Keppra - instructions for use, doses, side effects, contraindications

Levetiracetam - the active substance of the drug Keppra® is a derivative of pyrrolidone (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide) differs in chemical structure from known antiepileptic drugs.

Mechanism of action

The mechanism of action of levetiracetam is not fully understood. Experiments in vitro and in vivo showed that levetiracetam does not affect the basic characteristics of cells and normal neurotransmission.

Research in vitro showed that levetiracetam affects the intra-neuronal concentration of Ca²⁺, partially inhibiting the current of Ca²⁺ through N-type channels and, reducing the release of calcium from intra-neuronal depots. Besides, levetiracetam partially restores currents through GABA and glycine-dependent channels, reduced by zinc and β-carbolines. Also in studies in vitro it was determined that levetiracetam binds to a specific site in the brain tissue. The binding site is a 2A synaptic vesicle protein, which is thought to be involved in the fusion of vesicles and the exocytosis of neurotransmitters. Levetiracetam and the associated analogs differ in binding affinity to the synaptic vesicle protein 2A, which correlates with the degree of antiepileptic protection in the audiogenic model of epilepsy in mice. This fact suggests that the interaction between levetiracetam and the 2A protein of synaptic vesicles obviously contributes to the anticonvulsant mechanism of action of the drug.

Pharmacodynamic effects

Levetiracetam induces antiepileptic protection in a variety of animal models of partial and primary generalized seizures, without manifesting a pro-convulsive effect. The main metabolite of levetiracetam is not active.

In humans, the activity of levetiracetam in relation to epilepsy and with partial,and with generalized seizures (epileptiform discharges / photoparoxysmal reaction) confirms its broad pharmacological profile.

Clinical efficacy and safety

Additional therapy in the treatment of partial seizures with secondary generalization or without it in adults, adolescents and children from the age of 4 with epilepsy

The efficacy of levetiracetam in adults was confirmed in three double-blind, placebo-controlled trials using 1000 mg, 2000 mg and 3000 mg / day, divided into two doses with a treatment duration of up to 18 weeks. It was shown that the proportion of patients who showed a 50% or more reduction in the frequency of partial seizures per week relative to the baseline with a stable dose (12/14 weeks) was 27.7%, 31.6% and 41.3% who took levetiracetam in a dose of 1000, 2000 or 3000 mg, respectively, and 12.6% in patients taking placebo.

Children

The efficacy of levetiracetam in children (aged 4 to 16 years) was established in a double-blind, placebo-controlled, 14-week study of 198 patients. Patients in this study took levetiracetam in a constant dose of 60 mg / kg / day (in two divided doses).

44.6% of patients taking levetiracetam, and 19.6% of patients receiving placebo demonstrated a 50% or more reduction in the frequency of partial seizures per week relative to baseline. Against the backdrop of continuing long-term treatment, 11.4% of patients had no seizures for at least 6 months and 7.2% for at least 1 year.

In placebo-controlled clinical trials, 35 infants younger than 1 year of age with partial seizures, of which only 13 were <6 months old.

Monotherapy in the treatment of partial seizures with secondary generalization or without it in patients with 16 years of age and older with newly diagnosed epilepsy

The efficacy of levetiracetam in monotherapy was comparable to that of controlled-release carbamazepine in parallel groups in a double-blind study in 576 patients 16 years of age and older with newly diagnosed or newly diagnosed epilepsy. Patients were included in the study only with unprovoked partial seizures or generalized tonic-clonic seizures.Patients were randomized to 400-1200 mg / day controlled release carbamazepine or leuketracetam 1000-3000 mg / day, up to 121 weeks depending on the response.

Absence of seizures within 6 months was noted in 73% of patients taking levetiracetam and 72.8% of patients receiving carbamazepine with controlled release; the adjusted absolute difference between treatment rates was 0.2% (95% confidence interval: -7.8-8.2). More than half of the patients had no seizures within 12 months (56.6% and 58.5% of patients on levetiracetam and carbamazepine with controlled release, respectively).

In a study reflecting clinical practice, concomitant antiepileptic drugs could be withdrawn in a limited number of patients who responded to additional levetiracetam therapy (36 adult patients out of 69).

Additional therapy for the treatment of myoclonic seizures in adults and adolescents with 12 years and older with juvenile myoclonic epilepsy

The efficacy of levetiracetam was established in a double-blind placebo-controlled study of 16 weeks for patients 12 years of age and older with idiopathic generalized epilepsy with myoclonic cramps in various syndromes. Most patients had juvenile myoclonic epilepsy. In this study, the dose levetiracetam was 3000 mg / day in two divided doses.

58.3% of patients taking levetiracetam, and 23.3% of patients taking placebo had at least a 50% reduction in the number of days with myoclonic seizures per week. During the ongoing long-term treatment, 28.6% of patients did not have myoclonic seizures for at least 6 months, and 21% of patients for at least one year.

Additional therapy for the treatment of primary generalized tonic-clonic seizures in adults and adolescents with age 12 and older with idiopathic generalized epilepsy

The efficacy of levetiracetam was established in a 24-week, double-blind, placebo-controlled study that included adults, adolescents, and a limited number of children with idiopathic generalized epilepsy with primary generalized tonic clonic seizures,with various syndromes (juvenile myoclonic epilepsy, juvenile absence-epilepsy, child absent-epilepsy, or epilepsy with generalized tonic-clonic convulsions upon awakening). In this study, the daily dose of levetiracetam was 3000 mg / day for adults and adolescents, or 60 mg / kg / day for children, divided into two doses.

72.2% of patients who took levetiracetam, and 45.2% of patients taking placebo showed a 50% or more reduction in seizure frequency during the week in patients with PGTK seizures. In a continuing long-term follow-up, 47.4% of patients had no tonic-clonic seizures for at least 6 months, and 31.5% of patients had no tonic-clonic seizures for at least one year.

Pharmacokinetics:

The pharmacokinetic profile is described on the basis of oral administration. The dose of levetiracetam 1500 mg with intravenous administration is bioequivalent to a dose of 1500 mg taken internally in the form of tablets. A single dose of levetiracetam 1500 mg diluted in 100 ml of 0.9% sterile isotonic solution and administered intravenously for 15 minutes is equivalent to a dose of 1500 mg of levetiracetam taken orally in three 500 mg administrations.

Intravenous administration of a dosage of up to 4000 mg / day diluted in 100 ml of 0.9% sterile isotonic solution and administered for 15 minutes and a dosage of up to 2500 mg / day diluted in 100 ml of 0.9% sterile isotonic solution and administered within 5 minutes. The resulting pharmacokinetic profile and safety profile did not reveal any safety problems.

Levetiracetam is a highly soluble substance with a high penetrating ability. Levetiracetam has linear pharmacokinetics with low intra- and intersubject variability. The clearance of levetiracetam remains constant after repeated administration of the drug. The time-independent pharmacokinetic profile was also confirmed by intravenous administration of 1500 mg twice daily for 4 days.

There was no dependence of pharmacokinetics on sex, race or time of day. The pharmacokinetic profile is comparable in healthy volunteers and patients with epilepsy.

Adults and teenagers

Distribution

The maximum concentration (C_mOh) after an intravenous single administration of 1500 mg was achieved after 15 minutes and was 51 ± 19 μg / ml. Neither levetiracetam, nor its main metabolite is significantly associated with plasma proteins (<10%). The volume of distribution (V_d) is approximately 0.5-0.7 l / kg, which is close to the total volume of fluid in the body.

Metabolism

Levetiracetam is inactive metabolized in the human body. The main metabolic pathway (24% of the dose) is the enzymatic hydrolysis of the acetamide group. Formation of the primary metabolite ucb L057 occurs without the participation of cytochrome P450 isoenzymes of the liver. Metabolite ucb L057 is pharmacologically inactive.

In addition, two secondary metabolites were identified. The first is formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), and the second - with the opening of the pyrrolidone ring (0.9% dose). Other unidentified components account for only 0.6% of the dose, levetiracetam and its main metabolite were not mutually transformed in vivo.

In conditions in vitro levetiracetam and its main metabolite do not suppress the main isoforms of human liver cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), the activity of glucuronyl transferases (UGT1A1 and UGT1A6) and epoxy hydroxylase. Besides, levetiracetam does not affect the glucuronization of valproic acid in vitro.

In human hepatocyte culture levetiracetam had little impact on CYP1A2, SULT1E1 and UGT1A1 or did not change their activity at all. Levetiracetam induced easy induction CYP2B6 and CYP3A4.

Based on the results of the evaluation of interactions with oral contraceptives, digoxin and warfarin in conditions in vitro and in vivo no significant induction of enzymes is expected in conditions in vivo. Thus, the probability of interaction between Keppra® and other drugs, and vice versa, is unlikely.

Excretion

Half-life (T_1/2) from the blood plasma of an adult is 7 ± 1 h and does not depend on the dose, mode of administration or frequency of administration. The average overall clearance is 0.96 ml / min / kg. The main way of excretion by the kidneys is on average 95% of the dose (about 93% of the dose is withdrawn within 48 hours). Excretion with faeces is 0.3% of the dose.

The total excretion level of levetiracetam and its main metabolite in the urine in the first 48 hours is 66% and 24% of the dose, respectively. Renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml / min / kg, respectively, indicating that levetiracetam is excreted by glomerular filtration followed by tubular reabsorption,and that the primary metabolite of the drug is also excreted by active tubular secretion in addition to glomerular filtration. The removal of levetiracetam is correlated with the clearance of creatinine.

Elderly patients

In elderly patients T_1/2 increases by 40% and is 10-11 hours, which is associated with impaired renal function in this category of people.

Patients with impaired renal function

The clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, patients with moderate to severe renal insufficiency are recommended to select a dose depending on the creatinine clearance. In the anuric terminal stage of renal failure in adult patients, T_1/2 is 25 hours between dialysis sessions and 3.1 hours during dialysis. 51% of levetiracetam is removed during a 4-hour dialysis session.

Patients with impaired hepatic function

In patients with impaired liver function of mild and moderate severity, no significant changes in the clearance of levetiracetam occur. In most patients with severe impairment of liver function with concomitant renal failure, the clearance of levetiracetam decreases by more than 50%.

Children from 4 to 12 years old

In children, the pharmacokinetics of levetiracetam administered intravenously has not been studied. However, according to pharmacokinetic parameters of levetiracetam, pharmacokinetics in adults after intravenous administration and pharmacokinetics in children after oral administration, the value AUC (area under the curve) is expected to be comparable after intravenous and oral administration of levetiracetam in children aged 4 to 12 years. After a single oral administration of levetiracetam (at a dose of 20 mg / kg) to children with epilepsy (aged 6 to 12 years), the half-life of levetiracetam was 6.0 hours. The total clearance of levetiracetam, weight-adjusted, was approximately 30% higher than in adults with epilepsy.

After repeated oral administration at a dose of 20-60 mg / kg / day for children with epilepsy (aged 4 to 12 years) levetiracetam quickly absorbed. The maximum plasma concentration is achieved after 0.5-1.0 hours after administration. The maximum plasma concentration and area under the curve increased linearly and proportionally to the dose. The half-life is approximately 5 hours. The total clearance is 1.1 ml / min / kg.

Indications:

This dosage form can be used as a temporary alternative if oral dosage forms are not possible.

As a monotherapy in the treatment of:

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

In the complementary therapy in the treatment:

partial seizures with secondary generalization or without it in adults and children older than 4 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 under 4 years of age (safety and efficacy not established).

Carefully:

- Patients of advanced age (over 65 years);

- liver disease in the stage of decompensation;

- renal insufficiency.

Pregnancy and lactation:

Pregnancy

In post-marketing data obtained from several prospective pregnancy registries, more than 1,000 cases of monotherapy with levetiracetam in the first trimester of pregnancy have been recorded. In general, these data do not indicate a significant increase in the risk of serious congenital malformations, although teratogenic risk can not be completely ruled out. Therapy with several antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, which is why monotherapy in pregnant women is more appropriate. Studies in animals have shown the reproductive toxicity of levetiracetam. Levetiracetam should not be prescribed during pregnancy and in women with a preserved reproductive function that do not use contraception, except in cases of clinical necessity.

Physiological changes in the body of a woman during pregnancy can affect the concentration of levetiracetam in plasma. 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 during the third trimester).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 the fetal matter.

Breastfeeding period

Levetiracetam is excreted in breast milk, so breastfeeding during treatment with the drug is not recommended.

However, if treatment with levetiracetam is necessary during the feeding period, the risk / benefit ratio of treatment should be carefully weighted relative to the importance of feeding.

Fertility

In animal studies, no effect on fertility was found. Clinical data on the effect on fertility are not available, the potential risk to humans is unknown.

Dosing and Administration:

Treatment can be started with both intravenous administration and oral administration.

The transition from oral to intravenous administration and back can be carried out with preservation of the dose and the frequency of administration.

One vial of concentrate for solution for infusion contains 500 mg of levetiracetam (100 mg / ml).

The daily dose is divided into two doses in the same dose.

This dosage form is intended only for intravenous use and before use, the concentrate must be diluted with a solvent of at least 100 ml; is administered intravenously for 15 minutes.

Instructions for preparation and dosing of the solution

Dose	Amount of preparation	Volume of solvent	Infusion time	Frequency of administration	Daily dose
250 mg	2.5 ml (half a vial of 5 ml)	100 ml	15 minutes	2 times a day	500 mg / day
500 mg	5 ml (1 bottle of 5 ml)	100 ml	15 minutes	2 times a day	1000 mg / day
1000 mg	10 ml (2 bottles of 5 ml each)	100 ml	15 minutes	2 times a day	2000 mg / day
1500 mg	15 ml (3 bottles of 5 ml each)	100 ml	15 minutes	2 times a day	3000 mg / day

The following solvents can be used:

- solution of sodium chloride 0,9% for injections;

- Ringer's lactate solution for injection;

- 5% dextrose solution for injection.

This medication is intended solely for single use; The unused solution must be disposed of.

Keppra® concentrate for the preparation of an infusion solution is physically compatible and chemically stable for at least 24 hours, provided it is diluted with these solvents and stored in polyvinyl chloride bags at controlled room temperature of 15-25 ° C.

Do not use the drug when changing the color of the solution or the appearance of mechanical inclusions.

Monotherapy in adults and adolescents over 16 years of age

Treatment should begin with a dose of 250 mg 2 times a day, which can be increased to 500 mg 2 times a day after 2 weeks. In the future, this dose can be increased by 250 mg 2 times a day every 2 weeks, depending on the clinical response. The maximum daily dose is 1500 mg 2 times a day.

As part of complementary therapy in adults over 18 years and adolescents (aged 12 to 17 years) with a body weight of 50 kg and more

Treatment should begin with a dose of 500 mg 2 times a day. This dose can be used from the first day of treatment. Depending on the clinical response and the tolerability of the drug, the daily dose can be increased to a maximum of 1500 mg twice a day. A change (increase or decrease) in a dose of 500 mg twice a day can be done every 2-4 weeks.

Duration of treatment

Clinical experience of infusion application of levetiracetam in the period exceeding 4 days is absent.

Discontinuation of treatment

If it is necessary to stop treatment, it is carried out gradually (for example,in adults and adolescents with a body weight of more than 50 kg, the dose is reduced by 500 mg twice a day every 2-4 weeks; For children and adolescents weighing less than 50 kg, the dose is reduced by no more than 10 mg / kg 2 times a day every two weeks).

Special Populations

Elderly patients (65 years and older)

Elderly patients with impaired renal function should adjust the dose (see section "Patients with impaired renal function").

Patients with impaired renal function

The daily dose should be adjusted based on the indicators of kidney function.

Guidelines for adjusting the dose for adults with impaired renal function are given in the following table. The dose is selected based on the amount of creatinine clearance (CK) in ml / min. For adults and adolescents with a body weight of 50 kg or more, the QC value in ml / min can be calculated on the basis of the serum creatinine level (mg / dL) according to the following formula:

CK (ml / min) = [140 - age (years)] x body weight (kg) (x 0.85 for women) / 72 x QC_serum (mg / dL)

The QC is then corrected for body surface area (PPT) according to the following formula:

KK (ml / min / 1.73 m²) = SC (ml / min) x 1.73 / PPT of the facility (m²)

Dose adjustment for adults and adolescents with a body weight of more than 50 kg with impaired renal function

Renal insufficiency	KK (ml / min / 1.73 m²)	Dosing regimen
Norm	>80	from 500 to 1500 mg twice a day
Lightweight	50-79	from 500 to 1000 mg twice a day
Moderate	30-49	from 250 to 750 mg twice a day
Heavy	<30	from 250 to 500 mg twice a day
Terminal stage (patients on dialysis)⁽¹⁾		from 500 to 1000 mg once a day⁽²⁾

⁽¹⁾ On the first day of treatment, a saturating dose of 750 mg is recommended.

⁽²⁾ 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 insufficiency, since the clearance of levetiracetam depends on the function of the kidneys. This recommendation is based on the results of a study involving adult patients with impaired renal function.

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 old and adolescent females; ks= 0.7 for adolescent males.

Dose adjustment for children and adolescents with a body weight of less than 50 kg with impaired renal function

Renal insufficiency	KK (ml / min / 1.73 m²)	Dosing regimen
Renal insufficiency	KK (ml / min / 1.73 m²)	Children older than 4 years and adolescents with a body weight of 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) twice daily
Heavy	<30	5-10 mg / kg (0.05-0.10 ml / kg) twice daily
Terminal stage (patients on dialysis)		10-20 mg / kg (0.10-0.20 ml / kg) once a day ⁽¹⁾⁽²⁾

⁽¹⁾On the first day of treatment, a saturating dose of 15 mg / kg (0.15 ml / kg) is recommended.

⁽²⁾After dialysis, an additional dose of 5-10 mg / kg (0.05-0.10 ml / kg) is recommended,

Patients with impaired hepatic function

Patients with a malfunction of the liver of mild and moderate severity of the correction of the dosing regimen is not required. In patients with severe impairment of liver function, the degree of decrease in creatinine clearance may not fully reflect the severity of renal failure. In such cases, when the creatinine clearance is <60 ml / min / 1.73 m² it is recommended to reduce the daily dose by 50%.

Children

The doctor should choose the most suitable dosage form, dosage form and dosage, depending on the age, weight and dosage required.

Monotherapy

The safety and efficacy of Keppra® in children and adolescents under 16 years of age in monotherapy is not established. Data not available.

Additional therapy in children from 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg

The initial therapeutic dose is 10 mg / kg twice a day. The dose can be increased to 30 mg / kg twice a day, depending on the clinical response and tolerability. The dose can be changed (increased or decreased) by no more than 10 mg / kg twice a day every two weeks. The minimum effective dose should be used. Children with a body weight of 50 kg or more should use the same dose as in adults.

Featured children and adolescents dosage:

Body mass	Initial dose: 10 mg / kg twice daily	Maximum dose: 30 mg / kg 2 times a day
15 kg⁽¹⁾	150 mg twice daily	450 mg twice daily
20 kg⁽¹⁾	200 mg twice daily	600 mg twice daily
25 kg	250 mg twice daily	750 mg twice a day
From 50 kg⁽²⁾	500 mg twice a day	1500 mg twice a day

⁽¹⁾In children with a body weight of 25 kg or less, it is preferable to begin treatment with Keppra solution for ingestion 100 mg / ml.

⁽²⁾ Children and adolescents with a body weight of 50 kg or more should use the same dose as in adults.

Additional therapy in infants and children under 4 years of age

The safety and effectiveness of the use of Keppra® in the form of a concentrate for the preparation of a solution for infusions in infants and children under the age of 4 years have not been established.

The data available to date are listed in the "Side effect" and "Pharmacokinetics" sections, but there are no recommendations for choosing doses.

Side effects:

Security Profile Overview

The following profile of adverse events is based on an analysis of the results of placebo-controlled studies on all the indications studied, as well as on the experience of post-marketing application of levetiracetam. The most frequent adverse reactions were nasopharyngitis, drowsiness, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar for different age groups (adults and children) and approved indications for epilepsy use.

Undesirable reactions are listed below for systems and organs and the frequency of occurrence: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1,000, <1/100); rarely (≥1 / 10,000, <1/1 000) and very rarely (<1/10 000).

Infections and invasions

Often: nasopharyngitis

Rarely: infection

On the part of the blood and lymphatic system

Infrequently: thrombocytopenia, leukopenia

Rarely: agranulocytosis, pancytopenia, neutropenia

From the immune system

Rarely: drug allergy with eosinophilia and systemic manifestations (DRESS-syndrome), hypersensitivity (including angioedema and anaphylaxis)

From the side of metabolism and nutrition

Often: anorexia

Infrequent: weight gain, weight loss

Rarely: hyponatremia

Mental disorders

Often: Depression, hostility / aggressiveness, anxiety, insomnia, nervousness / irritability

Infrequently: suicide attempts, suicidal intentions, psychotic disorders, behavioral disorders, hallucinations, anger, confusion, panic attacks, emotional lability / mood swings, agitation

Rarely: suicide, personality disorder, thinking disorder

From the nervous system

Often: drowsiness, headache

Often: convulsions, imbalance, dizziness, lethargy, tremor

Infrequently: amnesia, memory impairment, impaired coordination / ataxia, paresthesia, decreased concentration of attention

Rarely: choreoathetosis, dyskinesia, hyperkinesia

From the side of the organ of vision

Infrequently: diplopia

From the side of the hearing organ and labyrinthine disorders

Often: vertigo

On the part of the respiratory system, the organs of the thorax and the mediastinum

Often: cough

From the gastrointestinal tract

Often: abdominal pain, diarrhea, indigestion, vomiting, nausea

Rarely: pancreatitis

From the liver and biliary tract

Infrequently: change in functional liver samples

Rarely: hepatic failure, hepatitis

From the side of the kidneys and urinary tract

Rarely: acute renal failure

From the skin and subcutaneous tissues

Often: rash

Infrequently: alopecia, eczema, itching

Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme

From the musculoskeletal and connective tissue

Infrequently: muscle weakness, myalgia

General disorders

Often: asthenia / fatigue

Injuries and complications of manipulation

Infrequently: accidental damage

Description of individual adverse reactions

The risk of anorexia is higher with the simultaneous use of levetiracetam and topiramate.

In a number of cases of alopecia, hair restoration was observed after the removal of levetiracetam.

In some cases of pancytopenia, bone marrow depression was recorded.

Children

In placebo-controlled and open-label advanced trials, levetiracetam was treated with 190 patients aged 1 month to 4 years. Sixty of them received levetiracetam in placebo-controlled trials. In placebo-controlled and open advanced studies, levetiracetam was treated with 645 patients aged 4 to 16 years. 233 of them received levetiracetam in placebo-controlled trials. The data for both age groups are supplemented by the results of the use of levetiracetam in the post-marketing period.

In addition, in the post-marketing security study levetiracetam received 101 infants under the age of 12 months. There were no new safety threats associated with the use of levetiracetam in infants with epilepsy less than 12 months of age.

The safety profile of levetiracetam is generally comparable for different age groups and approved indications for epilepsy use. The safety profile of children in placebo-controlled clinical trials was comparable to the safety profile of levetiracetam in adults, except for behavioral and mental disorders that were more frequent in children than in adults.

In children and adolescents aged 4 to 16 years compared with other age groups andsafety profile in general often recorded following undesirable reaction: vomiting (very often, 11.2%), agitation (often 3.4%), changeability of mood (often 2.1%), emotional lability (often 1.7 %), aggressiveness (often, 8.2%), behavioral disorders (often, 5.6%) and lethargy (often, 3.9%).

In children aged 1 month to 4 years, compared with other age groups and the safety profile as a whole, the following adverse reactions were more often recorded: irritability (very often 11.7%) and coordination impairment (often 3.3%).

In a double-blind, placebo-controlled study, the safety profile of children evaluated the cognitive and neuropsychological effects of Keppra® in children aged 4-16 years with partial seizures. According to the study, it was concluded that the drug Keppra® was not different from placebo (non-inferior to him) with regard to changes in the amount of points on the sections "Attention and Memory" and "Combined Screening Memory" Leiter-R scale (Leiter-R) in patients who underwent a study in accordance with the protocol.

As a result of the analysis of the behavioral and emotional status with the help of a validated tool - the Achenbach questionnaire (Achenbach), aggressive behavior was revealed in the group of patients taking Keppra®. However, patients who took Keppra® during long-term follow-up in the open phase of the study did not show a worsening of behavioral and emotional status, in particular, the indicators of aggressive behavior did not deteriorate compared to baseline.

Overdose:

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

Treatment: There is no specific antidote for levetiracetam. Treatment of an overdose is symptomatic and may include hemodialysis. The efficiency of excretion in hemodialysis for levetiracetam is 60%, for its primary metabolite - 74%.

Interaction:

Antiepileptic drugs

The results of pre-registration clinical trials conducted in adults showed that levetiracetam does not affect the plasma concentration of known antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and these antiepileptic drugs do not affect the pharmacokinetics of levetiracetam.

As in adults, the data in favor of clinically significant drug interactions in children receiving levetiracetam in a dose up to 60 mg / kg / day, are absent.

Retrospective analysis of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that the use of levetiracetam oral mode adjunctive therapy had no effect on the equilibrium concentration in the serum of carbamazepine and valproate, taken at the same time. Nevertheless, according to available data, the clearance of levetiracetam in children receiving treatment with enzyme-inducing antiepileptic drugs is 20% higher. No dose adjustment is required.

Probenecid

It was shown that probenecid, a tubular secretion blocker (500 mg 4 times / day), inhibits renal clearance of the main metabolite of levetiracetam, but not of levetiracetam itself. Nevertheless, the concentration of this metabolite remains low.

Methotrexate

With the simultaneous use of levetiracetam and methotrexate, it was noted that the clearance of methotrexate decreases, leading to an increase in the concentration of methotrexate in the blood to potentially toxic levels or an extension of the period of maintenance of this concentration.Patients receiving both drugs should monitor the level of methotrexate and levetiracetam in blood plasma.

Oral contraceptives and other pharmacokinetic interactions

Levetiracetam in a daily dose of 1000 mg does not affect the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); and also does not change the endocrine function (luteinizing hormone and progesterone).

Levetiracetam in a daily dose of 2000 mg does not change the pharmacokinetics of digoxin and warfarin; and does not change prothrombin time.

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

Alcohol

There are no data on the interaction of levetiracetam with alcohol.

Special instructions:

Impaired renal function

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

Suicide

In the treatment with antiepileptic drugs, in particular levetiracetam, there were reports of completed suicides, suicidal attempts, suicidal thinking and behavior.In a meta-analysis of randomized placebo-controlled studies of antiepileptic drugs, a small increase in the risk of developing suicidal thinking and behavior was found. The mechanism of increasing the risk is not known.

Thus, in the treatment with levetiracetam, it is necessary to monitor the signs of depression and (or) suicidal thinking and behavior and, if necessary, conduct appropriate treatment. Patients (and their caregivers) need to be warned that if they show signs of depression and / or suicidal thinking or behavior, they should consult a doctor.

Children

The available data on the use of levetiracetam in children indicate a lack of influence of this drug on growth and puberty. Nevertheless, the long-term effects on learning ability, mental capacity, growth, endocrine function, puberty and childbearing potential of children remain unknown.

Excipients

The preparation contains 0.83 mmol (or 19 mg) of sodium per ampoule. This should be taken into account for patients on a diet with sodium restriction.

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

Levetiracetam has a minimal or moderate effect on the ability to drive vehicles and control mechanisms. Due to possible differences in individual sensitivity, some patients may develop drowsiness or other symptoms from the central nervous system, especially at the beginning of treatment or after increasing the dose. Therefore, such patients are advised to use caution when performing tasks requiring skilled skills, for example, when driving vehicles or when working with machinery. Patients should refrain from driving or working with machinery until they are confident that their ability to perform the tasks listed above is not compromised.

Form release / dosage:Concentrate for the preparation of a solution for infusions, 100 mg / ml.

Packaging:

5 ml of the solution in a glass vial sealed with Teflon stopper, rolled up with an aluminum cap, top coated with a polypropylene cover, providing control of the first opening.

5 bottles are placed in a contour mesh package.

2 contour packagings along with the instructions for use are placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000325

Date of registration:22.02.2011 / 22.07.2016

Expiration Date:Unlimited

The owner of the registration certificate: YUSB Farma S.A. YUSB Farma S.A. Belgium

Manufacturer: & nbsp

Aesica Pharmaceuticals Srl Italy

Representation: & nbspYUSB FARMA LLC YUSB FARMA LLC Russia

Information update date: & nbsp25.09.2016

Illustrated instructions

Instructions

Keppra® (Keppra®)