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

Excipients: croscarmellose sodium 10,750 mg, macrogol 6000 2,500 mg, silicon dioxide 5,188 mg, magnesium stearate 0.313 mg; opadrai 85F20694 -8.063 mg [dye indigokarmin (E132), macrogol 3350, partially hydrolysed polyvinyl alcohol, talc, titanium dioxide (E171)].

In 1 tablet 500 mg contains:

active substance: levetiracetam - 500 mg;

Excipients: croscarmellose sodium 21,500 mg, macrogol 6000 5,000 mg, silicon dioxide 10,375 mg, magnesium stearate 0.625 mg; opadray 85F32004 -16,125 mg [iron coloring yellow oxide (E172), macrogol 3350, partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide (E171)].

In 1 tablet 1000 mg contains:

active substance: levetiracetam - 1000 mg;

Excipients: croscarmellose sodium 43,000 mg, macrogol 6,000 10,000 mg, silicon dioxide 20,750 mg, magnesium stearate 1,250 mg; opadrai 85F18422-32.250 mg [macrogol 3350, partially hydrolysed polyvinyl alcohol, talc, titanium dioxide (E171)].

Description:

Tablets 250 mg: blue oval-shaped tablets, film-coated, with biconvex surfaces, with one-sided risk, on one side of which there is engraving "ucb", on the other - "250"; on the fracture are homogeneous, white.

Tablets 500 mg: light yellow oval-shaped tablets, film-coated, with biconvex surfaces, with one-sided risk, on one side of which there is engraving "ucb", on the other - "500"; on the fracture are homogeneous, white.

Tablets 1000 mg: white oval-shaped tablets covered with a film sheath, with biconvex surfaces, with a one-sided risk, on one side of which there is engraving "ucb", on the other - "1000"; on the fracture are homogeneous, white.

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 Keppra preparation, is a derivative of pyrrolidone (the S-enantiomer of a-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 have shown that levetiracetam does not affect the basic characteristics of cells and normal neurotransmission.

In vitro studies have shown that levetiracetam affects the intra-neuronal concentration of Ca^2-, 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 (3-carbolines.) Also in in vitro studies, 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 generalized seizures (epileptiform discharges / photoparoxysmal reaction) is confirmed by 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 baseline with a constant 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.

Pediatric population

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 showed 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 children younger than 1 year of age with partial seizures participated, 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 studylasting 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 in a week. During continued long-term treatment, 28.6% of patients did not have myoclonic seizures for at least 6 months, and 21% of patients had not had 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:

There was no dependence of pharmacokinetics on sex, race and time of day.

Suction. Levetiracetam a highly soluble substance with a high penetrating power. After oral administration levetiracetam well absorbed from the gastrointestinal tract. Absorption occurs completely and is linear in nature, due to which the concentration in the blood plasma can be predicted, based on the accepted dose of levetiracetam expressed in mg / kg of body weight.The degree of absorption does not depend on the dose and time of food intake. Bioavailability is approximately 100%. The maximum concentration in plasma (C_max) is achieved 1.3 hours after oral administration of levetiracetam in a dose of 1000 mg and at a single admission is 31 μg / ml, after repeated administration (2 times a day) 43 μg / ml. The equilibrium state is achieved after 2 days with a two-time intake of the drug.

Distribution. The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%. Volume of distribution (V_d) is about 0.5-0.7 l / kg.

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. The 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 former is formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), and the second is formed by 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 are not subjected to mutual enantiometric conversion in vivo.

In vitro levetiracetam and its main metabolite do not suppress the main isoforms of human 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 effect on CYP1A2, SULT1E1 and UGT1A1 or did not change their activity at all. Levetiracetam induced easy induction of CYP2B6 and CYP3A4. Based on the results of the evaluation of interactions with oral contraceptives, digoxin and warfarin under in vitro and in vivo conditions, no significant induction of enzymes is expected 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 excreted 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. The 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 also 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.

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.

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

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

Children (4-12 years)

T_1/2 in children aged 4-12 years after a single oral administration of the drug at a dose of 20 mg / kg body weight is 6 hours. The total clearance of levetiracetam in children aged 4-12 is approximately 30% higher and is directly related to body weight.

After repeated oral administration (dose from 20 to 60 mg / kg / day) in children with epilepsy (from 4 to 12 years) levetiracetam quickly absorbed. The peak plasma concentration was observed 0.5-1.0 hours after administration. There was a linear, dose-proportional increase in the peak plasma concentration and the area under the curve. The half-life was about 5 hours. The apparent overall clearance was 1.1 ml / min / kg.

Indications:

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 from 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.

Carefully:

- Patients of advanced age (over 65 years);

- liver disease in the stage of decompensation;

- renal insufficiency.

Pregnancy and lactation:

In post-registration 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,as a result, monotherapy in pregnant women is more appropriate. Studies in animals have shown the toxicity of levetiracetam for reproductive function.

Levetiracetam should not be given during pregnancy and in women with a preserved genital function that does not use contraception, except in cases of clinical necessity.

Physiological changes in the body of a woman during pregnancy can affect the plasma concentration of levetiracetam as well as other antiepileptic 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 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 both the mother and the fetus.

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 breastfeeding, the risk / benefit ratio should be carefully weighed against 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:

Inside, regardless of food intake.

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

Tablets are taken with a sufficient amount of liquid.

Tablets are not intended for children under 6 years due to the inability to correctly select a dose.

Monotherapy

Adults and teenagers from 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). The maximum daily dose is 3000 mg (1500 mg twice a day).

In the complementary therapy

Adults and adolescents (12 to 17 years) 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.

Children from 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 (10 mg / kg body weight 2 times a day) can be performed every 2 weeks until the recommended daily dose is 60 mg / kg body weight (30 mg / kg body weight 2 times day). With intolerance of the recommended daily dose, it is possible to reduce it. The minimum effective dose should be used. The doctor should prescribe the drug in the most suitable dosage form and dosage, depending on the age, body weight of the patient and the required therapeutic dose.

Due to the lack of the required dosage tablets are not designed to treat children weighing less than 25 kg, for administration dose of less than 250 mg, and for patients having difficulties in swallowing.

In these cases, it is recommended to start treatment with taking the drug in the form of a solution for oral administration.

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

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

Adult Dose Adjustment

Renal insufficiency	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
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 *)	-	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 insufficiency	KK (ml / min / 1.73 m²)	Dosing regimen Children older than 4 years and adolescents weighing less than 50 kg
Norm	>80	10-30 mg / kg 2 times a day
Lightweight	50-79	10-20 mg / kg 2 times a day
Moderate	30-49	5-15 mg / kg 2 times per day
Heavy	<30	5-10 mg / kg 2 times a day
Terminal stage (patients on dialysis)		10-20 mg / kg once a day⁽¹⁾⁽²⁾

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

⁽²⁾recommended maintenance dose after dialysis 5-10 mg / kg

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 decompensated impairment of liver function and renal insufficiency, the decrease in creatinine clearancemay not fully reflect the severity of renal failure. In such cases, when the creatinine clearance is <60 ml / min / 1.73m² it is recommended to reduce the daily dose by 50%.

For children younger than 6 years, the recommended dosage form is oral solution.

If it is required to stop taking the drug, it is recommended to cancel the treatment gradually, reducing the single dose by 500 mg every 2-4 weeks (in adults and adolescents weighing more than 50 kg). 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 levetiracetam) should be gradually phased out.

The available information on the use of the drug in children does not indicate any of its negative effects on development and puberty. However, the long-term effects of levetiracetam therapy on children's ability to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

Patients with kidney disease and uncompensated 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.

Due to reports of cases of suicide, suicidal intentions and suicide attempts in the treatment with levetiracetam, patients should be warned to immediately notify the attending physician of any symptoms of depression or suicidal intentions.

Side effects:

The following profile of adverse events is based on an analysis of the results of placebo-controlled studies, as well as the experience of the 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 of adults and children.

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).

Infectious and parasitic diseases

Very often: nasopharyngitis.

Rarely: infections.

Violations of the blood and lymphatic system

Infrequent: thrombocytopenia, leukopenia

Rarely: pancytopenia, agranulocytosis, neutropenia

Immune system disorders

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

Disorders from the metabolism and nutrition

Often: anorexia.

Infrequently: weight gain, weight loss.

Rarely: hyponatremia.

Disorders of the psyche

Often: depression, hostility / aggressiveness, anxiety, insomnia, nervousness / irritability.

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

Rarely: suicide, personality disorder, thinking disorder

Impaired nervous system:

Very 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.

Disturbances on the part of the organ of sight

Infrequently: diplopia, blurred vision.

Hearing disorders and labyrinthine disorders

Often: vertigo.

Disturbances from the respiratory system, chest and mediastinal organs

Often: cough.

Disorders from the gastrointestinal tract

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

Rarely: pancreatitis.

Disturbances from the liver and bile ducts

Infrequent: changes in functional liver samples.

Rarely: hepatic insufficiency, hepatitis.

Disorders from the kidneys and urinary tract:

Rarely: acute renal failure.

Disturbances from the skin and subcutaneous tissues

Often: rash.

Infrequently: alopecia, eczema, itching.

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

Disturbances from musculoskeletal and connective tissue

Infrequent: muscle weakness, myalgia.

Rarely: rhabdomyolysis and increased levels of creatine phosphokinase in the blood.

General disorders:

Often: asthenia / fatigue.

Trauma, intoxication and complications of manipulation

Infrequent: 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, restoration of the hair was observed after the removal of levetiracetam.

In some cases of panzigopenia, bone marrow depression was recorded. The prevalence of rhabdomyolysis and increase in the level of creatine phosphokinase in the blood is significantly higher in patients from Japan, compared with representatives of other nationalities.

The safety profile of children in placebo-controlled clinical trials was comparable to the safety profile of levetiracetam in adults. In children and adolescents aged 4 to 16 years, the following undesirable reactions were more frequent: vomiting (very often, 11.2%), excitation (often, 3.4%), moodiness (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, the following adverse reactions were more often reported: irritability (very often 11.7%) and impaired coordination (often, 3.3%).

In a double-blind, placebo-controlled study whose goal was to show that the drug was as good as a placebo, the cognitive and neuropsychological effects of Keppra in children 4 to 16 years of age with partial seizures were evaluated.Based on the results of the study, it was concluded that Keppra did not differ from the placebo (not inferior to him) with respect to changes in the sum of points in the "Attention and Memory" and "Combined Memory Screening" scans of the Leiter-R scale in patients who underwent a study in accordance with the protocol, compared with the initial visit.

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

Overdose:

Symptoms: drowsiness, agitation, 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 (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 the progrombin time.

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

Food and alcohol

Food does not affect the degree of absorption of levetiracetam, but slightly reduces the rate of absorption.

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.

Number of blood elements

Cases of a decrease in the number of blood corpuscles (neutropenia, agranulocytosis, leukopenia, thrombocytopenia and pancytopenia) have been described in connection with the use of levetiracitam. A blood test, with the counting of blood cells, is recommended for patients who develop severe weakness, hyperthermia, recurrent infections, or blood clotting disorders.

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.

Pediatric population

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

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

The effect of Keppra® on the ability to drive vehicles and control mechanisms has not been specifically studied.Nevertheless, due to the different individual sensitivity to the drug from the central nervous system during the treatment period (some patients may experience drowsiness), it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Pills coated with a film coating, 250 mg, 500 mg and 1000 mg.

Packaging:

For 10 tablets in a planar cell package (blister) [PVC / aluminum foil].

For 3 or 6 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 25 ° C, in a dry place.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N014627 / 01

Date of registration:23.12.2008 / 11.01.2017

Expiration Date:Unlimited

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

Manufacturer: & nbsp

USB PHARMA, S.A. Belgium

R-PHARM, JSC Russia

Representation: & nbspYUSB FARMA LLC YUSB FARMA LLC Russia

Information update date: & nbsp11.01.2018

Illustrated instructions

Instructions

Keppra® (Keppra®)