Composition, form of production and packaging
The syrup for children is colorless or slightly yellowish, with peach flavor and sweet peach taste.
1 ml
sodium valproate 50 mg
Excipients: sodium hydroxide, lycasin 80/55, sodium saccharin, sodium cyclamate, methylhydroxybenzoate, propylhydroxybenzoate, sodium chloride, flavoring raspberries (9/372710) and peach (9/030307), purified water.
100 ml - bottles of dark glass (1) complete with a measuring syringe - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Antiepileptic drug, which has central muscle relaxant and sedative effect. It shows antiepileptic activity in various types of epilepsy.
The main mechanism of action, apparently, is associated with the influence of valproic acid on the GABAergic system: the drug increases the content of gamma-aminobutyric acid (GABA) in the central nervous system (CNS) and activates GABA-ergic transmission. Therapeutic efficacy begins with a minimum concentration of 40-50 mg / l and can reach 100 mg / l. At a concentration of more than 200 mg / l, a dose reduction is necessary.
PHARMACOKINETICS
Bioavailability of the drug is about 100%. Valproic acid penetrates into the cerebrospinal fluid and through the blood-brain barrier. T 1/2 is 15-17 hours. Equilibrium concentration in the plasma is achieved after 3-4 days of admission.
The connection with plasma proteins is high (90-95%), dose-dependent and saturable. It is excreted mostly with urine in the form of glucuronide. Valproic acid is not an inducer of the enzymes of the cytochrome P450 metabolic system. Unlike most other antiepileptic drugs, it does not affect the degree of both its own biotransformation, and the biotransformation of other substances, such as estrogens, progestogens and vitamin K antagonists.
INDICATIONS
In adults, as a monotherapy or in combination with other antiepileptic drugs:
- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic); the Lennox-Gastaut syndrome;
- treatment of partial epileptic seizures (partial seizures with or without secondary generalization);
- treatment and prevention of bipolar affective disorders.
In children as monotherapy or in combination with other antiepileptic drugs:
- treatment of generalized epileptic seizures (clonic, tonic, tonic-clonic, absences, myoclonic, atonic); the Lennox-Gastaut syndrome;
- treatment of partial epileptic seizures (partial seizures with or without secondary generalization).
DOSING MODE
The dosage regimen is selected individually depending on the age and body weight of the patient.
The initial daily intake for adults and children weighing more than 25 kg is usually 10-15 mg / kg. Then the dose is gradually increased by 5-10 mg / kg per week until the optimal effect is achieved. The average daily dose of 30 mg / kg body weight can be increased under the control of the concentration of the drug in blood plasma to 60 mg / kg.
The dose of the drug is calculated in milligrams (1 ml of the drug contains 40 mg of valproic acid). Take with food.
The daily dose is recommended to be divided into 2-3 doses.
Solution for ingestion is issued in a vial with a measuring cap. Use the drug with a measuring cap.
SIDE EFFECT
From the side of the central nervous system: ataxia; cases of cognitive impairment with a progressive offensive up to the development of a complete picture of dementia syndrome (reversible within a few weeks or months after discontinuation of the drug); a state of confusion or convulsions; stupor or lethargy, sometimes leading to a transient coma (encephalopathy); reversible parkinsonism; headache, dizziness, slight postural tremor and drowsiness, changes in behavior, mood or mental state (depression, fatigue, hallucinations, aggressiveness, hyperactive state, psychoses, unusual arousal, motor anxiety or irritability), dysarthria.
On the part of the digestive system: often at the beginning of treatment - gastrointestinal disorders (nausea, vomiting, gastralgia, decreased appetite or increased appetite, diarrhea), which usually occur for several days without drug withdrawal; abnormal liver function; pancreatitis, up to severe lesions with a fatal outcome (in the first 6 months of treatment, more often at 2-12 weeks).
On the part of the organs of hematopoiesis and the system of hemostasis: oppression of bone marrow hematopoiesis (anemia, leukopenia or pancreatinia);thrombocytopenia, decreased fibrinogen and platelet aggregation, leading to the development of hypocoagulation (accompanied by prolonged bleeding time, petechial hemorrhages, bruising, bruising, bleeding, etc.).
On the part of the urinary system: enuresis; cases of reversible Fanconi syndrome (unclear genesis).
On the part of the endocrine system: dysmenorrhea, secondary amenorrhea, enlargement of the mammary glands, galactorrhea.
Allergic reactions: skin rash, hives, vasculitis; angioedema, photosensitization, cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, multiform erythema.
Laboratory indicators: isolated and moderate hyperammonemia without changes in liver function tests, especially with polytherapy (drug cancellation is not required); Possible hyperammonemia associated with neurologic symptoms (further examination is required); may increase the activity of "liver" transaminases;decreased fibrinogen content or increased bleeding time, usually without clinical symptoms and especially at high doses (valproic acid has an inhibitory effect on the second stage of platelet aggregation); hyponatremia.
Other: teratogenic risk; diplopia, nystagmus, flashing of "flies" before the eyes, alopecia; reversible or irreversible hearing loss; peripheral edema; increase in body weight; violation of the menstrual cycle, amenorrhea, impairment of the immune system.
CONTRAINDICATIONS
Hypersensitivity to valproic acid or other components of the drug; acute hepatitis; chronic hepatitis; liver disease in history, porphyria; combination with mefloquine;combination with St. John's wort; It is not recommended to use in combination with lamotrigine.
Carefully. Oppression of bone marrow hemopoiesis (leukopenia, thrombocytopenia, anemia), organic brain diseases, liver and pancreatic disease in history;hypoproteinemia, mental retardation in children, congenital fermentopathy, renal failure.
PREGNANCY AND LACTATION
In animal studies, a teratogenic effect is shown.
According to available data, in humans, valproic acid mainly causes disruption of the development of the neural tube: myelomeningocele, spina bifida (1-2%). Cases of facial dysmorphia and developmental limb development abnormalities (especially limb shortening), as well as developmental defects of the cardiovascular system are described.
The risk of malformations is higher with combined antiepileptic therapy than with monotherapy with valproic acid.
In view of the foregoing, during pregnancy, the use of the drug is only possible if the intended benefit to the mother exceeds the potential risk to the fetus. During pregnancy, antiepileptic treatment with valproic acid should not be interrupted if it is effective. In such cases, monotherapy is recommended; The minimum effective daily dose should be divided into two doses.
In addition to anti-epileptic therapy, folic acid preparations (at a dose of 5 mg / day) can be added, they minimize the risk of developing neural tube defects.
Valproic acid can cause hemorrhagic syndrome in newborns, which, apparently, is associated with hypofibrinogenemia. There have been cases of development of fetal affinity with lethal outcome. Perhaps this is due to a decrease in a number of clotting factors.
The newborn is required to determine the number of platelets, the level of fibrinogen in the plasma and the factors of blood coagulation.
Valproic acid is excreted in breast milk in concentrations from 1% to 10%. It is recommended to stop breastfeeding while taking the drug.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution: kidney failure. When using Valparin В® in patients with renal insufficiency, it is recommended to take into account the increased concentration of free form of valproic acid in the blood plasma and to reduce the dose.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated: acute hepatitis; chronic hepatitis; liver disease in anamnesis.
Prior to treatment and during the first 6 months of therapy, periodic monitoring of liver function is necessary, especially in patients at risk.
Among the classic tests, the tests reflecting protein synthesis in the liver and especially the prothrombin index are most important. With a significant decrease in the concentration of prothrombin, a pronounced decrease in fibrinogen content, clotting factors, increased bilirubin concentration and transaminase activity, treatment with ValparinВ® should be stopped.
The risk of developing side effects from the liver is increased when combined anticonvulsant therapy, as well as in children.
Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk:
- nonspecific common symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;
- relapse of epileptic seizures on the background of antiepileptic therapy.
It is necessary to warn the patient, and if it is a child, then his family, the need to immediately notify the doctor about the occurrence of these symptoms. In addition to clinical examination in such cases, an analysis of liver function should be performed immediately.
APPLICATION FOR CHILDREN
The risk of developing side effects from the liver in children is increased.
SPECIAL INSTRUCTIONS
Prior to treatment and during the first 6 months of therapy, periodic monitoring of liver function is necessary, especially in patients at risk.
Among the classic tests, the tests reflecting protein synthesis in the liver and especially the prothrombin index are most important. With a significant decrease in the concentration of prothrombin, a pronounced decrease in fibrinogen content, clotting factors, increased bilirubin concentration and transaminase activity, treatment with ValparinВ® should be stopped. If the patient receives salicylates concurrently, they should also be immediately withdrawn, since salicylates and valproic acid share common metabolic pathways.
The risk of developing side effects from the liver is increased when combined anticonvulsant therapy, as well as in children.
Early diagnosis is based primarily on clinical examination. In particular, two factors that may precede jaundice should be taken into account, especially in patients at risk:
- nonspecific common symptoms, usually appearing suddenly, such as asthenia, anorexia, extreme fatigue, drowsiness, sometimes accompanied by repeated vomiting and abdominal pain;
- relapse of epileptic seizures on the background of antiepileptic therapy.
It is necessary to warn the patient, and if it is a child, then his family, the need to immediately notify the doctor about the occurrence of these symptoms. In addition to clinical examination in such cases, an analysis of liver function should be performed immediately.
In rare cases, severe forms of pancreatitis, sometimes with a fatal outcome. These cases were observed irrespective of the patient's age and duration of treatment, although the risk of developing pancreatitis decreased with increasing age of the patients. Lack of liver function in pancreatitis increases the risk of death.
It should be emphasized that in the treatment of both ValparinВ® and other antiepileptic drugs, there may be a small, isolated and temporary increase in hepatic transaminase activity, especially at the beginning of treatment, in the absence of any clinical symptoms. In this case, a more complete examination (including, in particular, the determination of the prothrombin index) is recommended so that, if necessary, the dose should be reviewed and the analyzes repeated, depending on the changes in the parameters.
Before the beginning of therapy, before surgery, with the appearance of bruising or spontaneous bleeding, a general blood test (including determination of the number of platelets, bleeding time and coagulogram parameters) is necessary.
If the symptomatology of the "acute" abdomen and such gastrointestinal symptoms as nausea, vomiting and / or anorexia occur against the background of treatment, it is necessary to determine the activity of amylase in the blood to exclude acute pancreatitis. With increased activity of pancreatic enzymes, the drug should be withdrawn, taking alternative therapeutic measures.
When using Valparin В® in patients with renal insufficiency, it is recommended to take into account the increased concentration of free form of valproic acid in the blood plasma and to reduce the dose.
If it is necessary to prescribe the drug to patients with systemic lupus erythematosus and other diseases of the immune system, the expected therapeutic effect and possible risk of therapy should be evaluated, since with the use of Valparin В® in extremely rare cases, violations from the immune system were noted.
It is not recommended to prescribe the drug to patients with a deficiency of urea enzymes. In such patients, several cases of hyperammonemia accompanied by a stupor and / or coma have been described.
During the treatment, drinks containing ethanol are not allowed.
Patients should be warned about the risk of weight gain at the beginning of treatment and recommend compliance with the diet to minimize such effects.
Impact on the ability to drive vehicles and manage mechanisms. During the treatment period, patients should be careful when driving vehicles and other activities that require high concentration and speed of psychomotor reactions.
OVERDOSE
Symptoms: nausea, vomiting, dizziness, diarrhea, impaired breathing function, muscle hypotension, hyporeflexia, miosis, coma with muscle hypotension, hyporeflexia, miosis, respiratory depression, metabolic acidosis; cases of intracranial hypertension associated with cerebral edema are described.
Treatment: in the hospital - gastric lavage, if after taking the drug has passed no more than 10-12 hours; monitoring the state of the cardiovascular and respiratory systems and maintaining an effective diuresis. In very severe cases, dialysis is performed. As a rule, the prognosis is favorable, however, several cases of lethal outcome have been described.
DRUG INTERACTION
Contraindicated combinations
Mefloquine: risk of epileptic seizures in patients with epilepsy due to increased metabolism of valproic acid and a convulsant effect of mefloquine.
Hypericum perforated: 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 until the development of toxic epidermal necrolysis. In addition, an increase in the concentration of lamotrigine in plasma (its metabolism in the liver is slowed down by valproic acid). If a combination is necessary, careful clinical and laboratory testing is required.
Combinations requiring special precautions
Carbamazepine: an increase in the concentration of the active metabolite of carbamazepine in plasma with signs of overdose. In addition, a decrease in the concentration of valproic acid in plasma, associated with increased metabolism of valproic acid in the liver under the influence of carbamazepine. Recommended: clinical observation, determination of plasma concentrations of drugs and, possibly, correction of their dose, especially at the beginning of treatment.
Carbapenems, monobactams: meropenem, panipenem, and, by extrapolation, aztreonam and imipenem: an increased risk of seizures due to a decrease in the concentration of valproic acid in the blood plasma. It is recommended: clinical observation, determination of plasma drug concentrations, valproic acid dose adjustment may be required during treatment with an antibacterial agent and after its withdrawal.
Felbamate: an increase in the concentration of valproic acid in the blood plasma with a risk of overdose. Recommended: clinical and laboratory monitoring and, possibly, a review of the dose of valproic acid during treatment with felbamate and after its cancellation).
Phenobarbital, primidon: increasing the concentration of phenobarbital and primidone in the plasma with signs of their overdose, usually in children. In addition, a decrease in the concentration of valproic acid in the plasma, associated with an increase in its hepatic metabolism under the influence of phenobarbital or primidone.Recommended: clinical monitoring for the first 15 days of combined treatment with immediate reduction in dose of phenobarbital or primidone at the first signs of sedation determining concentrations of both anticonvulsants blood.
Phenytoin: change in the concentration of phenytoin in plasma, reduce the danger of valproic acid concentrations associated with increased valproic acid metabolism in the liver under the influence of phenytoin. Recommended: clinical monitoring with the determination both of concentrations of antiepileptic drugs in plasma, and if necessary - correction of their doses.
Topiramate: the risk of hyperammonemia or encephalopathy. Recommended: clinical and laboratory monitoring during the first month of treatment, and in case of ammoniemii symptoms.
Neuroleptics, inhibitors of monoamine oxidase (MAO), antidepressants, benzodiazepines: Valproic acid potentiates the action of psychotropic drugs such as antipsychotics, MAO inhibitors, antidepressants, benzodiazepines. Recommended: clinical monitoring and, if necessary, correction of the dose.
Erythromycin and cimetidine: increases valproic acid concentration in plasma.
Zidovudine: valproic acid can increase the concentration of AZT in the plasma, which leads to an increase of toxicity of zidovudine.
Combinations to be taken into consideration
Nimodipine (oral and, by extrapolation, parenterally)nimodipine amplification hypotensive effect due to a reduction of its metabolism under the influence of valproic acid and increase in plasma concentration.
Acetylsalicylic acid: amplification effects of valproic acid due to increase of its concentration in plasma.
While the use of vitamin K antagonists anticoagulants requires careful monitoring of the prothrombin index.
Other forms of interaction
of valproic acid has no effect-inducing enzyme, and therefore does not affect the effectiveness of hormonal contraceptives containing a combination of estrogen and progesterone.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Store at a temperature not higher than 30 В° C, protected from light. Keep out of the reach of children.
Shelf life. 2 years. Do not use after the time specified on the package.
