Valopixime - instructions for use, dose, side effects, contraindications

Excipients: ethyl cellulose 7.20 mg, hypromellose (high molecular weight) 105.60 mg, silicon dioxide colloidal aqueous 30.00 mg, sodium saccharinate (E 954) 6.00 mg, silicon dioxide colloidal anhydrous 2.4 mg;

film sheath 1: macrogol-6000 1.20 mg, hypromellose (low molecular weight) 4.20 mg, titanium dioxide (E171) 0.60 mg;

film sheath 2: methacrylic acid and ethyl acrylate copolymer (1: 1) * 4.80 mg, macrogol-6000 0.6 mg, talc 0.60 mg.

* contains 0.47% sodium lauryl sulfate and 2.3% polysorbate-80.

Description:

Oblong film-coated tablets are white with a risk on both sides.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.G.01 Valproic acid

Pharmacodynamics:

Valproic acid is an antiepileptic agent that has a central muscle relaxant and sedative effect. The mechanism of action is associated with an increase in the content of gamma-aminobutyric acid in the central nervous system (by inhibiting gamma-aminobutyric acid transaminase,as well as a decrease in the re-uptake of gamma-aminobutyric acid in the brain), resulting in reduced excitability and convulsive readiness of the motor zones of the brain. According to another hypothesis valproic acid affects the sites of postsynaptic receptors, imitating or enhancing the inhibitory effect of gamma-aminobutyric acid. A possible direct effect on membrane activity is associated with changes in conductivity for potassium.

Pharmacokinetics:

Absorption

The bioavailability of sodium valproate and valproic acid when administered is close to 100%. Therapeutic concentration is in the range of 40-100 mg / l. At levels above 200 mg / l, a dose reduction is required. Time to reach the maximum concentration (T_m_Oh) is 12 hours (range 3-24 hours).

The equilibrium concentration is achieved within 3-14 days of regular intake of the drug.

Distribution

The volume of distribution depends on the age and is usually 0.13-0.23 l / kg body weight or in young people 0.13-0.19 l / kg body weight.

Communication with blood plasma proteins (mainly with albumin) is high (80-95%), dose-dependent and saturable. In elderly patients, patients with renal and hepatic insufficiency, the association with plasma proteins decreases.In severe renal disease insufficiency of concentration free (therapeutically active) fraction of valproic acid can be increased to 8.5-20%.

With hypoproteinemia, the total concentration of valproic acid (free fraction associated with blood plasma proteins) may not change, but may also decrease due to an increase in the metabolism of free valproic acid fraction (not associated with blood plasma proteins).

Valproic acid penetrates into the cerebrospinal fluid and into the brain. Concentration Valproic acid in CSF actually corresponds to concentration of the free fraction of the drug in the blood serum. Valproic acid penetrates the placenta and into the breast milk of nursing mothers. With an equilibrium concentration of valproic acid in the blood serum, its concentration in breast milk is from 1% to 10% of its serum concentration.

Metabolism

Metabolism is carried out in the liver by glucuronidation, and beta, omega, and omega-1 oxidation. More than 20 metabolites were revealed, metabolites after omega-oxidation possess hepatotoxic action.

Valproic acid does not have an inducing effect on the enzymes included in the metabolic system of cytochrome P450: unlike most dantiepileptic drugs, valproic acid does not affect the degree of both its own metabolism and the degree of metabolism of other substances, such as estrogens, progestogens and indirect anticoagulants.

Excretion

Valproic acid is mainly derived kidneys after conjugation with glucuronic acid and beta-oxidation. Less than 5% of valproic acid is excreted by the kidneys in unchanged form.

Plasma clearance of valproic acid in patients with epilepsy is 12.7 ml / min.

The half-life is 10-15 hours. When combined with antiepileptic drugs, inducing microsomal enzymes of the liver, plasma clearance of valproic acid increases, and the half-life decreases, the degree of their change depends on the degree of induction of microsomal enzymes of the liver with other antiepileptic drugs.

The values of the half-life in children over two months of age are close to those of adults.

In patients with cirrhosis of the liver and in the recovery phase after acute hepatitis, the half-life of valproic acid increases.

In case of an overdose, an increase in the half-life of up to 30 hours was observed.

Only free valproic acid in the blood is subject to hemodialysis (10%).

Peculiarities of pharmacokinetics in pregnancy

With increasing volume the distribution of valproic acid in the third trimester of pregnancy, its renal and hepatic clearance increases. In this case, despite taking the drug in a constant dose, it is possible to reduce serum concentrations valproic acid. In addition, during pregnancy, the relationship of valproic acid with plasma proteins can change, which may lead to an increase in serum free (therapeutically active) fraction of valproic acid.

In comparison with the form covered with enteric-coated shell, the form of prolonged action in equivalent doses is characterized by the following:

- absence of delayed intake after receiving;

- prolonged absorption;

- identical bioavailability;

- a smaller value of C_m_Oh (decrease in C_m_Oh by about 25%), but with a more stable plateau phase from 4 to 14 hours after administration;

- a more linear correlation between the dose and concentration of the drug in the blood plasma.

Indications:

In adults

- for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoclonic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs);

- for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs);

- for the treatment and prevention of bipolar affective disorders.

Children

- for the treatment of generalized epileptic seizures: clonic, tonic, tonic-clonic, absences, myoconic, atonic; Lennox-Gastaut syndrome (in monotherapy or in combination with other antiepileptic drugs);

- for the treatment of partial epileptic seizures: partial seizures with or without secondary generalization (in monotherapy or in combination with other antiepileptic drugs.

Contraindications:

- Hypersensitivity to valproate sodium, valproic acid, semlariate valproate, valpromide or to any of the components of the drug;

- acute hepatitis;

- chronic hepatitis;

- severe liver disease (especially drug-induced hepatitis) in a history of the patient and (or) his close blood relatives;

- severe liver damage with lethal when using valproic acid in close blood relatives of the patient;

- severe violations of the liver or pancreas;

- hepatic porphyria;

- combination with mefloquine;

- combination with St. John's wort;

- hemorrhagic diathesis, thrombocytopenia;

- disrupting the carbamide cycle of urea formation (including near blood relatives);

- mitochondrial diseases, caused by mutation of a nuclear gene POLG, encoding DNA polymerase γ (for example, Alpers-Guttenlohera syndrome), suspected of such diseases;

- Children under 6 years of age (risk of falling into the airway during swallowing).

Carefully:

- Liver diseases and a pancreas in the anamnesis;

- pregnancy;

- congenital fermentopathy;

- when oppression of bone marrow hematopoiesis (leukopenia, anemia, thrombocytopenia);

- renal insufficiency (dose adjustment is required);

- hypoproteinemia;

- in patients receiving several anticonvulsants drugs, because of the increased risk of liver damage;

- with simultaneous admission drugs provoking convulsive seizures or reducing the threshold of convulsive readiness, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazine derivatives, derivatives butyrophenone, chloroquine, bupropion, tramadol (risk of provoking convulsive seizures);

- with simultaneous admission antipsychotics, inhibitors monoamine oxidase (MAO), antidepressants, benzodiazepines (the possibility of potentiating their effects);

- with simultaneous admission phenobarbital, primidon, phenytoin, lamotrigine, zidovudine, felbamate, acetylsalicylic acid, indirect anticoagulants, cimetidine, erythromycin, carbapenems, rifampicin, nimodipine, rubinamide (especially in children), protease inhibitors (lopinavir, ritonavir), colestyramine (due to pharmacokinetic interactions at the level of metabolism or binding by blood plasma proteins, plasma concentrations of these drugs and / or valproic acid);

- with simultaneous application carbamazepine (risk of potentiating the toxic effects of carbamazepine and reducing plasma concentration of valproic acid);

- with simultaneous application of topiramate and acetazolamide (risk of encephalopathy);

- in patients with existing insufficiency carnitine palmitoyltransferase (CBT) type II (higher risk of rhabdomyolysis).

Pregnancy and lactation:

Pregnancy

The risk associated with the development of epileptic seizures during pregnancy: during pregnancy, a particular risk for both the mother and the fetus due to the possibility of a lethal outcome, represents the development of generalized tonic-clonic epileptic seizures, epileptic status with the development of hypoxia.

The risk associated with the use of the drug during pregnancy: experimental studies of reproductive toxicity performed on animals demonstrated the presence of teratogenic action in valproic acid.

The available clinical data confirm that an increased frequency of occurrence of large and small developmental defects is observed in children whose mothers received valproic acid in connection with epilepsy (neural tube malformations, craniofacial deformities, cleft lip and wolf mouth, craniostenosis,developmental malformations of limbs (including bilateral aplasia of the radius), cardiovascular system, kidneys and urinary tract, as well as multiple defects fetal development affecting various organ systems) compared with the frequency of their occurrence with the use during pregnancy of some other antiepileptic drugs. The risk of neural tube defects in children whose mothers received valproic acid therapy was 1-2%, compared with the risk in the general population: 0.06-0.07% (6-7 cases per 10,000 newborns).

Meta-analysis data, including registers and cohort studies, showed that the incidence of congenital malformations in children whose mothers received valproic acid monotherapy due to epilepsy was 10.73% (95%, confidence interval 8.16-13.29 ). This therapy entails a higher risk of serious congenital malformations compared with the risks in the general population, which are approximately 2-3%. The available data indicate the dose-dependent nature of this undesirable phenomenon, but a threshold dose above which there is a risk can not be established.

The risk of congenital malformations in children whose mothers received valproic acid with monotherapy due to epilepsy was approximately 1.5 times higher than in cases of monotherapy with phenytoin, 2.3 times higher than with monotherapy with carbamazepine or phenobarbital and approximately 3, 7 times higher than with monotherapy with lamotrigine.

Also reported on the development afibrinogenemii with a lethal outcome, aplasia, disorders development of speech, dysmorphia, anticonvulsant syndrome fetus, wolf mouth, hypospadias. The available data suggest the existence of a relationship between intrauterine exposure to valproic acid and delayed development (in particular, a decline in the verbal IQ) in children born to mothers with epilepsy, who took valproic acid. It was found that 30-40% of children exposed to intrauterine effects of valproic acid have delays in the early stages of development, in particular, retardation of walking and speech, lower intellectual abilities, poor speech skills and memory problems are also noted.

According to a prospective cohort study, with the participation of children of primary school age (6 years) who underwent intrauterine exposure valproic acid (N = 62), the coefficient of mental development (IQ) was on average 7-10 units lower than the rate of mental development in children whose mothers during pregnancy took other antiepileptic drugs. The delay in development was often combined with malformations and phenomena of dysmorphism.

However, in cases of delayed development in such children, it is difficult to pinpoint the cause-and-effect relationship with valproic acid intake because of the possibility the simultaneous impact of other factors, such as a low level of intelligence of the mother or both parents, genetic, social factors, environmental factors, the lack of effectiveness of treatment aimed at preventing epileptic seizures in the mother during pregnancy.

There was also reported an increased risk of developing various autistic disorders (approximately 3-fold) and child autism (approximately 5-fold) compared with the general population. There is limited evidence that confirms that children exposed to intrauterine effects of valproic acid have a risk of developing attention deficit disorder and of hyperactivity.

Both monotherapy with valproic acid and combination therapy with the inclusion of valproic acid are associated with an unfavorable outcome pregnancy. However, according to available data, combined antiepileptic therapy including valproic acid is associated with a higher risk of adverse pregnancy outcome compared to valproic acid monotherapy (ie, the risk of fetal abnormalities is less when valproic acid is used in monotherapy). The risk factors for the development of fetal malformations are: a dose of more than 1000 mg / day (but a smaller dose does not exclude this risk) and the combination of valproic acid with other anticonvulsants.

In connection with the above data, the drug should not be used in pregnancy and in women with childbearing potential without extreme necessity. AT In particular, its use is possible in situations where other antiepileptic drugs are ineffective or the patient does not tolerate them.

The need to use the drug or the possibility of refusing its use should be decided before the drug is started or revised if the woman who receives the drug is planning a pregnancy.

Women with childbearing potential should use effective methods of contraception during treatment with the drug. Women with childbearing potential should be informed of the risks and benefits of using valproic acid during pregnancy.

If a woman is planning a pregnancy or has a pregnancy diagnosed, the need to treat with valproic acid should be reassessed depending on the indications:

- in bipolar disorders, consideration should be given to discontinuing treatment with valproic acid;

- when epilepsy is indicated, the question of continuing treatment with valproic acid or its withdrawal is decided after a reassessment of the benefit-risk ratio. If, after a reassessment of the ratio of benefit and risk, treatment with the drug should be continued during pregnancy, it is recommended to apply it in the minimum effective daily dose divided into several receptions. It should be noted that in pregnancy it is preferable to use dosage forms of the sustained release preparation.

A month before conception and within two months after it, antiepileptic treatment should be addedfolic acid (at a dose of 5 mg per day), since this can minimize the risk of malformations of the neural tube.

A permanent special prenatal control should be performed to identify possible defects in the formation of the neural tube or other malformations of the fetus.

Risk for newborns

There have been reports of the development of single cases of hemorrhagic syndrome in newborns whose mothers were taking valproic acid during pregnancy.

Hemorrhagic syndrome is associated with hypofibrinogenemia and, possibly, is caused by a decrease in the content of coagulation factors. Hemorrhagic syndrome should be distinguished from vitamin K deficiency caused by phenobarbital and other inducers of microsomal liver enzymes. Therefore, in newborns born to mothers who received valproic acid, it is necessary to determine the number of platelets in the blood, the plasma concentration of fibrinogen, clotting factors and coagulogram. Reported cases of hypoglycemia in newborns, whose mothers were taking valproic acid during the third trimester of pregnancy.

Hypothyroidism was reported in newborns whose mothers received valproic acid during pregnancy.

In newborns whose mothers have taken valproic acid in the last trimester of pregnancy, withdrawal can occur (in particular, manifestations of agitation, irritability, hyperreflexia, tremor, hyperkinesia, muscle tone disorders, tremors, seizures, difficulty in feeding).

Breastfeeding period

The excretion of valproic acid in breast milk is low, its concentration in milk is 1-10% concentration in serum.

Based on the literature data and a small clinical experience, mothers may plan breastfeeding with monotherapy, but the profile of adverse drug effects, especially hematologic disorders caused by them, should be taken into account.

Fertility

In men valproic acid can reduce mobility spermatozoa and cause male infertility. Women reported on the development of amenorrhea, polycystic ovary, increased testosterone levels. Fertility was restored after the drug was discontinued.

Dosing and Administration:

Tablets are taken without crushing or chewing them.

Valopixime is used when appointing a doctor, the dosage regimen is selected individually.

Tablets, without chewing, drink a lot of liquid (for example, a glass of water), if possible, 1 hour before meals.

The daily dose can be taken in 1-2 divided doses. The required amount is precisely determined by the doctor in each specific case.

Use in one dose is possible with well-controlled epilepsy.

This dosage form is contraindicated for children under 6 years of age and with a body weight of less than 17 kg (risk of falling into the airway during swallowing).

Valopixime is a form of sustained release of the active ingredient, which avoids abrupt increases in valproic acid concentration in the blood after taking the drug and longer maintains a constant concentration of valproic acid in the blood for 24 hours.

Dosing regimen for epilepsy

The daily dose is selected individually by the attending physician.

It is necessary to select the minimum effective dose to prevent the development of epileptic seizures (especially during pregnancy).

The daily dose should be adjusted according to age and body weight.A stepwise (gradual) increase in the dose is recommended until the minimum effective dose is reached.

There was no clear relationship between the daily dose, plasma concentration and therapeutic effect. Therefore, the optimal dose should be determined mainly by the clinical response. Determining the concentration of valproic acid in blood plasma can serve as a supplement to clinical observation if epilepsy is not controlled or there is a suspicion of side effects. The range of therapeutic concentration in the blood is usually 40-100 mg / l (300-700 μmol / l).

With monotherapy the initial dose is usually 5-10 mg of valproic acid per kg of body weight, which is gradually increased every 4-7 days at a rate of 5 mg of valproic acid per kg of body weight to the dose necessary to achieve control of epileptic seizures.

Average daily doses (with prolonged use):

- for children 6-14 years (body weight 20-30 kg) - 30 mg valproic acid / kg body weight (600-1200 mg);

- for adolescents (body weight 40-60 kg) - 25 mg valproic acid / kg body weight (1000-1500 mg);

- for adults and elderly patients (body weight from 60 kg and above) - an average of 20 mg valproic acid / kg body weight (1200-2100 mg).

Although the daily dose is determined depending on the age and body weight of the patient, a wide range of individual sensitivity to valproate should be taken into account.

If epilepsy can not be controlled at such doses, they can be increased under the control of the patient's condition and the concentration of valproic acid in the blood.

In some cases, the full therapeutic effect of valproic acid does not appear immediately, but develops within 4-6 weeks. Therefore, do not exceed the recommended daily average dose before this time.

Most patients who are already taking other long-acting forms of valproic acid can be transferred to the drug form of this prolonged-release drug immediately or for several days, and patients should continue to take the previously selected daily dose.

For patients who have taken antiepileptic drugs earlier, transfer to Valopixime should be carried out gradually, reaching the optimal dose of the drug for about 2 weeks. In this case, it is necessary to reduce the dose of the antiepileptic drug previously taken, especially phenobarbital.If previously taken antiepileptic drug is canceled, then its cancellation should be carried out gradually.

Since other antiepileptic drugs can reversibly induce microsomal liver enzymes, it is necessary to monitor the concentrations of valproic acid in the blood within 4-6 pellets after taking the last dose of these drugs and, if necessary (as the metabolic-inducing effect of these drugs decreases), to reduce the daily dose of valproic acid.

If necessary, combinations of valproic acid with other antiepileptic drugs should be added gradually to treatment.

Dosing regimen for manic episodes with bipolar disorders

Adults

The daily dose is selected by the attending physician andIndividually.

In clinical trials, an initial dose of 20 mg of sodium valproate per kg of body weight showed an acceptable safety profile.

Release forms with sustained release can be taken once or twice a day. The dose should increase as quickly as possible before reaching the minimum therapeutic dose, which causes the desired clinical effect.

The average daily dose is in the range of 1000-2000 mg of sodium valproate. Patients receiving a daily dose above 45 mg / kg / day should be under close medical supervision.

Continuation of treatment of manic episodes in bipolar disorders should be conducted by taking individually Papproved minimum effective dose.

Children and teens

The efficacy and safety of the drug in the treatment of manic episodes in bipolar disorders in patients younger than 18 years of age have not been evaluated.

The use of the drug in patients of special groups

In patients with renal insufficiency and / or hypoproteinemia, the possibility of increasing the concentration of free (therapeutically active) fraction of valproic acid in the blood serum should be taken into account, and if necessary to reduce the dose of valproic acid, focusing on the choice of the dose mainly on the clinical picture, and not on the total content of valproic acid in the blood serum (free fraction and fraction associated with blood plasma proteins) in order to avoid possible errors in the selection of a dose.

Girls, women with childbearing potential and pregnant women

Therapy should be prescribed and controlled by the drug a specialist with experience in the treatment of epilepsy / bipolar disorder. Treatment should be started only when Other treatment regimens are ineffective or if they are poorly tolerated (see section "Special instructions"), should carefully and regularly assess the benefits and risks of therapy. Valproate is best prescribed as a monotherapy with the lowest effective dose, if possible using a sustained release dosage form to avoid too high concentrations in the blood plasma. The daily dose should be taken at least two times.

Side effects:

According to the World Health Organization (WHO), adverse events are classified according to their frequency of development as follows: very frequent (> 1/10), frequent (> 1/100, <1/10), infrequent (> 1/1000, <1/100), rare (> 1 / 10000, <1/1000) and very rare (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Violations of the blood and lymphatic system

often: anemia, thrombocytopenia;

infrequently: pancytopenia, leukopenia, neutropenia.

Leukopenia and pancytopenia can be with or without bone marrow depression.

The picture of blood returns to normal after drug withdrawal (see section "Special instructions").

rarely: disorders of bone marrow hematopoiesis, including isolated aplasia / hypoplasia of erythrocytes, macrocytic anemia, macrocytosis, agranulocytosis, decrease in blood clotting factors (at least one), deviation from the norm of blood clotting parameters (increase in prothrombin time, increase in activated partial prothrombin time, an increase in thrombin time, an increase in the international normalized relationship (INR)).

Spontaneous bruises and bleeding testify to the need to discontinue the drug and conduct a survey (see section "Special instructions").

Disturbances from the nervous system

Often: tremor;

often: transient and / or dose-dependent lung postural tremor and drowsiness, extrapyramidal disorders, headache, stupor, convulsions, memory impairment, nystagmus;

infrequently: ataxia; coma, encephalopathy, inhibition, including reversible parkinsonism, paresthesia;

rarely: Dementia, combined with brain atrophy, reversible within a few weeks or months after discontinuation of the drug, cognitive impairment.

Several rare cases of stupor and lethargy, sometimes leading to transient coma / encephalopathy. They can be isolated or combined with an increase in the frequency of convulsive seizures (despite treatment), which decreases with the withdrawal of the drug or a decrease in its dose. These cases were mainly observed during combined therapy (in particular, with phenobarbital or topiramate) or after a sharp increase in the dose of valproic acid (see section "Interaction with other medicinal products ").

Hyperammonemia, combined with neurologic symptoms (in this case, the patient requires an additional examination).

It was reported on the development of sedation. In monotherapy, it appeared in rare cases at the very beginning of treatment and was usually temporary.

Also, sudden aggression, hyperactivity and behavioral disorders were noted.

Disturbances on the part of the organ of sight

frequency is unknown: diplopia.

Hearing disorders and labyrinthine disorders

often: deafness (cause-and-effect relationship not established).

Disorders from the gastro- intestinal tract

Often: nausea;

often: vomiting, gum changes (mainly, gingival hyperplasia), stomatitis, epigastric pain, diarrhea, which, when The continued use of the drug usually disappears a few days after discontinuation of therapy. The frequency of adverse events can be reduced by taking the drug during or after a meal;

infrequently: pancreatitis, sometimes with lethal outcome (see section "Special instructions");

frequency is unknown: spasms in abdomen, anorexia, increased appetite.

Disorders from the kidneys and urinary tract

infrequently: kidney failure;

rarely: enuresis, tubulointerstitial nephritis, Fanconi syndrome (defect of proximal tubule function leading to glucosuria, aminoaciduria, phosphaturia and uricosuria). There are several separate reports on the development of the reversible Fanconi syndrome, the development mechanism of which is still unclear.

Disturbances from the skin and subcutaneous tissues

often: transient or dose-related alopecia (including androgenic alopecia against the background of developed hyperandrogenism, polycystic ovary, as well as alopecia against the background of developed hypothyroidism; hair growth usually resumes within six months, with hair becoming more curly than before), hypersensitivity, lesions nails and nail bed;

infrequently: angioneurotic edema, rash, hair disorders (such as abnormal hair structure, hair color changes, abnormal hair growth (disappearance of waviness or, conversely, the appearance of curly hair in persons with initially straight hair)), hirsutism, acne;

rarely: toxic epidermal necrolysis (see section "Interaction with other medicinal products "), Stevens-Johnson syndrome, polymorphic erythema, rash, rash syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

Disorders from the metabolism and nutrition

often: increased appetite, hyponatremia, weight gain. Since obesity is a risk factor for development the syndrome of polycystic ovaries should be carefully monitored by patients with an increase in body weight (see section "Special instructions"):

rarely: isolated and moderate hyperamonia in the absence of changes in indicators functional liver samples and neurological manifestations, which does not require the withdrawal of the drug. If there is vomiting, ataxia, blurred consciousness should discontinue drug treatment (see section "Special instructions").

Disorders from the endocrine system

infrequently: syndrome of inadequate secretion of antidiuretic hormone, hyperandrogenism (hirsutism, virilization, acne, male alopecia and / or increase in androgen concentration in the blood);

rarely: hypothyroidism.

Vascular disorders

often: bleeding and hemorrhage (see section "Special instructions");

infrequently: vasculitis.

Disturbances from musculoskeletal and connective tissue

infrequently: reduction of mineral bone density, osteopenia, osteoporosis and fractures in patients on long-term therapy;

rarely: systemic lupus erythematosus (see section "Special instructions"), rhabdomyolysis (see the sections "With caution", "Special instructions").

Data on the effect of valproic acid on bone metabolism are lacking.

General disorders

infrequently: hypothermia, small peripheral edema.

Laboratory and instrumental baths

rarely: decrease in the content of clotting factors, pathological results a study of blood coagulation, a biotin deficiency / biotinidase deficiency.

Disturbances from the liver and bile ducts

often: lesions of the liver.

There have been reports of cases of severe liver damage, including liver failure, which sometimes led to death. Perhaps a slight increase in the activity of "liver" enzymes, especially at the beginning of treatment, which is transient (see section "Special instructions").

Violations of the genitals and mammary gland

often: dysmenorrhea;

infrequently: amenorrhea;

rarely: male infertility, polycystic ovary;

rarely: gynecomastia;

frequency is unknown: irregular menstruation, breast enlargement, galactorrhea.

Disturbances from the respiratory system

infrequently: pleural effusion.

Disorders of the psyche

often: confusion, hallucinations, aggression *, agitation *, attention impairment *, depression (with the combination of valproic acid with other anticonvulsants);

rarely: behavioral changes *, psychomotor hyperactivity *, learning disability *, depression (with monotherapy with valproic acid).

* Similar undesirable phenomena occur mainly in children.

Congenital, hereditary and genetic disorders (see section "Application during pregnancy and during breast-feeding").

Neoplasms

rarely: myelodysplastic syndrome.

Overdose:

Clinical manifestations acute massive overdose usually occur in the form of coma with hypotonia of the muscles, hyporeflexia, miosis, respiratory depression, metabolic acidosis. Cases of intracranial hypertension associated with edema of the brain were described. With a massive overdose, a lethal outcome is possible, but usually the prognosis is favorable when overdosed.

Symptoms: overdose may vary, reported on the development of convulsive seizures with very high plasma concentrations of valproic acid.

Treatment: emergency assistance for overdose in the hospital should be as follows: gastric lavage, which is effective within 10-12 hours after taking the drug, monitoring the state of the cardiovascular and respiratory systems and maintaining an effective diuresis. In some cases, naloxone. In very severe cases of massive overdose, hemodialysis and hemoperfusion were effective.

Interaction:

The effect of valproic acid on other drugs

Neuroleptics, monoamine oxidase (MAO) inhibitors, antidepressants, benzodiazepines

Valproic acid can potentiate action psychotropic drugs, such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; so when they are used simultaneously with the drug

Valopixime recommends thorough medical supervision and, if necessary, dosage adjustment. Simultaneous use with olanzapin may cause the appearance of undesirable phenomena such as neutropenia, tremor, dryness of the oral mucosa, increased appetite, weight gain, speech impairment, drowsiness.

Clozapine and haloperidol

With simultaneous use with clozapine or haloperidol, no significant interactions were observed.

Lithium preparations

Valproic acid does not affect serum lithium concentrations.

Phenobarbital

Valproic acid increases the plasma concentrations of phenobarbital (due to a decrease in its hepatic metabolism), in connection with which the development of sedative action of the latter, especially in children, is possible.Therefore, careful medical observation of the patient during the first 15 days of combined therapy with immediate reduction of the dose of phenobarbital in case of development of sedation and, if necessary, determinationnorf plasma concentrations of phenobarbital.

Primidone

Valproic acid increases plasma concentrations of primidone with an increase in its side effects (such as sedation); with long-term treatment, these symptoms disappear. A thorough clinical observation of the patient is recommended, especially at the onset of a combination therapy with a primidone dose adjustment if necessary.

Phenytoin

Valproic acid reduces the total plasma concentrations of phenytoin. Besides, valproic acid increases the concentration of the free fraction of phenytoin with a risk of developing symptoms of an overdose (valproic acid expels phenytoin from the connection with the proteins of the blood plasma and slows down its hepatic metabolism). Therefore, careful clinical observation of the patient and the definition concentrations of phenytoin and its free fraction in the blood.

Carbamazepine

With the simultaneous use of valproic acid and carbamazepine, the occurrence of clinical manifestations of the toxicity of carbamazepine has been reported, since valproic acid can potentiate the toxic effects of carbamazepine. Recommended thorough clinical observation of such patients, especially at the onset of combined therapy with correction if necessary of a dose of carbamazepine.

Lamotrigine

Valproic acid slows the metabolism of lamotrigine in the liver and increases the half-life of lamotrigine by almost 2 times. This interaction can lead to an increase in the toxicity of lamotrigine, in particular, to the development of severe skin reactions, including toxic epidermal necrolysis. Therefore, careful clinical observation and, if necessary, correction (reduction) of the dose of lamotrigine is recommended.

Zidovudine

Valproic acid can increase plasma concentrations of zidovudine, which leads to an increase in zidovudine toxicity.

Felbamat

Valproic acid can reduce the average clearance value of felbamate by 16%.

Nimodipine (for oral administration and, for extrapolation, solution for parenteral administration)

An increase in the hypotensive effect of nimodipine due to an increase in its plasma concentration (inhibition metabolism of nimodipine with valproic acid).

Rufinamide

In patients taking rubinamide and starting valproic acid, a significant increase in the concentration of rubinamide in the blood plasma is possible. The most noticeable increase in concentration was observed in children weighing less than 30 kg.

The effect of other drugs on valproic acid

Antiepileptic drugs that can induce microsomal liver enzymes (including phenytoin, phenobarbital, carbamazepine) reduce the plasma concentrations of valproic acid. In the case of combination therapy doses of valproic acid should be adjusted depending on the clinical response and the concentration of valproic acid in the blood.

Felbamat

When combined with felbamate and valproic acid, the clearance of valproic acid is reduced by 22-50%, and the plasma concentrations of valproic acid are accordingly increased. Plasma concentrations of valproic acid should be monitored.

Meflohin to chloroquine

Meflohin and chloroquine accelerate the metabolism of valproic acid, can cause seizures, so when they are used simultaneously with valproic acid, an epileptic fit may develop.

Kolestyramine can reduce the absorption of valproic acid.

Preparations of St. John's wort Ppodof the

With the simultaneous use of valproic acid and preparations of St. John's wort, it is possible to reduce the anticonvulsant efficacy of valproic acid.

Drugs that have a high and strong bond with blood plasma proteins (acetylsalicylic acid)

In the case of concomitant use of valproic acid and drugs that have a high and strong association with plasma proteins (acetylsalicylic acid), it is possible to increase the concentration of the free valproic acid fraction.

Indirect anticoagulants

With the simultaneous use of valproic acid and indirect anticoagulants, careful monitoring of the prothrombin index is required.

Cimetidine, erythromycin

Serum concentrations of valproic acid may increase in the case of simultaneous application of cimetidine or erythromycin (as a result of slowing of its hepatic metabolism).

Carbapenems (panipenem, meropenem, imipenem)

Reducing the concentration of valproic acid in the blood with its simultaneous use with carbapenems led to a 60-100% reduction in valproic acid in the blood for two days of joint therapy and was sometimes associated with the occurrence of seizures. Carbapenems should not be used concomitantly in patients with a selected dose of valproic acid because of their ability to rapidly and rapidly reduce valproic acid concentrations in the blood. If carbapenem treatment can not be avoided, careful monitoring of valproic acid concentrations in the blood should be performed.

Rifampicin

Rifampicin can reduce the concentration of valproic acid in the blood, which leads to a loss of the therapeutic effect of Valopixime. Therefore, it may be necessary to increase the dose of Valopixime with simultaneous Ppandtion of rifampicin.

HIV protease inhibitors

Caution should be taken with valproic acid concomitantly with HIV protease inhibitorsritonavir, lopinavir) because of the possible decrease in the concentration of valproic acid in the blood plasma. It is recommended thatA careful monitoring of valproic acid in the blood.

Other interactions

Topiramate and acetazolamide

Simultaneous application Valproic acid and topiramate or acetazolamide was is associated with encephalopathy and / or hyperammonemia. Patients receiving either of these two drugs should be under careful medical observation for the development of symptoms of hyperammonemic Encephalopathy.

Estrogen-progestogen preparations

Valproic acid does not have the ability to induce liver enzymes and therefore does not reduce the effectiveness of estrogen-progestogenic drugs in women who use hormonal methods of contraception.

Ethanol and other potentially hepatotoxic substances

When used simultaneously with valproic acid, it is possible to increase the hepatotoxic effect of valproic acid.

Clonazepam

The simultaneous use of clonazepam with valproic acid may lead in a few cases to an increase in the expression of absent status.

Myelotoxic drugs

With their simultaneous use with valproic acid, the risk of oppression increasesbone marrow hematopoiesis.

Special instructions:

Severe liver damage

Predisposing factors

Clinical experience shows that patients at risk are patients who receive several antiepileptic drugs at the same time, children under the age of three with severe seizures, especially in the presence of brain damage, mental retardation and / or congenital metabolic or degenerative diseases; patients, simultaneously taking salicylates (since salicylates are metabolized along the same metabolic pathway as valproic acid).

After three years of age, the risk of liver damage is significantly reduced and progressively decreases as the patient's age increases. In most cases, liver damage occurred during the first 6 months of treatment, most often between 2 and 12 weeks of treatment and usually with valproic acid as part of a combination antiepileptic therapy.

Symptoms, suspicious for liver damage

For early diagnosis of liver damage, clinical monitoring of patients is mandatory.In particular, attention should be paid to the appearance of the following symptoms that may precede the onset of jaundice, especially in patients at risk (see above):

- nonspecific symptoms, especially sudden onset, such as asthenia, anorexia, lethargy, drowsiness, which are sometimes accompanied by repeated vomiting and abdominal pain;

- resumption of convulsive seizures in patients with epilepsy.

It is necessary to warn patients or their families (when using the drug by children) that they should immediately report the occurrence of any of these symptoms to the treating doctor. If they occur, patients should immediately undergo a clinical examination and a laboratory test indicators of liver function.

Identify

Determination of functional liver samples should be performed before treatment and then periodically during the first 6 months of treatment. Among the usual studies, the most informative studies reflect the state of protein-synthetic liver function, especially the prothrombin index. Confirmation of abnormal prothrombin index,especially in combination with deviations from the norm of other laboratory parameters (a significant reduction in fibrinogen and coagulation factors, an increase in the concentration of bilirubin and an increase in the activity of transaminases) requires the discontinuation of Valopixime. For the purpose of precaution, if patients receive salicylates concomitantly, their administration should also be discontinued, as they are metabolized along the same metabolic pathway as valproic acid.

Pancreatitis

There have been reports of severe cases of pancreatitis, up to a legal outcome. Children are at increased risk of developing pancreatitis, with increasing age, the risk is reduced. Severe convulsions, neurologic disorders, or anticonvulsant therapy may be risk factors for the development of pancreatitis. Hepatic insufficiency, combined with pancreatitis, increases the risk of death.

Patients who experience severe abdominal pain, nausea, vomiting, and / or anorexia should be examined immediately. If the diagnosis is confirmed pancreatitis,in particular with increased activity of pancreatic enzymes in the blood, the use of valproic acid should be discontinued and appropriate treatment initiated.

Suicidal thoughts and attempts

There have been reports of suicidal thoughts or attempts in patients receiving antiepileptic drugs for certain indications. Meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed a slight increase in the risk of suicidal thoughts and attempts. The mechanism of this effect is unknown. Therefore, patients receiving Valopixime should be monitored continuously for suicidal thoughts or attempts, and if necessary, appropriate treatment should be provided. Patients and caregivers are advised when the patient has suicidal thoughts or attempts to immediately consult a doctor.

Carbapenems

Simultaneous use of carbapenems is not recommended (see the section "Interaction with other medicinal products").

Women with childbearing potential

In connection with the high teratogenic potential and risk of developmental disorders in children,in the treatment of girls, women with childbearing potential and pregnant women, valproic acid should be prescribed only if alternative therapy is ineffective or poorly tolerated by the patient. Care and risk should be carefully evaluated when using the drug at pubertal age and in women with childbearing potential who receive valproic acid and plan pregnancy, or in the event of pregnancy. Women with childbearing potential must use effective contraception during therapy, they should be informed of the risks associated with the use of valproic acid during pregnancy (the risk of teratogenicity and developmental disorders), and regular monitoring is required during therapy.

You should immediately consult with your doctor if you are suspected of having a pregnancy or are likely to become pregnant.

When treating women planning a pregnancy, it is necessary to make every effort to translate them, if possible, to an alternative therapy before conception.

Methods for monitoring the safety of Valopixime

Before starting the drug Valopixime and periodically during the first 6 months of treatment, especially in patients at risk of developing liver disease, should carry out a study of liver function. As with most antiepileptic drugs, it is possible slight increase activity "hepatic" enzymes, especially at the beginning of treatment, which occurs without clinical manifestations and is transient. These patients need more a detailed study laboratory indicators, including a prothrombin index, and may require dose adjustment and, if necessary, a repeat clinical and laboratory examination.

Before the beginning of therapy or when it is necessary to perform a surgical operation, in case of spontaneous subcutaneous hematoma or bleeding, it is recommended to conduct a hematological blood test (determine the leukocyte blood count, including platelet count, bleeding time and coagulogram).

Renal insufficiency

It may be necessary to reduce the dose of valproic acid due to an increase in the concentration of its free fraction in the blood serum.

In case of impossibility of monitoring plasma concentrations of valproic acid, the dose of the drug should be adjusted based on clinical observation of the patient.

Insufficiency of urea enzymes

When suspicion of a deficiency of enzymes in the carbamide cycle, the use of valproic acid is not recommended. Such patients described several cases of hyperammonemia with a stupor or coma. In these cases, metabolic studies should be performed prior to treatment with valproic acid.

In children with unexplained gastrointestinal symptoms (anorexia, vomiting, cytolysis cases), lethargy or coma in history, with mental retardation or with a family history of death of a newborn or child, studies of metabolism should be conducted prior to treatment with valproic acid, in particular, determination of ammonia (the presence of ammonia and its compounds in the blood) on an empty stomach and after eating.

Patients with systemic lupus erythematosus

Although it has been shown that during the treatment with Valopixim, the immune system functions are extremely rare, the potential benefit of using it is to be compared with the potential risk for prescribing patients with systemic lupus erythematosus.

Weight gain

Patients should be warned about the risk of weight gain at the beginning of treatment, and measures, mostly dietary, should be taken to minimize this phenomenon.

Patients with mitochondrial diseases

Valproic acid can cause or worsen clinical signs of mitochondrial diseases caused by a mutation of a nuclear gene POLG, encoding DNA polymerase γ. The incidence of acute hepatic insufficiency caused by the use of valproic acid and deaths from liver diseases was higher in patients with mitochondrial diseases (for example, Alpers-Guttenlohera syndrome).

The probability of mitochondrial diseases in patients with mitochondrial diseases in a family history should be assessed, or in the presence of the following symptoms: unexplained encephalopathy, refractory epilepsy (focal, myoclonic), epilepsy,developmental delay, psychomotor regression, sensorimotor neuropathy, myopathy, cerebellar ataxia, ophthalmoplegia or complicated migraine in the occipital part of the head.

Patients with diabetes mellitus

Given the risk of adverse effects of valproic acid on the pancreas, the use of the drug in patients with diabetes should carefully monitor the concentration of glucose in the blood.

In the study of urine for the presence of ketone bodies in patients, it is possible to obtain false-positive results, since valproic acid mainly excreted by the kidneys, partially in the form of ketone bodies.

Patients infected with the human immunodeficiency virus (HIV)

In vitro it was found that valproic acid stimulates HIV replication under certain experimental conditions.

The clinical significance of this fact is unknown. In addition, the value of these data obtained in the studies in vitro, for patients receiving the maximum suppressive antiviral therapy. However, these data should be taken into account in interpreting the results of continuous monitoring of viral load in HIV-infected patients taking valproic acid.

Patients with existing insufficiency carnitine palmitoyltransferase (CBT) type II

Patients with existing type II CPT deficiency should be warned about a higher risk of rhabdomyolysis when taking valproic acid.

Ethanol

During treatment with valproic acid, ethanol is not recommended.

Special precautions when destroying an unused preparation

There is no need for special precautions when destroying an unused preparation.

Effect on the ability to drive transp. cf. and fur:

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:Tablets with prolonged release, coated film coating, 300 mg.

Packaging:

10 tablets per blister from Al/Al foil.

For 5, 10 or 20 blisters together with instructions for use in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002240

Date of registration:20.09.2013 / 06.12.2016

Expiration Date:20.09.2018

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SALUTAS PHARMA, GmbH Germany

DRAGENOPHARM APOTHEKER PUSCHL, GmbH & Co. KG. KG Germany

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp19.01.2017

Illustrated instructions

Instructions

Valopixime (Valopixim)