Levetiracetam 1000 mg, 30 pcs.

1 film-coated tablet contains:

active substance: 

• levetiracetam 1000.0 mg;

Excipients: 

• calcium stearate 12.0 mg 

• silicon dioxide colloidal 12.0 mg, 

• croscarmellose sodium 40.0 mg, 

• mannitol 80.8 mg 

• povidone K-30 25.2 mg 

• microcrystalline cellulose (type 101) 70 mg;

film coating composition: Opadray II 85F205008 blue 40.0 mg, including: polyvinyl alcohol 16.00 mg, macrogol (polyethylene glycol) 8.08 mg, talc 5.92 mg, titanium dioxide 8.20 mg, dye indigo carmine 1, 72 mg, charming red dye 0.08 mg.

Pharmacodynamics

Levetiracetam is a derivative of pyrrolidone (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 obvious that it differs from the mechanism of action of known antiepileptic drugs. 

In vitro and in vivo experiments have shown that levetiracetam does not affect the basic characteristics of cells and normal transmission. In vitro studies have shown that it affects the intronurial concentration of Ca2 + ions, partially inhibiting the flow of Ca2 + ions through N-type channels and decreasing the release of calcium from intranuronal depots. 

In addition, it partially restores currents through the GABA- and glycine-dependent channels, reduced by zinc and carbolines. One of the proposed mechanisms is based on the proven binding of the synaptic vesicles SV2A to the glycoprotein contained in the gray matter of the brain and spinal cord. It is believed that in this way an anticonvulsant effect is realized, which is expressed in counteracting hypersynchronization of neural activity. 

Levetiracetam also acts on GABA receptors and glycine receptors, modulating these receptors through various endogenous agents. The drug does not alter normal neurotransmission, however, it suppresses epileptiform neuronal outbreaks induced by the GABA agonist biculin and excitation of glutamate receptors. 

The activity of the drug is confirmed in relation to both focal and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction).

Pharmacokinetics

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

Suction.

After oral administration, levetiracetam is well absorbed from the gastrointestinal tract. Levetiracetam is highly soluble in water and has high penetration. 

Absorption occurs completely and is linear in nature, due to which the concentration in the blood plasma can be predicted based on the dose of levetiracetam expressed in mg / kg body weight. The degree of absorption does not depend on the dose and time of food intake. 

Bioavailability is approximately 100%. The maximum plasma concentration (Cmax) is achieved 1.3 hours after oral administration of levetiracetam at a dose of 1000 mg and with a single dose is 31 μg / ml, after repeated administration (2 times a day) —43 μg / ml. The equilibrium state is reached after 2 days with a double dose of the drug.

Distribution.

The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%. The volume of distribution (Vd) is approximately 0.5-0.7 L / kg, which approximately corresponds to the volume of water in the body. 

There are no data on the distribution of the drug over the tissues.

Metabolism.

Levetiracetam is poorly metabolized in the human body.

The main route of metabolism (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 liver cytochrome P450. The metabolite ucb L057 is pharmacologically inactive. Levetiracetam does not affect the enzymatic activity of hepatocytes.

In vitro, levetiracetam and its main metabolite did not inhibit the main forms of cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, 1A2), as well as the activity of glucuronyl transferase (UGT1A1, UGT1A6) and epoxide hydroxylase. Did not affect glucuronidation of valproic acid in vitro.

Breeding.

The elimination half-life (T1 / 2) from the blood plasma of an adult is 7 ± 1 h and does not depend on the route of administration and the dosage regimen. The average total clearance is 0.96 ml / min / kg. 95% of the drug is excreted by the kidneys. The renal clearance of levetiracetam and its metabolite is 0.6 and 4.2 ml / min / kg, respectively.

Pharmacokinetics in special clinical cases

Elderly patients

In elderly patients, T1 / 2 increases by 40% and amounts to 10-11 hours, which is associated with impaired renal function in this category of people.

Renal failure

In patients with impaired renal function, the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, patients with renal insufficiency are advised to select a dose depending on creatinine clearance (see section "Dosage and Administration"). 

In the terminal stage of renal failure in adult patients, T1 / 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.

Impaired liver function

In patients with impaired liver function of mild to moderate severity, significant changes in the clearance of levetiracetam do not occur. In most patients with severely impaired liver function with concomitant renal failure, the clearance of levetiracetam is reduced by more than 50%.

Children aged 4-12

After a single dose of the drug at a dose of 20 mg / kg, T1 / 2 in children 4-12 years old is 6 hours. The total clearance of levetiracetam in children 4-12 years old is approximately 30% higher and is directly dependent on body weight.

After repeated administration of the drug at a dose of 20-60 mg / kg body weight for children 4-12 years old, the maximum plasma concentration is reached after 0.5-1.0 hours and increases linearly and in proportion to the dose.

As monotherapy (drug of first choice) in the treatment

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

As part of complex therapy in the treatment

• partial seizures with or without secondary generalization in adults and children over 6 years old suffering from epilepsy;

• myoclonic seizures in adults and adolescents over 12 years old suffering from juvenile myoclonic epilepsy;

• primary generalized convulsive (tonic-clonic) seizures in adults and adolescents over 12 years old, suffering from idiopathic generalized epilepsy.

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

Carefully:

• elderly patients (over 65 years old);

• decompensated liver disease;

• renal failure (creatinine clearance less than 50 ml / min).

Security Profile Summary

The adverse events profile presented below is based on an analysis of the combined placebo-controlled clinical studies of levetiracetam for all indications, as well as post-registration data. 

The most commonly reported adverse reactions were nasopharyngitis, drowsiness, headache, fatigue, and dizziness. The safety profile of levetiracetam as a whole does not differ depending on age (in adults and children).

WHO classification of the incidence of side effects:

very often - ≥1 / 10 appointments (> 10%)

often - from ≥1 / 100 to <1/10 appointments (> 1% and <10%)

infrequently - from ≥1 / 1000 to <1/100 appointments (> 0.1% and <1%)

rarely - from ≥1 / 10000 to <1/1000 appointments (> 0.01% and <0.1%)

very rarely - <1/10000 appointments (<0.01%)

Infectious and parasitic diseases

Very common: nasopharyngitis.

Rarely: infections.

Disorders from the blood and lymphatic system

Infrequently: thrombocytopenia, leukopenia.

Rarely: pancytopenia, agranulocytosis, neutropenia.

Immune System Disorders

Rarely: drug reaction with eosinophilia and systemic manifestations (DRESS).

Metabolic and nutritional disorders

Often: anorexia.

Infrequently: decrease or increase in body weight.

Rarely: hyponatremia.

Mental disorders

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

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

Rarely: suicide, personality disorder, impaired thinking.

Disorders of the nervous system

Very often: drowsiness, headache.

Often: convulsions, dizziness, tremors, imbalance, lethargy.

Infrequently: impaired coordination of movements or ataxia, amnesia, impaired attention, impaired memory, paresthesia.

Rarely: choreoathetosis, dyskinesia, hyperkinesia.

Visual impairment

Infrequently: diplopia, violation of accommodation.

Hearing impairment and labyrinthine disorders

Often: vertigo.

Respiratory system disorders

Often: cough.

Gastrointestinal Disorders

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

Rarely: pancreatitis.

Violations of the liver and biliary tract

Infrequently: changes in functional liver tests.

Rarely: liver failure, hepatitis.

Disorders of the skin and subcutaneous tissue

Often: skin rash.

Infrequently: eczema, itching, alopecia.

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

Musculoskeletal and connective tissue disorders

Infrequently: muscle weakness, myalgia.

Common disorders:

Often: asthenia / fatigue

Injuries, complications of procedures:

Infrequently: accidental damage

Description of selected adverse reactions

With the simultaneous use of topiramate and levetiracetam, the risk of anorexia increases.

In some cases, alopecia underwent a reverse development after discontinuation of levetiracetam.

In some patients with pancytopenia, bone marrow depression was detected.

Children

The profile of adverse events of levetiracetam, in general, does not differ depending on age (in adults and children), and also does not depend on approved indications for use (epilepsy options). 

With the exception of behavioral and psychiatric adverse reactions that occurred more frequently in children than in adults, in the placebo-controlled studies, the safety profile of levetiracetam in children was comparable to that in adults. 

In children aged 4-16 years, vomiting (very often, 11.2%), agitation (often, 3.4%), mood changes (often, 2.1%), emotional lability (often, 1.7%) , aggression (often, 8.2%), impaired behavior (often, 5.6%) and lethargy (often, 3.9%) were noted more often than in other age groups and the general safety profile. In children aged 1 month to 4 years, irritability (very often, 11.7%) and impaired coordination of movements (often, 3.3%) were noted more often than in other age groups and the general safety profile.

The cognitive and neuropsychological effects of levetiracetam in children 4-16 years old with partial seizures were evaluated in double-blind, placebo-controlled studies of the safety profile. It was shown that levetiracetam does not differ (no less safe) from placebo in changes from the original values ​​on the scale Attention and Memory Leiter-R (Leiter-R Attention and Memory), the scale of Comprehensive Monitoring of Memory (Memory Screen Composite)

in patients subjected to protocol analysis. The results of the study of behavioral and emotional functions, confirming that aggressive behavior occurs when levetiracetam is used, were obtained using a standardized method using a validated tool - the Achenbach Child Behavior Checklist. 

However, in patients taking levetiracetam for a long time as part of an open study, behavioral and emotional dysfunctions did not occur, in particular, the level of aggressive behavior did not differ from the initial one.

Anticonvulsants

According to pre-registration clinical studies, levetiracetam does not affect the serum concentrations of other anticonvulsants: phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone - and these anticonvulsants do not affect the pharmacokinetics of levetiracetam.

However, there is evidence that the clearance of levetiracetam in children taking anticonvulsant drugs, inducers of microsomal liver enzymes, increases by 22%.

Probenecid

Probenecid (500 mg 4 times a day) is a blocker of tubular secretion in the kidneys, it is shown that it inhibits the renal clearance of the main metabolite, but not levetiracetam. However, the concentration of the main metabolite remains low. 

Other drugs excreted by active tubular secretion are expected to reduce renal clearance of the main

metabolite. The effect of levetiracetam on probenecid has not been studied; the effect of levetiracetam on other drugs excreted by active tubular secretion, including non-steroidal anti-inflammatory drugs, sulfonamide and methotrexate, is not known.

Oral contraceptives and other pharmacokinetic interactions

Levetiracetam at a dose of 1000 mg per day did not affect the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); hormonal status (the content of luteinizing hormone and progesterone) did not change. 

Levetiracetam at a dose of 2000 mg per day did not affect the pharmacokinetics of digoxin and warfarin, the prothrombin time did not change. The simultaneous use of digoxin, oral contraceptives and warfarin did not affect the pharmacokinetics of levetiracetam.

Antacids

There are no data on the effect of antacids on the absorption of levetiracetam.

Food and alcohol

Food does not affect the degree of absorption of levetiracetam, but somewhat reduces its speed. There are no data on the interaction of levetiracetam with ethanol.

Inside, drinking plenty of fluids, regardless of food intake, 2 times a day.

Adults and adolescents over 16 years of age, the initial dose is 500 mg 2 times a day, from the first day of treatment. Depending on the clinical response and tolerance, the daily dose may be increased to 1,500 mg 2 times a day (a 500 mg dose increase is possible every 2-4 weeks).

An individual dose selection is recommended for elderly people and patients with chronic renal failure. With normal renal function and CC more than 80 ml / min, the recommended dose and frequency of administration is from 500 to 1500 mg 2 times a day, with mild renal failure and CC 50-79 ml / min - from 0.5 to 1 g 2 times a day with an average degree of renal failure and KK of 30-49 ml / min - from 250 to 750 mg 2 times a day, with a severe degree of renal failure and KK less than 30 ml / min - from 250 to 500 mg 2 times a day.

At the terminal stage of chronic renal failure, from 0.5 to 1 g once a day, after dialysis, an additional dose of 250-500 mg is recommended. Dialysis patients are advised to take a saturating dose of 750 mg on the first day of levetiracetam treatment.

In severe violations of the liver and CC less than 70 ml / min - a decrease in the daily intake dose by 50%.

Symptoms: drowsiness, agitation, aggressiveness, anxiety, depression 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 is carried out in a hospital using hemodialysis (the effectiveness of dialysis for levetiracetam is 60%, for its primary metabolite - 74%).

Withdrawal of therapy

Drug withdrawal is recommended to be carried out gradually. For example, in adults and adolescents with a body weight of more than 50 kg, the dose should be reduced in increments of 500 mg 2 times a day no more than every 2-4 weeks; in children, dose reduction should be carried out in increments of not more than 10 mg / kg 2 times a day, not more often than every two weeks.

Concomitant antiepileptic drugs (during the transition of patients to levetiracetam therapy), it is advisable to cancel gradually.

Renal failure

The use of levetiracetam in patients with renal failure may require dose adjustment. In patients with severe hepatic insufficiency, it is recommended to evaluate renal function before starting dose selection (see section Dosage and Administration).

Suicide

Patients taking anticonvulsants (including levetiracetam) experienced suicide, attempted suicide, suicidal thoughts and behavior. In connection with the foregoing, it is necessary to monitor patients with symptoms of depression or suicidal thoughts and behavior and prescribe appropriate therapy for them. 

Patients (and those caring for them) should be informed about the need to seek medical help if they experience symptoms of depression and (or) suicidal thoughts and behavior.

Children

The tablets are not intended for use in children under the age of 6 years. For children under 6 years of age, the recommended dosage form is an oral solution.

According to reports, levetiracetam does not affect growth and puberty. However, the long-term effects on learning, intelligence, growth, endocrine function, puberty, and fertility in children are not known.

Impact on the ability to drive vehicles and mechanisms

The influence of the drug levetiracetam on the ability to drive vehicles and control mechanisms has not been specifically studied. 

However, due to different individual sensitivity to the drug, some patients may experience drowsiness and other disorders of the central nervous system, especially at the beginning of therapy and after increasing the dose. 

Therefore, it is recommended to refrain from driving vehicles and engaging in potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.