents for some indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a slightly increased risk of suicidal ideation and behavior. The mechanism by which this risk occurs remains unknown, and available data do not exclude the possibility of an increased risk due to the use of valproic acid. Therefore, patients should be closely monitored for signs of suicidal ideation and behavior, and initiation of appropriate treatment should be considered. Patients (and caregivers) should be advised to seek immediate medical attention if suicidal ideation or behavior occurs. Diabetics Because valproate is eliminated primarily through the kidneys, it may result in false positive urine test results for possible diabetes. Epilepsy Sudden cessation of valproate may result in an increased incidence of epileptic seizures. Long -term treatment during long -term treatment carried out in combination with other antiepileptic drugs, including diphenin, can appear symptoms and signs of brain damage (encephalopathy) (increased frequency of epileptic seizures, lack of desire, stupor, muscle weakness, impaired motor functions ( Parkinsonism, dystonia, choreforming discinesia), serious changes in EEG). Pregnancy during pregnancy is not recommended to begin treatment with a convoy. If the pregnant woman already receives the drug, then due to the risk of increasing seizures, treatment should not be interrupted. The drug must be used in the smallest effective doses, avoiding a combination with other anticonvulsants and, if possible, regularly monitoring the level of the drug in plasma. Women who can get pregnant should receive an appropriate consultation from a specialist due to the presence of a risk of teratogenic effect on the fetus. -the risk associated with epilepsy and antiepileptic drugs in children born of epilepsy mothers receiving antiepileptic drugs, the total indicator of congenital malformations exceeded 2-3 times (about 3 %), which is noted in the total population. Despite the fact that during combined therapy, more children with congenital malformations were reported, the appropriate role of treatment and disease was not established in initiating the appearance of congenital malformations. Congenital defects that were found in most cases were splitting the lips and anomalies of the cardiovascular system. Epidemiological studies indicated the relationship between the intrauterine effects of valproic acid and the risk of developmental delay. Many factors, including epilepsy on the part of the mother, can contribute to this risk, while it is difficult to conduct a quantitative assessment of such relative deposits and the antiepileptic treatment of the mother. Despite the mentioned potential risks, the sudden cessation of antiepileptic treatment should be avoided, as this can cause epileptic seizures that can be dangerous for both the fetus and the mother. - risks in connection with manic episodes for bipolar disorder and valproat, this drug should not be prescribed during pregnancy and women with reproductive potential, if there is no urgent need (for example, in situations where other types of treatment are ineffective or not tolerated by patients ). During the treatment of a woman with reproductive potential, effective contraceptive agents should take. - The risks associated with the intake of Walproat notes an increased indicator of developmental malformations (including cases of facial dysmorphism, anxpadia or numerous congenital malformations, especially limbs) among children born to mothers with epilepsy that received valproat. The use of valproat is associated with defects in the nervous tube, such as the hernia of the spinal cord and cerebral membranes and the clever of the spine. The observation frequency of this type of side effects is from 1 to 2%. Among the children exposed to Walproat in the womb, the autistic spectrum disorders were also reported. Features of the influence of the drug on the ability to drive a vehicle or potentially dangerous mechanisms are not recommended to engage in activities that require increased attention and high speed of psychomotor reactions (driving vehicles and mechanism management). Overdose Symptoms: nausea, vomiting, dizziness, diarrhea, respiratory dysfunction, muscle hypotonia, hyporeflexia, miosis, coma. Treatment: gastric lavage (no later than 10-12 hours), activated carbon, nallo ovson, hemodialysis, hemoperfusion, forced diuresis, maintaining breathing and functions of the cardiovascular system. The output and packaging form of 10 or 20 capsules are placed in a contour cell package from the PVC or PVC/PVDH film and aluminum foil. 5 contour packages (No. 20) or 10 contour packages (No. 10), together with the instructions for medical use in the state and Russian languages, are placed in a pack of cardboard. Storage conditions Store at a temperature not exceeding 25°C, in a dry place, protected from light. Keep out of the reach of children! The shelf life of 5 years does not use the drug after the expiration of the shelf life. Conditions of vacation from pharmacies according to the recipe, Industriestrasse 1, A-8502 Lannach, Austria, owner of the OOO “Valeant” registration certificate, Russia address of the organization that accepts in the territory of the Republic of Kazakhstan by consumer quality of the products of the OOO Valeant in the Kazakhstan Kazakhstan, 050059,, Almaty, Al-Farabi Avenue, d. 17, business block 4B, office 1104 telephone + 7 727 3 111 516, fax +7 727 3 111 517 Email: O [Email Protected]
Interactions of the drug Convulex solution for injection
Before starting intravenous administration of sodium valproate simultaneously with other antiepileptic drugs, their plasma concentrations should be determined in order to adjust the individual dose of orally taken antiepileptic drugs. Phenobarbital, primidone, phenytoin and carbamazepine, when used simultaneously with sodium valproate, accelerate its elimination from the body and reduce its level in the blood plasma, which can lead to a decrease in the effectiveness of sodium valproate therapy. Mefloquine, when used in combination, accelerates the metabolism of sodium valproate and can cause the development of epileptic seizures. With simultaneous use of cimetidine and erythromycin, the concentration of valproate in the blood plasma may increase (due to a decrease in its metabolism in the liver). With the combined use of sodium valproate with panipenem and meropenem, the concentration of sodium valproate in the blood serum decreases, which can lead to the development of epileptic seizures. In case of simultaneous use of sodium valproate and drugs that bind to blood proteins (acetylsalicylic acid), the concentration of the free fraction of valproate in the blood serum may increase. Sodium valproate potentiates the effect of psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines; in such cases, clinical studies should be conducted to determine an adequate dose. Sodium valproate potentiates the effect of alcohol. Sodium valproate increases the concentration of phenobarbital in the blood plasma and enhances its sedative effect, mainly in children. If it is necessary to use such a combination, the level of phenobarbital in the blood plasma should be monitored. Valproate increases plasma primidone levels and potentiates the sedative effect with prolonged use. Clinical studies of patients' condition should be conducted before starting combination therapy to select an adequate dose. Sodium valproate reduces the total concentration of phenytoin in blood plasma. In addition, sodium valproate increases the free fraction of phenytoin in overdose (valproate displaces phenytoin from its binding to blood proteins and reduces its hepatic metabolism). When used simultaneously with carbamazepine, sodium valproate potentiates the toxic effect of the latter. Clinical and laboratory parameters should be monitored before and during concomitant use of carbamazepine and sodium valproate. Sodium valproate reduces the metabolism of lamotrigine and reduces its half-life. A dose reduction of lamotrigine may be necessary. Concomitant use of lamotrigine and sodium valproate may increase the risk of skin reactions (mainly in children). Valproate increases the plasma concentration of zidovudine and its toxicity.
CONVULEX drops for oral administration 300 mg/ml bottle 100 ml
Contraindicated combinations 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 convulsant effect of mefloquine. St. John's wort: risk of reducing the concentration of valproic acid in the blood plasma. Combinations not recommended 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 concentration of the active metabolite of carbamazepine in plasma to the point 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 combination 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 that should be taken into account Acetylsalicylic acid: enhanced 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 of the drug Convulex solution for injection, symptoms and treatment
If an overdose of sodium valproate is suspected, a suicide attempt should first be ruled out. At therapeutic plasma concentrations (approximately 40–100 mcg/ml), sodium valproate has no toxic effect. Very rarely, acute toxicity of sodium valproate can occur in adults and children at serum concentrations significantly higher than 100 mcg/ml. Symptoms: severe sedation, impaired balance and coordination of movements, myasthenia gravis, hyporeflexia, miosis, heart block, metabolic acidosis, coma (on the EEG - an increase in slow waves and background activity). Treatment: there is no specific antidote. Therapy should be aimed at accelerating the elimination of valproate and maintaining vital body functions. It is advisable to carry out hemodialysis and hemoperfusion, the administration of activated charcoal and intravenous administration of naloxone.
Convulex solution for intravenous administration 100 mg/ml 5 ml ampoules 5 pcs. in Moscow
Valproic acid enhances the effects, including side effects, of other antiepileptic drugs (phenytoin lamotrigine), antidepressants, antipsychotic drugs (neuroleptics), anxiolytics, barbiturates, monoamine oxidase inhibitors (MAOIs), thymoleptics, ethanol.
The addition of valproic acid to clonazepam in isolated cases can lead to increased severity of absence status.
With simultaneous use of valproic acid with barbiturates or primidone, an increase in the concentration of the latter in the blood plasma is observed.
Increases the T1/2 of lamotrigine (inhibits liver enzymes and causes a slowdown in the metabolism of lamotrigine, as a result of which its T1/2 is extended to 70 hours in adults and to 45-55 hours in children).
Reduces the clearance of zidovudine by 38% while its T1/2 does not change.
Tricyclic antidepressants, MAO inhibitors, antipsychotics (neuroleptics) and other drugs that lower the threshold for seizure activity reduce the effectiveness of the drug.
When taking the drug Convulex® simultaneously with ethanol and other drugs that depress the central nervous system (tricyclic antidepressants, MAO inhibitors, antipsychotic drugs), increased depression of the central nervous system is possible.
When combined with salicylates, an increase in the effects of valproic acid is observed (displacement from plasma proteins).
Konvulex® enhances the effect of antiplatelet agents (acetylsalicylic acid) and indirect anticoagulants.
When combined with phenobarbital, phenytoin, carbamazepine, and mefloquine, the content of valproic acid in the blood serum decreases (acceleration of metabolism).
Felbamate increases the concentration of valproic acid in plasma by 35-50% (dose adjustment is necessary).
Myelotoxic drugs - increased risk of inhibition of bone marrow hematopoiesis.
Valproic acid does not induce liver enzymes and does not reduce the effectiveness of oral contraceptives.
Ethanol and hepatotoxic drugs increase the likelihood of developing liver damage.
Valproic acid can either increase or decrease the serum concentration of ethosuximide due to changes in metabolism.
Meropenem reduces the plasma concentration of valproic acid, which may lead to a decrease in the anticonvulsant effect.
When used simultaneously with topiramate, the risk of developing hyperammonemia and encephalopathy increases.
