Levetiracetam Canon pills 250mg, 30pcs

Composition

1 film-coated tablet contains:

Active ingredient:  

• levetiracetam 250.0 mg;

excipients:  

• calcium stearate 3.0 mg,

• colloidal silicon dioxide 3.0 mg,

• croscarmellose sodium 10.0 mg, mannitol 20.2 mg,

• povidone K-30 6.3 mg, microcrystalline cellulose (type 101) 17.5 mg;

film shell composition:  

Opadray II 85F205008 blue 10.0 mg, including: polyvinyl alcohol 4.00 mg, macrogol (polyethylene glycol) 2.02 mg, talc 1.48 mg, titanium dioxide 2.05 mg, indigo carmine dye 0.43 mg, red charming dye 0.02 mg

Pharmacological action

Pharmacodynamics

Levetiracetam is a derivative of pyrrolidone (the S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide), which 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.

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

In addition, it partially restores currents through GABA-and glycine-dependent channels reduced by zinc and carbolines. One of the proposed mechanisms is based on the proven binding to the synaptic vesicle glycoprotein SV2A, which is contained in the gray matter of the brain and spinal cord. It is believed that in this way the anticonvulsant effect is realized, which is expressed in countering the 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, but it suppresses epileptiform neuronal bursts induced by the GABA agonist bicuculin and the excitation of glutamate receptors.

The activity of the drug was confirmed against both focal and generalized epileptic seizures (epileptiform manifestations /photoparoxysmal reaction).

Pharmacokinetics

There was no correlation of pharmacokinetics with gender, race, or time of day.

Suction.

After oral use, levetiracetam is well absorbed from the gastrointestinal tract. Levetiracetam is highly soluble in water and has a high penetrating power.

Absorption occurs completely and is linear, so that the concentration in blood plasma can be predicted based on the dose of levetiracetam taken, 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 plasma concentration (Cmax) is reached 1.3 hours after oral use of levetiracetam at a dose of 1000 mg and with a single dose is 31 mcg / ml, after repeated use (2 times a day) -43 mcg/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 roughly corresponds to the volume of water in the body.

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

Metabolism.

Levetiracetam is poorly metabolized in the human body.

The main route of metabolism (24% of the dose taken) is the enzymatic hydrolysis of the acetamide group. The formation of the primary metabolite (ucb L057) occurs without the involvement of liver cytochrome P450. The ucb L057 metabolite 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 P 450 (CYP3A4,2A6,2C9,2C19,2D6,2E1,1A2), as well as the activity of glucuronyl transferase (UGT1A1, UGT1A6) and epoxide hydroxylase. It did not affect valproic acid glucuronidation in vitro.

Output.

The half-life (T1 / 2) from adult blood plasma is 7±1 h and does not depend on the method of use and 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 is 10-11 hours, which is associated with impaired renal function in this category of people.

Kidney 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 recommended to adjust the dose depending on creatinine clearance (see the section “Dosage and use”).

In end-stage 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

No significant changes in levetiracetam clearance occur in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment and concomitant renal insufficiency, the clearance of levetiracetam decreases by more than 50%.

Children aged 4-12 years

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

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

Indications

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

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

In the complex therapy in the treatment

• of partial seizures with secondary generalization or without that adults and children over 6 years of age with epilepsy;

• myoclonic seizures in adults and adolescents 12 years and older with juvenile myoclonic epilepsy;

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

Contraindications

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

With caution:

• elderly patients (over 65 years of age);

• liver diseases in the stage of decompensation;

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

Side effects

Summary of the security profile

The adverse event profile presented below is based on an analysis of combined placebo-controlled clinical trials of levetiracetam for all indications, as well as post-marketing data.

The most frequently reported adverse reactions were nasopharyngitis, drowsiness, headache, fatigue, and dizziness. The safety profile of levetiracetam generally does not differ by age (in adults and children).

WHO classification of frequency of side effects:

very common – ≥1/10 appointments (>10%)

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

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

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

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

Infectious and parasitic diseases

Very often:  nasopharyngitis.

Rarely:  infections.

Disorders of 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 are common:  anorexia nervosa.

Infrequently: decrease or increase in body weight.

Rarely:  hyponatremia.

Mental disorders

Are Common:  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:  completed suicide, personality disorder, thinking disorder.

Nervous system disorders

Very often:  drowsiness, headache.

Often:  convulsions, dizziness, tremor, disequilibrium, lethargy.

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

Rarely:  choreoathetosis, dyskinesia, hyperkinesia.

Visual disturbances

Infrequently: diplopia, accommodation disorder.

Hearing disorders and labyrinth disorders

are common: vertigo.

Respiratory system disorders

are common: cough.

Gastrointestinal disorders

are Common: abdominal pain, diarrhea, dyspepsia, nausea, vomiting.

Rarely: pancreatitis.

Liver and biliary tract disorders

Infrequently: changes in functional liver tests.

Rare: liver failure, hepatitis.

Skin and subcutaneous tissue disorders

are common: skin rash.

Infrequently: eczema, pruritus, 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 individual adverse reactions

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

In some cases, alopecia was reversed after discontinuation of levetiracetam.

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

Children

The adverse event profile of levetiracetam generally does not differ by age (in adults and children), nor does it depend on approved indications for use (variants of epilepsy).

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

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

The cognitive and neuropsychological effects of levetiracetam in children aged 4-16 years with partial seizures were evaluated in double-blind, placebo-controlled safety profile studies. Levetiracetam has been shown to be no different (no less safe) from placebo by changes from baseline values on the Leiter-R Attention and Memory scale, the Memory Screen Composite scale

in patients who were analyzed according to the protocol. The results of the study of behavioral and emotional functions, confirming that aggressive behavior occurs against the background of levetiracetam use, were obtained using a standardized method using a validated tool-the Achenbach Child Behavior Checklist.

However, patients who took levetiracetam long-term in open-label studies did not experience behavioral and emotional disorders, in particular, the level of aggressive behavior did not differ from the baseline.

Interaction

Anticonvulsants

According to pre-marketing clinical studies, levetiracetam does not affect the serum concentrations of other anticonvulsant drugs: phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone – and these anticonvulsant drugs 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 renal tubular secretion blocker and has been shown to inhibit the renal clearance of the main metabolite, but not levetiracetam. However, the concentration of the main metabolite remains low.

It is expected that other drugs excreted through active tubular secretion may reduce the 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 nonsteroidal 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 (luteinizing hormone and progesterone levels) did not change.

Levetiracetam at a dose of 2000 mg per day did not affect the pharmacokinetics of digoxin and warfarin, and the prothrombin time did not change. Concomitant 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 slightly reduces its rate. There are no data on the interaction of levetiracetam with ethanol.

How to take, course of use and dosage

Inside, with a sufficient amount of liquid, regardless of food intake,2 times a day.

For 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 tolerability, the daily dose can be increased to 1500 mg 2 times a day (an increase in the dose by 500 mg is possible every 2-4 weeks).

Individual dose selection is recommended for the elderly and patients with CRF. With normal renal function and creatinine clearance of more than 80 ml / min, the recommended dose and frequency of use is from 500 to 1500 mg 2 times a day, with mild renal failure and creatinine clearance of 50-79 ml / min-from 0.5 to 1 g 2 times a day, with moderate renal failure and creatinine clearance of 30-49 ml / min-from 250 to 750 mg 2 times a day, with severe renal failure and creatinine clearance of less than 30 ml / min-from 250 to 500 mg 2 times a day.

At the end stage of CRF-from 0.5 to 1 g once a day, after dialysis, an additional dose of 250-500 mg is recommended. Patients on dialysis should receive a 750 mg saturating dose on the first day of treatment with levetiracetam.

In severe hepatic impairment and creatinine clearance less than 70 ml / min, the daily dose is reduced by 50%.

Overdose

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

Treatment: in the acute period —artificial vomiting and gastric lavage followed by the appointment of activated charcoal.

There is no specific antidote for levetiracetam. If necessary, symptomatic treatment is performed in a hospital setting using hemodialysis (the effectiveness of dialysis for levetiracetam is 60%, for its primary metabolite -74%).

Special instructions

Discontinuation of therapy

Discontinuation of the drug is recommended gradually. For example, in adults and adolescents with a body weight of more than 50 kg, dose reduction should be carried out in increments of 500 mg 2 times a day no more often than every 2-4 weeks; in children, dose reduction should be carried out in increments of no more than 10 mg / kg 2 times a day no more often than every two weeks.

Concomitant antiepileptic drugs (during the transfer of patients to levetiracetam therapy) should be discontinued gradually.

Kidney failure

The use of levetiracetam in patients with renal insufficiency 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 use).

Suicide

Patients taking anticonvulsants (including levetiracetam) have reported suicide, suicide attempts, suicidal thoughts, and behavior. In this regard, patients with symptoms of depression or suicidal thoughts and behaviors should be monitored and given appropriate therapy.

Patients (and their caregivers) should be informed about the need to seek medical attention if they experience symptoms of depression and / or suicidal thoughts and behaviors.

Children

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

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

Influence on the ability to drive vehicles and mechanisms

The effect of levetiracetam on the ability to drive vehicles and manage mechanisms has not been specifically studied.

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

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

Storage conditions

At a temperature not exceeding 25 ° C in the manufacturer’s packaging. Keep out of reach of children.

Shelf

life is 2 years.

Active ingredient

Levetiracetam

Conditions of release from pharmacies

By prescription

Dosage form

Tablets