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

Excipients: povidone 30 - 9.1 mg, croscarmellose sodium - 4.8 mg, silicon colloidal dioxide - 1.4 mg, sodium stearyl fumarate - 2.8 mg; film sheath: hypromellose 2910/5 - 5,10 mg, macro code 6000 - 0,51 mg, talc 2,046 mg, titanium dioxide - 0.87 mg, simethicone emulsion (water 67.4% simethicone 30.0%, methylcellulose 2.5%, sorbic acid 0.1%) - 0.087 mg, indigocarmine - 0.09 mg.

Film coated tablets 500 mg

active substance: levetiracetam - 500.0 mg;

Excipients: povidone 30-18.2 mg, croscarmellose sodium 9.6 mg, silicon colloidal dioxide 2.8 mg, sodium stearyl fumarate 5.6 mg; film sheath: hypromellose 2910/5 - 10.2 mg, macrogol 6000 - 1.02 mg, talc - 4.18 mg, titanium dioxide - 1.74 mg, simethicone emulsion (water 67.4% simethicone 30.0% methylcellulose 2 , 5%, sorbic acid 0.1%) - 0.17 mg, ferric oxide, yellow oxide - 0.09 mg.

Film coated tablets 750 mg

active substance: levetiracetam - 750.0 mg;

Excipients: povidone 30-27.3 mg, croscarmellose sodium 14.4 mg, silicon colloidal dioxide 4.2 mg, sodium stearyl fumarate 8.4 mg; film sheath: hypromellose 2910/5 - 15.3 mg, macrogol 6000 - 1.53 mg, talc-6.29 mg, titanium dioxide - 2.61 mg, simethicone emulsion (water 67.4%, simethicone 30.0%, methylcellulose 2 , 5%, sorbic acid 0.1%) 0.26 mg, iron dye oxide yellow 0.037 mg, iron oxide red oxide 0.073 mg.

Tablets, film-coated 1000 mg

active substance: levetiracetam - 1000.0 mg;

Excipients: povidone 30-36.4 mg, croscarmellose sodium 19.2 mg, silicon colloidal dioxide 5.6 mg, sodium stearyl fumarate 11.2 mg; film jacket: hypromellose 2910/5 - 20.40 mg, macrogol 6000 - 2.04 mg, talc-8.53 mg, titanium dioxide - 3.48 mg, simethicone emulsion (water 67.4%. simethicone 30.0%, methylcellulose 2 , 5%, sorbic acid 0.1%) - 0.35 mg.

Description:

250 mg tablets: oblong blue pills covered with a film sheath, with a risk on both sides.

Tablets 500 mg: oblong tablets from light yellow to yellow, film-coated, with a risk on both sides.

Tablets 750 mg: oblong tablets from pink to orange, covered with a film sheath, with a risk on both sides.

Tablets 1000 mg: oblong white or almost white tablets coated with a film sheath, with a risk on both sides.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.14 Levetiracetam

Pharmacodynamics:

Levetiracetam, the active substance of the preparation Zenitetram®, is a derivative of pyrrolidone (the S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), differs in chemical structure from known antiepileptic drugs. The mechanism of action of levetiracetam is not fully understood, but it is clear that it differs from the mechanism of action of the remaining antiepileptic drugs. Experiments in vitro and in vivo indicate that levetiracetam does not cause a violation of the basic characteristics of cells and the normal transmission of nerve impulses.

In in vitro studies, it was shown that levetiracetam affects the concentration of Ca²⁺ inside neurons by partially inhibiting calcium channels of type N and reducing the release of Ca²⁺ from neurons. In addition, the drug partially neutralizes the inhibitory effect of zinc and beta-carbolines on GABA- and glycine-dependent ion fluxes. In addition, in vitro studies it has been shown that levetiracetam binds to a specific center of the brain of rodents. This binding site is a protein of synaptic vesicles A2, responsible for the fusion of vesicles and the release of neurotransmitters. Levetiracetam and its analogues have a pronounced affinity for the protein of synaptic A2 vesicles, which correlates with their anticonvulsant activity in the model of audiogenic epilepsy in mice. These data indicate that the interaction between levetiracetam and the synaptic vesicle protein A2 appears to contribute to the antiepileptic mechanism of action of this drug.

Levetiracetam provides protection against convulsive seizures in various models of partial and primarily generalized convulsive seizures in animals, without providing a proconvulsant effect. Its main metabolite has no activity. In humans, the activity of the drug in both partial and generalized epileptic seizures (epileptiform discharges / photoparosymal response) confirmed a broad profile of the pharmacological activity of levetiracetam.

Clinical efficacy and safety

Auxiliary therapy of partial seizures with secondary generalization or without it in adults, adolescents, children and infants at the age of 1 month, with epilepsy.

The efficacy of levetiracetam in adult patients was demonstrated in three double-blind, placebo-controlled trials when used at doses of 1000, 2000 and 3000 mg / day, divided into 2 doses; The duration of therapy was then up to 18 weeks. In the pooled data analysis, the proportion of patients who achieved a reduction in the frequency of partial seizures per week by 50% from baseline and more with constant doses (12/14 weeks) was 27.7%, 31.6% and 41.3% of patients receiving levetiracetam in doses of 1000, 2000 and 3000 mg / day, respectively, and 12.6% of patients receiving a placebo.

Use in the pediatric population

The efficacy of levetiracetam in children (aged 4 to 16 years) was established in a double-blind, placebo-controlled study of 198 patients who received the drug for 14 weeks. In this study, patients received levetiracetam at a fixed dose of 60 mg / kg per day (divided into 2 doses).

In 44.6% of patients who received levetiracetam, and 19.6% of patients receiving placebo experienced a reduction in the frequency of partial seizures per week by 50% of baseline or more. When continuing therapy with the drug for a long time, it was shown that 11.4% of patients had no seizures for at least 6 months, 7.2% - for at least 1 year.

The efficacy of levetiracetam in children (aged 1 month to 4 years) was established in a double-blind, placebo-controlled study that included 116 patients who received the drug for 5 days. In this study, patients were given daily doses of the solution for oral administration of 20 mg / kg, 25 mg / kg, 40 mg / kg or 50 mg / kg per day based on the titration scheme, depending on age. In this study, a dose of 20 mg / kg / day was used with an increase to 40 mg / kg / day for infants aged 1 to 6 months and a dose of 25 mg / kg / day with an increase to 50 mg / kg / day for infants and children at the age from 6 months to 4 years. The total daily dose was administered in two divided doses.

The primary measure of effectiveness was the frequency of response (the percentage of patients with a decrease in the average daily frequency of convulsive seizures from the baseline by 50% or more) assessed by the central institution's 48-hour video EEG in disguised manner.The efficacy analysis included 109 patients who had at least 24 hours of EEG video in the initial and estimated periods. 43.6% of patients treated with levetiracetam and 19.6% of patients receiving placebo were regarded as responding to treatment. The results are consistent across the age group. When the drug was continued for a long time, it was shown that 8.6% of patients had seizures for at least 6 months, 7.8% for at least 1 year.

Monotherapy for the treatment of partial convulsive seizures (with and without secondary generalizations) in patients aged 16 years and older with newly diagnosed epilepsy.

The efficacy of levetiracetam as monotherapy was established in a double-blind, parallel-group study designed to demonstrate no less efficacy compared to carbamazepine in a controlled release dosage form (CR); the study included 576 patients aged 16 years and older with a newly diagnosed or newly diagnosed epilepsy. Patients should have only partial seizures (without provocation) or generalized tonic-clonic convulsions.Patients were randomized to receive carbamazepine CR (at a dose of 400 mg / day to 1200 mg / day) or levetiracetam (at a dose of 1,000 mg / day to 3,000 mg / day); The duration of therapy was up to 121 weeks (depending on the response to treatment).

Absence of convulsive seizures within 6 months was noted in 73.0% of patients who received levetiracetam, and 72.8% of patients who received carbamazepine CR; The corrected absolute difference between the preparations was 0.2% (95% confidence interval: 7.8-8.2). More than half of the patients showed no seizures during 12 months (56.6% and 58.5% of patients who received levetiracetam and carbamazepine CR respectively).

In a study reflecting the conditions of clinical practice, the concomitant antiepileptic drug could be discontinued only in a limited number of patients demonstrating response to adjuvant therapy with levetiracetam (36 adult patients out of 69).

Auxiliary therapy of myoclonic seizures in adults and adolescents with 12 years of juvenile myoclonic epilepsy.

The efficacy of levetiracetam was established in a double-blind,placebo-controlled study lasting 16 weeks, including patients aged 12 years and older, suffering from idiopathic generalized epilepsy with myoclonic seizures in the form of various syndromes. Most of them were diagnosed with juvenile myoclonic epilepsy.

In this study levetiracetam were administered at a dose of 3000 mg / day, divided into 2 doses. In 58.3% of patients who received levetiracetam, and 23.3% of patients receiving placebo had a decrease in the number of days per week in which myoclonic spasms were recorded, at least 50%. With prolonged therapy with the drug for a long time, myoclonic cramps were not observed in at least 6 months in 28.6% of patients, and in 21.0% for at least 1 year. Auxiliary therapy of primary generalized tonic-clonic convulsive seizures in adults and adolescents aged 12 years and older suffering from idiopathic generalized epilepsy.

The efficacy of levetiracetam was established in a double-blind, placebo-controlled study lasting 24 weeks, which included adults,adolescents and a limited number of children suffering from idiopathic generalized epilepsy and primary generalized tonic-clonic convulsive seizures in the form of various syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, child's absence epilepsy and epilepsy with large convulsive seizures on awakening). In this study levetiracetam injected at a dose of 3000 mg / day for adults and adolescents and 60 mg / kg per day for children divided into 2 doses.

Reduction in the frequency of primary generalized tonic-clonic seizures in the week by 50% or more was noted in 72.2% of patients who received levetiracetam, and 45.2% of patients receiving placebo. When the drug was continued for a long time, 47.4% of the patients had no tonic-clonic seizures for at least 6 months, and 31.5% had a minimum of 1 year.

Pharmacokinetics:

Levetiracetam is a substance with a high solubility and a high degree of permeability. The pharmacokinetic profile is characterized by linearity and low intra- and interindividual variability. With repeated intake of the drug, its clearance does not change.Evidence of the significant influence of sex, race or circadian rhythms is not obtained. Also, there were no differences in the pharmacokinetic profile in healthy volunteers and in patients with epilepsy.

As a result of full and linear absorption, the concentration of the drug in the blood plasma can be calculated from the internal dose of lisetiracetam. expressed in mg / kg of body weight. Therefore, there is no need to monitor the concentration of levetiracetam in the blood plasma.

In adults and children, a significant correlation was observed between the concentrations of the drug in saliva and blood plasma (the ratio of saliva / plasma concentration for the oral tablet dosage form and 4 hours after the dose for the oral dosage form was 1 to 1, 7).

Adults and teenagers

Suction

After oral administration levetiracetam quickly absorbed. Absolute bioavailability when taken orally approaches 100%.

The maximum concentration in plasma (C_max) is achieved after 1.3 hours after administration. The equilibrium state is achieved 2 days after the administration in a mode 2 times a day. The maximum concentrations (C_max) are usually 31 and 43 μg / ml with a single and repeated administration of the drug at a dose of 1000 mg 2 times a day, respectively.

The degree of absorption does not depend on the dose and it does not change under the influence of food.

Distribution

There is no data on the distribution of the drug in human tissues.

Neither levetiracetam, nor its basic metabolite does not bind to plasma proteins to a significant extent (<10%).

The volume of distribution of levetiracetam approximately corresponds to 0.5-0.7 l / kg, this value is close to the total volume of water in the body.

Biotransformation

Levetiracetam in the human body is not subjected to extensive metabolism. The main way of metabolism of the drug (24% of the dose) is the enzymatic hydrolysis of the acetamide group. Isozymes of liver cytochrome P450 do not participate in the formation of the main metabolite of the drug (ucb L057). Hydrolysis of the acetamide group takes place in a measurable degree in a large number of tissues, including blood cells. Metabolite ucb L057 is not pharmacologically active.

Also, two metabolites, contained in a small amount, were found. One of them was formed by hydroxylating the pyrrolidone ring (1.6% of the dose), the other by breaking the ring (0.9% of the dose). Other unidentified metabolites are only 0.6% of the administered dose.

The mutual conversion of enantiomers in vivo was not observed either for levetiracetam, or for its primary metabolite.

In vitro levetiracetam and its main metabolite are not inhibitors of the isoenzymes of the human cytochrome P450 system (CYP3A4, 2L6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferase (UGT1A1 AND UGT1A6), and epoxy hydroxylase. In addition, in vitro levetiracetam does not affect the glucuronation of valproic acid.

In human genatocyte culture levetiracetam has not or had little effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam induced easy induction of CYP2B6 and CYP3A4. Data on in vitro and in vivo interaction with oral contraceptives, digoxin and warfarin indicate that significant induction of enzymes in vivo is not expected. Thus, the interaction of levetiracetam with other substances or their effect on levetiracetam unlikely.

Elimination

Half-life (T_1/2) from plasma in adults was 7 ± 1 hour and did not change with a change in dose, route of administration or repeated administration of the drug. The average overall clearance was 0.96 ml / min / kg.

The main way of excretion is urinary excretion, on average 95% of the dose (approximately 93% of the dose was excreted within 48 hours).Excretion through the intestine makes up only 0.3% of the administered dose.

The total excretion in the urine of levetiracetam and its main metabolite during the first 48 hours is 66% and 24% of the dose, respectively.

The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml / min / kg, respectively, indicating removal of levetiracetam by glomerular filtration followed by partial reabsorption in the tubules; while the main metabolite is excreted by active tubular secretion in addition to glomerular filtration.

Elimination of levetiracetam correlates with creatinine clearance.

Elderly patients

In the elderly T_1/2, the drug is increased by approximately 40% (10-11 hours). This is due to a decrease in the function of the nights in this population.

Patients with impaired renal function

The values of the apparent overall clearance and levetiracetam and its main metabolite correlated with the values of creatinine clearance. Therefore, in patients with impaired renal function of moderate or severe severity, it is recommended to adjust the maintenance daily dose of levetiracetam based on the values of creatinine clearance.

In adult patients with anuria in the terminal stage of renal failure T_1/2, was approximately 25 and 3.1 hours during periods between and during dialysis sessions, respectively.

51% of levetiracetam is removed during a standard 4-hour dialysis session.

Patients with impaired hepatic function

In patients with impaired liver function of mild or moderate severity, no significant changes in the clearance of levetiracetam were observed. In most patients with severe impairment of liver function, the clearance of levetiracetam declined by more than 50% due to concomitant renal dysfunction.

Use in the pediatric population

Children (from 4 to 12 years)

After a single oral administration of levetiracetam at a dose of 20 mg / kg in children (aged 6 to 12 years) suffering from epilepsy, T_1/2, was 6.0 hours. The apparent clearance, corrected for body weight, was approximately 30% higher than in adult patients with epilepsy.

In children with epilepsy (aged 4-12 years), levetiracetam with repeated ingestion at a dose of 20-60 mg / kg / day absorbed rapidly. C_max in plasma was noted 0.5-1 hour after administration.The increase in the values of the maximum plasma concentration and the area under the curve was linear and proportional to the administered dose. T_1/2, was about 5 hours. The apparent overall clearance was 1.1 ml / min.

Infants and children (from 1 month to 4 years)

Children with epilepsy (aged 1 month to 4 years) after a single injection of oral solution (100 mg / ml) at a dose of 20 mg / kg levetiracetam was rapidly absorbed, and maximum plasma concentrations were observed after about 1 hour. The results of a study of pharmacokinetics indicate that T_1/2 (5.3 hours) was less than in adults (7.2 hours), and the apparent clearance was faster (1.5 ml / min / kg) than in adults (0.96 ml / min / kg).

In a population of pharmacokinetic analysis performed in patients aged 1 month to 16 years, body weight significantly correlated with apparent clearance (clearance increased with body weight increase) and an apparent volume of distribution. Age also influenced both parameters. This effect was more pronounced in infants of younger age and decreased with increasing age, disappearing to 4 years.

In both population-based pharmacokinetic analyzesa 20% increase in the apparent clearance of levetiracetam when it was co-administered with other antiepileptic drugs with a potential for induction of cytochrome P450 isoenzymes was detected.

Indications:

As a monotherapy (the drug of the first choice) in the treatment:

- partial seizures with secondary generalization or without it in adults and adolescents over 16 years with newly diagnosed epilepsy.

As part of complex therapy in the treatment of:

- partial seizures with secondary generalization or without it in adults and children over 6 years with epilepsy;

- Myoclonic seizures in adults and adolescents over 12 years with juvenile myoclonic epilepsy;

- Primary generalized convulsive (tonic-clonic) seizures in adults and adolescents over 12 years with idiopathic generalized epilepsy.

Contraindications:

Hypersensitivity to levetiracetam or other pyrrolidone derivatives, as well as to any components of the drug;

Children with body weight less than 25 kg (impossibility of accurate dosing);

Children under 6 years of age (the drug in this dosage form is not adapted for use in children under 6 years old).

Carefully:In elderly patients (over 65 years); with liver diseases in the stage of decompensation; with renal failure.

Pregnancy and lactation:

The results of several postmarketing prospective studies from more than 1,000 pregnant women taking levetiracetam as monotherapy during the first trimester of pregnancy, did not confirm a significant increase in the risk of serious fetal congenital malformations, but the teratogenic effects of levetiracetam on the fetus can not be excluded. Therapy with concomitant use of several pro-epileptic drugs is associated with a higher risk of congenital malformations in the fetus than with a single drug, so monotherapy should be considered as the preferred method of treatment during pregnancy. The results of animal studies have demonstrated the presence of reproductive toxicity when applying high doses of levetiracetam.

Adequate and strictly controlled clinical studies on the safety of levetiracetam in pregnant women have not been conducted,therefore, the drug should not be given to pregnant women and women of childbearing age who do not use adequate methods of contraception, except for clinically justified cases. Physiological changes in the body of a woman during pregnancy can affect the concentration in the plasma levetiracetam, as well as other progivoepileptic drugs. During pregnancy, there was a decrease in the concentration of levetiracetam in plasma. This decrease is more pronounced in the third trimester (up to 60% of the baseline concentration before the onset of pregnancy). Treatment with levetiracetam pregnant women should be carried out under special supervision. Interruptions in antiepileptic therapy may lead to a worsening of the course of the disease, which can harm the health of both the mother and the fetus.

In animal studies, fertility was not affected. There are no clinical studies.

Levetiracetam is excreted in breast milk, so breastfeeding is not recommended for treatment with the drug, unless the possible benefits of its use in the mother exceed the potential risk to the fetus.

Dosing and Administration:

Inside, regardless of food intake.

The daily dose of the preparation is divided into two doses in the same dose. Tablets are taken with a sufficient amount of liquid.

Monotherapy

Adults and teenagers over 16 years of age treatment should begin with a daily dose of 500 mg divided into 2 divided doses (250 mg twice a day). After 2 weeks, the dose may be increased to the initial therapeutic dose of 1000 mg (500 mg twice a day). If necessary, the dose can be changed by 250 mg twice a day every 2 weeks. The maximum daily dose is 3000 mg (1500 mg twice a day).

As part of complex therapy

Children older than 6 years and adolescents (12 to 17 years) with a body weight of less than 50 kg treatment should begin with a daily dose of 20 mg / kg body weight divided into 2 divided doses (10 mg / kg body weight 2 times a day). A dose change of 20 mg / kg body weight can be performed every 2 weeks until the recommended daily dose of 60 mg / kg body weight (30 mg / kg body weight 2 times a day). With intolerance of the recommended daily dose, it is possible to reduce it. The minimum effective dose should be used. The physician should prescribe the drug in the most suitable dosage form and dosage depending on the patient's body weight and the required therapeutic dose.

Children with a body weight of less than 25 kg are not recommended for treatment with the drug in this dosage form.

Children with a body weight of more than 50 kg are dosed according to the scheme given for adults.

Adults and adolescents over 16 years of age with a body weight of more than 50 kg treatment should begin with a daily dose of 1000 mg divided into 2 divided doses (500 mg twice a day). Depending on the clinical response and the tolerability of the drug, the daily dose can be increased to a maximum of 3000 mg (1500 mg twice a day). A dose change of 500 mg 2 times a day can be carried out every 2-4 weeks.

Because the levetiracetam is excreted from the body by the kidneys, when the drug is prescribed for patients with renal insufficiency and elderly patients, the dose should be adjusted depending on the amount of creatinine clearance (CC).

The creatinine clearance for men can be calculated based on the serum creatinine concentration, according to the following formula:

CK (ml / min) = [140 - age (years)] * body weight (kg) / 72 x KK_serum (mg / dL)

The creatinine clearance for women can be calculated by multiplying the obtained value by a factor of 0.85.

Then the QC is adjusted taking into account the body surface area (PPT) according to the following formula:

KK (ml / min / 1.73 m²) = KK (ml / min) / patient TFT (m²) (x 1,1,73)

Renal failure (severity)	CK (ml / min)	Dosing regimen
Norm	>80	from 500 to 1500 mg twice a day
Lightweight	50-79	from 500 to 1000 mg twice a day
Average	30-49	from 250 to 750 mg twice a day
Heavy	<30	from 250 to 500 mg twice a day
TThe terminal stage (patients on dialysis *)	-	from 500 to 1000 mg once a day **

* The first day of treatment is recommended to take a saturating dose of 750 mg.

** After dialysis, an additional 250-500 mg dose is recommended.

Children with renal insufficiency correction of the dose of levetiracetam should be made taking into account the degree of renal failure.

Creatinine clearance (ml / min / 1.73 m²) can be assessed based on serum creatinine (mg / dl) for adolescents and children using the following formula (Schwarz formula):

KK (ml / min / 1.73 m²) = Height (cm) x ks / KK_serum (mg / dL)

ks = 0.55 for children less than 13 years of age and adolescent females; ks = 0.7 for adolescent males.

Dosing for children and adolescents weighing less than 50 kg with impaired renal function.

Renal failure (severity)	QC (ml / min)	Dosing regimen
Renal failure (severity)	QC (ml / min)	Children over 6 years of age and adolescents weighing less than 50 kg
Norm	>80	10-30 mg / kg (0.10-0.30 ml / kg) twice daily
Lightweight	50-79	10-20 mg / kg (0.10-0.20 ml / kg) twice daily
Moderate	30-49	5-15 mg / kg (0.05-0.15 ml / kg) 2 times a day
Heavy	<30	5-10 mg / kg (0.05-0.10 ml / kg) twice daily
Terthe minal stage (patients on dialysis)	-	10-20 mg / kg (0.10 - 0.20 ml / kg) once a day (1) (2)

(1) 15 mg / kg (0.15 ml / kg) the recommended loading dose on the first day of treatment

(2) the recommended maintenance dose after dialysis is 5-10 mg / kg (0.05-0.10 ml / kg)

Patients with impaired liver function of mild to moderate severity correction of the dosing regimen is not required.

In patients with decompensated impairment of liver function and renal insufficiency the level of decrease in the clearance of creatinine may not fully reflect the severity of renal failure. In such cases, when creatinine clearance is <60 ml / min, a daily dose reduction of 50% is recommended.

Side effects:

General characteristics of the security profile

The adverse events profile presented below is based on an analysis of pooled placebo-controlled clinical trials for all the indications studied; a total of 3,416 patients received levetiracetam. These data are complemented by the use of levetiracetam in the relevant open-expanded clinical trials, as well as the experience of nostmarking.The most frequently observed adverse reactions were nasopharyngitis, drowsiness, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar in all age groups (in adults and children) and in all approved indications.

The frequency of adverse reactions was determined according to the following gradation (classification of the World Health Organization): very often - more than 1/10.

- often from more than 1/100 to less than 1/10.

- infrequently - from more than 1/1000 to less than 1/100.

- rarely - from more than 1/10000 to less than 1/1000.

- very rarely - from less than 1/10000, including individual messages.

Infectious and parasitic: very often - nasopharyngitis; rarely - infection.

Disturbances from the blood system and lymphatic system: infrequently, thrombocytopenia, leukopenia; rarely - pancytopenia (in some cases with oppression of bone marrow function), neutropenia, agranulocytosis.

Immune system disorders: rarely DRESS syndrome (drug hypersensitivity syndrome).

Disorders from the metabolism and nutrition: often - anorexia; infrequently, decrease in body weight, increase in body weight; rarely - hyponatremia.

Disorders of the psyche: often - depression, hostility or aggression, anxiety, insomnia, nervousness or irritability, emotional lability, mood swings; infrequently - suicide attempts, suicidal thoughts, psychotic disorders, panic attacks, behavioral disorders, hallucinations, anger, confusion, affective lability, mood changes, agitation; rarely - completed suicide, personality disorders, violation of thinking.

Impaired nervous system: very often - drowsiness, headache; often - convulsions, imbalance, dizziness, lethargy, tremor; infrequently - amnesia, memory impairment, ataxia, paresthesia, impaired attention; rarely - choreoathetosis, dyskinesia, hyperkinesia.

Disorders from the side of the organ of vision: infrequently - diplopia, blurred vision.

Disturbances from the organs of hearing and balance: often - vertigo.

Disturbances from the respiratory system, chest and mediastinal organs: often - a cough.

Disorders from the gastrointestinal tract: often - abdominal pain, diarrhea, indigestion, nausea, vomiting; rarely - pancreatitis.

Disorders from the liver and bile ducts: infrequently - changes in indicators of functional hepatic samples; rarely - hepatic insufficiency, hepatitis.

Disturbances from the skin and subcutaneous tissues: often - skin rash; infrequent-eczema, itchy skin, alopecia (in some cases, hair restoration was observed after drug withdrawal); rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Disturbances from the musculoskeletal and connective tissue: infrequently-muscular weakness, myalgia.

General disorders and disorders at the site of administration: often - asthenia, fatigue. Injuries, intoxications and complications of manipulation: infrequently - trauma.

Description of individual adverse reactions

The risk of anorexia increases with the joint use of tonyramate and levetiracetam. Several cases of alopecia have been observed (in several cases, after the removal of levetiracetam, recovery was noted).

Use in the pediatric population

In total levetiracetam treatment, 190 patients aged 1 month to 4 years were received in placebo-controlled studies and in open-label advanced studies.Sixty (60) of these patients were treated with levetiracetam in placebo-controlled studies. In total levetiracetam treatment, 645 patients aged 4 to 16 years were received in placebo-controlled studies and in open-label advanced studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In the data of both pediatric age groups, this data was supplemented by the experience of post-marketing application of levetiracetam.

The profile of undesirable phenomena of levetiracetam, as a rule, is similar in all age groups and when applied for all approved indications for epilepsy. The safety results for children in placebo-controlled studies were consistent with the safety profile of levetiracetam in adults, with the exception of behavioral changes and psychiatric adverse events observed more frequently in children than in adults. Vomiting (very often, 11.2%), excitation (often, 3.4%), mood changes (often, 2.1%), affective lability (often, 1, 7%), aggressiveness (often, 8.2%).behavioral disorders (often 5.6%) and drowsiness (often, 3.9%) were recorded more frequently than in other age groups or in the general safety profile. In infants and children aged 1 month to 4 years, irritability (very often 11.7%) and impaired coordination (often, 3.3%) were recorded more frequently than in other age groups or in the general safety profile.

A double-blind, placebo-controlled safety study in children, designed to demonstrate no less efficacy, evaluated the cognitive and neuropsychological effects of levetiracetam in children with partial convulsive seizures aged 4 to 16 years. In this study, it was concluded that levetiracetam does not differ (nc in effectiveness) placebo with respect to the change in the complex index of attention screening and associative memory on the Leiter-R scale from the baseline in the population who completed treatment according to the protocol. Results related to behavioral and emotional functioning showed worsening in patients treated with levetiracetam for aggressive behavior when measured using a standardized and systematic method using validated tools (Achenbach's Children's Behavioral Questionnaire (CBCL)).

However, patients who received levetiracetam in long-term outdoor observational study, an average of no marked deterioration in behavioral and emotional functioning, in particular when measured aggressive behavior deterioration was not observed from the initial level.

Overdose:

Symptoms: drowsiness, anxiety, aggressiveness, oppression of consciousness, respiratory depression, coma.

Treatment: in the acute period - the artificial challenge of vomiting and gastric lavage followed by the appointment of activated charcoal. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment in a hospital using hemodialysis (dialysis efficiency for levetiracetam is 60%, for its primary metabolite - 74%).

Interaction:

Antiepileptic drugs

According to clinical studies conducted in adult patients, levetiracetam ns had an influence on the concentration of other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) in the blood plasma, and the data antiepileptic drugs also ns effect on the pharmacokinetic parameters of levetiracetam.

With the joint administration of Zenicetam ® with topiramate, the likelihood of anorexia is increased.

As in adults, clinically significant drug interactions levetiracetam when used in children at doses up to 60 mg / kg per day was not noted.

A retrospective study of pharmacokinetic drug interactions in children and adolescents with epilepsy (aged 4 to 17 years) confirmed that additional therapy with levetiracetam when ingested did not affect the equilibrium plasma concentrations of carbamazepine and aaliroate when used concomitantly. However, the data obtained indicate an increase in the clearance of levetiracetam by 20% in children receiving antianyleptic drugs that are inducers of cytochrome P450 isoenzymes. In this case, dose adjustment is not required.

Probenecid

Probenecid (at a dose of 500 mg 4 times a day) - a drug that blocks tubular secretion in the kidneys, has demonstrated the ability to reduce the renal clearance of the main metabolite of levetiracetam, but not of levetiracetam itself. Nevertheless, the concentration of this metabolite in the body remains low.It is expected that other drugs released by active tubular secretion can also reduce the renal clearance of this metabolite. The effect of levetiracetam on probenecid has not been studied, and the effect of levetiracetam on other drugs that are released by active route (for example, NSAIDs, sulfonamides and methotrexate).

The drug Zenicetam ® in a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).

The drug Zeicetam® in a daily dose of 2000 mg does not change the pharmacokinetics of digoxin and warfarin.

Digoxin, oral contraceptives and warfarin do not affect the pharmacokinetics of Zenicetam ®.

The degree of absorption of the drug Zenicetam® does not change under the influence of food, while the rate of absorption decreases slightly.

Data on the effect of antacids on the absorption of Zeicetam® are not available.

In the literature, there are data on a decrease in the effectiveness of levetiracetam when administered concomitantly with an osmotic laxative - a macrogol. Therefore, the macro code should be taken one hour before or one hour after taking levetiracetam.

There are no data on the interaction of Zeicetam® with alcohol.

Special instructions:

If it is required to stop taking Zenicetam ®, then it is recommended to cancel the treatment gradually (reducing the single dose by 500 mg every 2-4 weeks). In children, the dose reduction should not exceed 10 mg / kg of body weight 2 times a day every 2 weeks.

Concomitant antiepileptic drugs (during the transfer of patients to receive Zenicetam®) should be gradually phased out.

The available information on the use of the drug in pediatric practice does not indicate any of its negative effects on the physical and sexual development of children. However, the long-term consequences of treatment on the ability of children to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

Patients with kidney disease and decompensated liver disease are recommended to study the function of the nights before treatment. If the function of the nights is disturbed, a dose adjustment may be required.

In connection with the available reports of cases of suicide,suicidal intentions and suicide attempts in the treatment with Zenicetam® should alert patients to immediately notify the attending physician of any symptoms of depression or suicidal intentions.

Effect on the ability to drive transp. cf. and fur:Effect of Zenicetam® on the ability to drive vehicles and engage in other potentially hazardous activities has not been studied. Nevertheless, due to the different individual sensitivity to the drug from the central nervous system during the treatment period, it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Tablets, film-coated 250 mg, 500 mg, 750 mg, 1000 mg.

Packaging:For 10 tablets in a PVC / Alu blister. By 1,2, 3, 5, 6, 8, 10, 12 or 20 blisters together with instructions for use in a cardboard package.

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 stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003115

Date of registration:23.07.2015 / 28.07.2017

Expiration Date:23.07.2020

The owner of the registration certificate:SANOFI RUSSIA, CJSCSANOFI RUSSIA, CJSC

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Representation: & nbspSanofi Russia, JSCSanofi Russia, JSCRussia

Information update date: & nbsp11.10.2017

Illustrated instructions

Instructions

Zenicetam® (Zenicetam)