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

Excipients: crospovidone 5.00 / 10.00 / 15.00 / 20.00 mg; Povidone K30 11.25 / 22.50 / 33.75 / 45.00 mg; silicon dioxide colloid 1.25 / 2.50 / 3.75 / 5.00 mg; Magnesium stearate 1.25 / 2.50 / 3.75 / 5.00 mg.

Sheath: 8.25 / 16.5 / 23.75 / 32 mg. In its composition, hypromellose 62.5 / 62.5 / 62.5 / 62.5%; Macrogol-400 6.58 / 6.58 / 6.58 / 6.58%; titanium dioxide 23.03 / 22.70 / 19.08 / 23.68%; talc 6.58 / 6.58 / 9.87 / 7.24%; indigo carmine 1.32% / - / - / -; iron dye yellow oxide - / 1,65% / - / -; dye sunset sunset yellow - / - / 1.58% / -; iron dye oxide red - / - / 0.40% / -.

Description:

250 mg tablets: Oval tablets covered with a film coating of blue color, with a risk on one side. On the cross-section the nucleus is white.

Tablets 500 mg: Oval pills covered with a film coating of yellow color, with a risk on one side. On the cross-section the nucleus is white.

Tablets 750 mg: Oval tablets covered with a film coating of orange color, with a risk on one side. On the cross-section the nucleus is white.

Tablets 1000 mg: Oval tablets, coated with a white film shell, with a risk on one side. On the cross-section the nucleus is white.

Pharmacotherapeutic group:Antiepileptic remedy

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.14 Levetiracetam

Pharmacodynamics:

Levetiracetam is a derivative of pyrrolidone (S-enantiomer α-ethyl-2-oxo-1-pyrrolidineacetamide) differs in chemical structure from known antiepileptic drugs (LS).

Mechanism of action

The mechanism of action of levetiracetam is not fully understood, but it is clear that it differs from the mechanism of action of known antiepileptic drugs. Based on the results of experiments in vivo and in vitro we can assume that levetiracetam does not change the basic characteristics of cells and the normal transmission of nerve impulses. Research in vitro showed that levetiracetam affects the intra-neuronal concentration of Ca2 + ions, partially inhibiting the current of Ca2 + through channels Ntype and reducing the release of calcium from intra-neural depots. Besides, levetiracetam partially restores currents through gammaaminobutyric acid (GABA) - and glycine-dependent channels, reduced by zinc and P-carbolines. One of the proposed mechanisms is based on proven binding to the glycoprotein of synaptic vesicles 2A contained in the gray matter of the brain and spinal cord. It is believed that this way the anticonvulsant effect of this drug is realized.

Pharmacodynamic effects

Levetiracetam prevents the development of convulsions in various experimental models of partial and primary generalized seizures without a proconvulsive effect. The main metabolite of levetiracetam is inactive.

In humans, the activity of the drug in relation to both partial and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction), confirms its wide spectrum of pharmacological action.

Pharmacokinetics:

Levetiracetam is a highly soluble substance with high permeability. The pharmacokinetic profile is linear with low intra- and interindividual variability. The clearance of the drug does not change after repeated injections. There was no dependence of pharmacokinetics on sex, ethnicity or time of day. Pharmacokinetic profiles are comparable in healthy volunteers and patients with epilepsy.

Due to complete absorption with a linear profile, the plasma concentration is predicted from the dose of levetiracetam expressed as mg / kg of body weight. Thus, there is no need to monitor the level of levetiracetam in blood plasma.

A significant correlation has been established between levetiracetam concentrations in plasma and saliva adults and children (the concentration ratio of the drug saliva / plasma varies from 1 to 1.7 for tablets for oral administration and for oral solution at 4 h after administration of the latter).

Suction

After oral administration levetiracetam is well absorbed from the gastrointestinal tract (GIT). 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 of body weight. The degree of absorption of levetiracetam does not depend on the dose and time of ingestion.

Absolute bioavailability is approximately 100%.

The maximum concentration of the drug in the blood 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

There is no data on the distribution in humans.

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

Biotransformation

Levetiracetam is poorly metabolized in the human body. The main metabolic pathway (24% dose) is the enzymatic hydrolysis of the acetamide group. Isozymes of liver cytochrome P450 do not participate in the formation of the main metabolite (ucb L057). Hydrolysis of the acetamide group occurs in many tissues, including blood cells. Metabolite ucb L057 pharmacologically inactive.

Two secondary metabolites were also detected. The former is formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), the second by the opening of the pyrrolidone ring (0.9% dose). Other unidentified metabolites are only 0.6% of the dose.

Optical isomerization of levetiracetam and its main metabolite under conditions in vivo not detected.

Levetiracetam and its main metabolite do not inhibit the main isoenzymes of human cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferase (UGT1A1 and UGT1A6) and epoxy hydroxylase in vitro. Levetiracetam also does not affect the glucuronation of valproic acid in vitro.

In human hepatocyte culture levetiracetam had little or no effect on the activity of isoenzymes CYP1A2, SULT1E1 and UGT1A1. Levetiracetam weakly induced isoenzyme activity CYP2B6 and CYP3A4. Data on the drug interaction with oral contraceptives, digoxin and warfarin in vitro and in vivo show that significant induction of enzymes in vivo not expected. Therefore, the interaction of levetiracetam with other substances or the interaction of other substances with levetiracetam is unlikely.

Excretion

The half-life (T_1/2) from the blood plasma of an adult is 7 ± 1 h and does not depend on the dose, route of administration and duration of application. The average overall clearance is 0.96 ml / min / kg.

95% of the drug is excreted by the kidneys (of which about 93% of the dose is excreted within 48 hours). Excretion with faeces is only 0.3% of the dose.

The total excretion of levetiracetam and its main metabolite is 66 and 24%, respectively, of the dose taken within the first 48 hours. Renal clearance of levetiracetam and its metabolite ucb L057 is 0.6 and 4.2 ml / min / kg, respectively, indicating the excretion of levetiracetam by glomerular filtration followed by tubular reabsorption, and the main metabolite, along with glomerular filtration, active tubular secretion.

Elimination of levetiracetam correlates with creatinine clearance (CC).

Elderly patients

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

Patients with renal insufficiency

The apparent clearance of levetiracetam and its main metabolite correlates with QC. Therefore, patients with renal insufficiency is recommended to select a dose depending on the CK.

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.

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 declines by more than 50%.

Children aged 4-12 years

The pharmacokinetics of levetiracetam in children is linear. After a single dose of 20 mg / kg T1/2 in children 6-12 years of age is 6 hours.The weight-corrected apparent apparent clearance is 30% greater than that of adults with epilepsy.

After prolonged use of the drug at a dose of 20 to 60 mg / kg / day, the absorption of levetiracetam in children 4-12 years of age is rapid. FROM_max is achieved within 0.5-1 h.

FROM_max and the area under the pharmacokinetic curve "concentration-time" (AUC) are linear and proportional to the dose. Terminal T1/2 is 5 hours. The apparent clearance is 1.1 ml / min / kg.

Indications:

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

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

As part of complex therapy in the treatment of the following conditions:

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

- Myoclonic seizures in adults and in 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 6 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

Adequate and strictly controlled clinical trials on the safety of levetiracetam in pregnant women have not been conducted, so the drug should not be administered during pregnancy, except in cases of extreme necessity. Physiological changes in the body during pregnancy may affect levetiracetam concentration in plasma, as well as other anti-epileptic 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 observed in the period preceding the pregnancy). Treatment with levetiracetam pregnant women should be carried out under special supervision.Breaks in antiepileptic therapy, its cancellation can lead to a worsening of the course of the disease, which can harm the health of both the mother and the fetus.

Breast-feeding

Levetiracetam is excreted in breast milk, so if it is necessary to use it during lactation, breastfeeding for the time of taking the drug is not recommended.

Fertility

In animal studies, levetiracetam has not been shown to influence fertility. Clinical data are not available, a possible risk in humans is unknown.

Dosing and Administration:

Inside, squeezed enough water, regardless of food intake. The daily dose is divided into 2 doses in the same dose.

As a monotherapy

Adults and teenagers over 16 years of age treatment should begin with a daily dose of 500 mg divided into 2 divided doses (250 mg twice a day). After 2 weeks, the dose may be increased to the initial therapeutic dose of 1000 mg (500 mg twice a day). The dose may be increased in increments of 250 mg twice a day every two weeks, depending on the clinical response. The maximum daily dose is 3000 mg (1500 mg twice a day).

As part of complex therapy

Children over 6 years 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). Dose change of 20 mg / kg

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

Children with a body weight of 20 kg or less are advised to begin 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.

Adults and adolescents over 16 years of age with a body weight of 50 kg and more 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.

Special Groups patientsta

Elderly (65 years and over)

In elderly patients with impaired renal function, it is recommended to adjust the dose.

Renal insufficiency

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 CC, daily dose is selected individually. KK (in ml / min) can be calculated from the serum creatinine (CS) concentration (in mg / dL).

KK for men can be calculated by the following formula:

CK (ml / min) = [140-years (years) * body weight (kg)] / 72 * CS, where CS is serum creatinine (mg / dL)

QC for women can be calculated using the following formula:

CK (ml / min) = [140-years (years) * body weight (kg) * 0.85] / 72 * CS

Table 1. The dosage regimen of Letimira® in adults and adolescents with impaired renal function with a body weight> 50 kg

Group	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
Medium	30-49	from 250 to 750 mg twice a day
Heavy	<30	from 250 to 500 mg twice a day
Terminal stage (patients on hemodialysis *)		from 500 to 1000 mg once a day **

* - on the first day of treatment, a loading dose of 750 mg is recommended;

** - After completion of hemodialysis, an additional 250 or 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, using recommendations given for adults.

Impaired liver 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 decompensated impairment of liver function and renal insufficiency The decrease in QC may not be fullyRTo reduce the severity of renal failure. In such cases, with a CS <70 ml / min, a daily dose reduction of 50% is recommended.

Children

The drug is prescribed in the most convenient dosage form and dosage depending on the age, body weight and the required dose.

Tablets are not intended for use in children younger than 6 years.

In such patients, the drug is recommended to be administered in the form of a solution for oral administration. In addition, the available dosages of the tablets are not intended for initial dose selection in children weighing less than 25 kg, patients who are unable to swallow tablets, and if necessary, taking a dose of <250 mg.In all these cases, it is recommended to use the solution for oral administration.

Monotherapy

The efficacy and safety of levetiracetam in children and adolescents under 16 years of age has not been established as monotherapy. No data available.

Auxiliary therapy in children 6-17 years old and 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 doses (10 mg / kg body weight 2 times a day). Depending on the clinical response and theaboutThe dose can be increased up to 30 mg / kg 2 times a day. The dose may be increased or decreased in steps of 10 mg / kg twice a day every two weeks. It is necessaryrichange the lowest effective dose. The dosage regimen in children with a body weight of 50 kg or more is not different from adults.

Table 3. Recommended doses in children from 6 years of age.

Body mass	Initial dose: 10 mg / kg 2 times a day	Maximum dose: 30 mg / kg 2 times a day
25 kg¹	250 mg twice daily	750 mg twice a day
From 50 kg²	500 mg twice a day	1500 mg twice a day

1- For children with a body weight of 25 kg or less, it is recommended to prescribe the drug in the form of a solution for oral administration, 100 mg / ml.

2- The dosage regimen in children with a body weight of 50 kg or more is not different from adults.

Side effects:

The below undesirable effects are given according to WHO classification in accordance with the following gradations of their frequency: very often: ≥10%; often: ≥1 - <10%; sometimes: ≥0.1 - <1%; rarely: 0.01-0.1%; very rarely: <0.01%, including individual reports; the frequency is unknown: according to the available data, it is not possible to establish the frequency of occurrence.

Disorders from the central nervous system (CNS): very often: drowsiness, asthenic syndrome

often: convulsions, dizziness, headache, hyperkinesia, tremor, imbalance, agitation, depression, emotional lability, mood swings, hostility / aggressiveness, insomnia, nervousness, irritability, personality disorders, thinking disorder; anxiety, vertigo

infrequently: amnesia, ataxia, decreased concentration of attention, memory impairment, suicide attempts and suicidal intentions, behavioral disorders, psychotic disorders, confusion, hallucinations, emotional lability. rarely: suicide, personality disorder, thinking disorder, choreoathetosis, dyskinesia, hyperkinesia

Vision disorders:

infrequently: diplopia, violation of accommodation.

Disturbances from the respiratory system:

often: increased cough.

Violations from the digestive tract:

often: abdominal pain, diarrhea, dyspepsia, nausea, vomiting, anorexia, weight gain;

infrequently: pancreatitis, changes in functional liver samples.

rarely: hepatic insufficiency, hepatitis, weight loss.

Disturbances from the skin and mucous membranes:

often: skin rash.

infrequently: eczema, itching; alopecia (in some cases, the restoration of the hair was observed after the drug was discontinued).

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

Change in laboratory indicators:

infrequently: leukopenia, thrombocytopenia.

rarely: neutropenia, pancytopenia (in some cases with bone marrow suppression). Other: individual messages - infections, nasopharyngitis, myalgia, muscle weakness, propensity to injury.

Overdose:

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

Treatment: after acute overdose, it is necessary to induce vomiting and rinse the stomach with the subsequent administration of activated charcoal. There is no specific antidote for levetiracetam.If necessary, symptomatic treatment in a hospital using hemodialysis (dialysis efficiency for levetiracetam is 60%, for its main metabolite - 74%).

Interaction:

The drug does not interact with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, primidon).

Levetiracetam in a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives (ethinyl estradiol, levonorgestrel). Levetiracetam in a daily dose of 2000 mg does not change the pharmacokinetics of digoxin and warfarin.

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

With joint admission with topiramate, the probability of anorexia is higher.

Also as in adults, there are no data on clinically significant drug interactions in children who received levetiracetam in a dose up to 60 mg / kg / day.

Completeness of absorption of levetiracetam when ingested does not change under the influence of food, while the rate of absorption is somewhat reduced.

Data on the interaction of levetiracetam with alcohol is not available.

Special instructions:

If It is required to stop taking the drug, then the cancellation of treatment is recommendedlgradually (reducing the single dose by 500 mg every 2-4 weeks). Children havesameThe dose should not exceed 10 mg / kg of body weight 2 times a day every 2 weeks. Concomitant antiepileptic drugs (during the transfer of patients to receive 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 consequences on children's ability to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

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

The risk of anorexia increases with simultaneous use with topiramate.

In connection with the reported reports of suicide, suicidal intentions and suicide attempts in the treatment with levetiracetam, patients should be warned aboutthe need to immediately inform the attending physician about the appearance of any depressive symptomsfromor suicidal intentions.

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

The effect of levetiracetam 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 side of the central nervous system during the treatment period, it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Pills film-coated 250 mg, 500 mg, 750 mg, 1000 mg.

Packaging:

For 10 tablets in a blister of PVC / PE / PVDC / / aluminum foil or PVC / PVDH // aluminum foil. 3 or 6 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002465

Date of registration:16.05.2014 / 16.01.2018

Expiration Date:16.05.2019

The owner of the registration certificate:Egis Pharmaceutical Plant OJSCEgis Pharmaceutical Plant OJSC Hungary

Manufacturer: & nbsp

REMEDICA, Ltd. Cyprus

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp05.03.2018

Illustrated instructions

Instructions

Letyram® (Letiram)