Levitsitam

General characteristics. Structure:

Active agent: levetiratsetama of 250 mg or 500 mg;

Excipients: cellulose microcrystallic, коповидон, кросповидон, starch corn prezhelatinizirovanny, magnesium stearate, a covering for drawing a cover of Opadry ІІ White (polyethyleneglycol, polyvinyl alcohol, talc, titanium dioxide (Е 171)).

Pharmacological properties:

Pharmacodynamics. Levetiratsetam – derivative a pirrolidona (S-enantiomer of alpha ethyl-2-oxo-1-pyrrolidine-acetamide) – on chemical structure differs from the known antiepileptic medicines. The mechanism of action of a levetiratsetam is insufficiently studied, but is established that it differs from the mechanism of effect of the known antiepileptic drugs. On the basis of the conducted researches in vitro and in vivo assume what does not change levetiratseta the main characteristics of a nervous cell and normal neurotransmission. Activity of drug is confirmed relatively both focal, and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction).

Pharmacokinetics. Absorption. After oral administration to levetiratseta it is well absorbed from digestive tract. Absorption happens completely and has linear character thanks to what concentration in a blood plasma can be predicted, proceeding from the accepted dose of a levetiratsetam expressed in body weight mg/kg. Extent of absorption of a levetiratsetam does not depend on a dose and time of meal. Bioavailability makes about 100%. The maximum concentration in plasma (Cmax)
it is reached in 1,3 h after oral administration of a levetiratsetam in a dose of 1000 mg and at a single dose makes 31 mkg/ml, after repeated reception (2 times a day) – 43 mkg/ml. Equilibrium concentration is reached in 2 days at double administration of drug. The pharmacokinetics of a levetiratsetam at children has linear character in the range of doses from 20 to 60 mg/kg/days, Cmax is reached in 0,5–1 hour.

Distribution. Linkng of a levetiratsetam and its main metabolite with proteins of plasma makes less than 10%. The volume of distribution (Vd) makes about 0,5-0,7 l/kg.

Metabolism. Formation of an inactive metabolite (ucb L057) primary pharmacological happens without liver P450 cytochrome participation. Levetiratsetam does not influence enzymatic activity of hepatocytes.

Removal. The elimination half-life (T1/2) makes of a blood plasma of the adult 7±1 hours and does not depend on a way of introduction and the mode of dosing. The average size of the general clearance makes 0,96 ml/min. 95% of drug are removed by kidneys. The renal clearance of a levetiratsetam and inactive primary metabolite (ucb L057) makes 0,6 and 4,2 ml/min. respectively.

At patients of advanced age the elimination half-life increases by 40% and makes 10–11 hours that is connected with depression of function of kidneys at this category of patients. During the 4-hour session of dialysis about 51% of a levetiratsetam are removed. At patients does not happen to an abnormal liver function of easy and average severity of significant changes of clearance of a levetiratsetam. At most of patients with heavy abnormal liver functions the clearance of a levetiratsetam decreases more than by 50% because of the accompanying renal failure. The elimination half-life at children after single oral administration of drug in a dose of 20 mg/kg of body weight makes 5–6 hours. The general clearance of a levetiratsetam at children is about 40% higher, than at adults, and is in direct dependence on body weight.

Indications to use:

- Monotherapy (drug of the first choice) at treatment:
with secondary generalization or without that at adults and children 16 years for which epilepsy is for the first time diagnosed are more senior than partial attacks.
- As a part of complex therapy at treatment:                         
with secondary generalization or without that at adults and children 4 years sick with epilepsy are more senior than partial attacks;
- at adults and children 12 years sick with juvenile myoclonic epilepsy are more senior than myoclonic spasms;
- at adults and children 12 years sick with idiopathic generalized epilepsy are more senior than initially generalized convulsive (toniko-clonic) attacks.

Route of administration and doses:

Pill is taken inside, washing down them with enough liquid, irrespective of meal. The daily dose is divided into two identical receptions.

Monotherapy at adults and детй 16 years are more senior it is necessary to begin with a dose 250 mg 2 times a day. In 2 weeks the dose can be increased to initial therapeutic – 500 mg 2 times a day. The maximum daily dose makes 1500 mg 2 times a day, that is should not exceed 3 g.

As a part of complex therapy at children 4 years are more senior treatment it is necessary to begin with a dose 10 mg/kg of body weight 2 times a day. Increase in a daily dose by 20 mg/kg of body weight can be carried out each 2 weeks before achievement of the recommended daily dose –        30 mg/kg of body weight 2 times a day. If necessary the daily dose can be reduced. It is recommended to apply a minimal effective dose. The recommended doses, depending on the body weight of the child:

* to children with body weight to 25 kg appoint to levetiratseta in other dosage form with a possibility of smaller dosing;

from 25 to 50 kg: an initial dose of-250 mg 2 times a day; the maximum –750 mg 2 times a day;

to children with body weight more than 50 kg carry out dosing according to the scheme provided for adults.

To adults and children 16 years with body weight more than 50 kg are more senior treatment it is necessary to begin with a dose 500 mg 2 times a day. Depending on a clinical picture and portability of drug the daily dose can be increased to maximum – 1500 mg 2 times a day. Increase in a dose by 500 mg 2 times a day can be carried out each 2-4 weeks.

As to levetiratseta it is brought out of an organism by kidneys, at purpose of drug patients with a renal failure and to patients of advanced age should adjust a dose depending on the level of the clearance of creatinine (CC).

Proceeding from concentration of serumal creatinine, KK for men it is possible to calculate by a formula:

                           [140 – age (advanced in years)] x Masa body (kg)

 KK (ml/min.) =-----------------------------------------------------------

                                               72 x ККсыворот. (mg/dl)

 

KK for women can be calculated, having increased the received value by coefficient 0,85.

The dosing mode at a renal failure

Severity of a renal failure	Clearance of creatinine, (ml/min.)	Dosing mode
Normal function of kidneys	> 80	from 500 to 1 500 mg 2 times a day
Easy degree	50-79	from 500 to 1000 mg 2 times a day
Average degree	30-49	from 250 to 750 mg 2 times a day
Heavy degree	<30	from 250 to 500 mg 2 times a day
End-stage (the patients who are on a hemodialysis *)		from 500 to 1000 mg of 1 times a day **

 
* In the first day of treatment reception of the sating dose of 750 mg is recommended.
** After dialysis reception of an additional dose of 250-500 mg is recommended.
At KK <70 ml/min. decrease in a daily dose by 50% is recommended.
Easy and moderate severity of correction of the mode of dosing is not required to patients with a liver failure.

Features of use:

Use during pregnancy or feeding by a breast.
Do not use drug during pregnancy except for cases of purpose of drug according to vital indications as it is necessary to consider that breaks in performing antiepileptic therapy can lead to an aggravation of symptoms that can do harm to health both mother, and a fruit. Drug gets into breast milk therefore in need of drug use breastfeeding needs to be stopped.

Children. Drug is not recommended for use to children 4 years due to the lack of data on safety and efficiency of drug are younger. The age restrictions predetermined by a disease form are presented in the section "Indications". To children with body weight less than 25 kg apply to levetiratseta in other dosage form.

In need of the termination of administration of drug cancellation is recommended to be carried out gradually (for example, at adults – reducing a single dose by 500 mg each 2-4 weeks; at children reduction of a single dose has to be carried out no more than on 10 mg/kg each 2 weeks). The drug uses given relatively known for today do not confirm to children influence on processes of growth and puberty.

At adults and children who suffer from a partial form of epilepsy and accepted to levetiratseta, increase in frequency of attacks is possible (approximately for 25% at adults and for 14% at children). But for today communication with administration of drug because at adults and children who received placebo similar was observed in       26% and 21% of cases respectively is not proved. When using drug for therapy of primary toniko-clonic attacks at adults and children with idiopathic generalized epilepsy of increase in frequency of attacks it was not noted. As to levetiratseta it is brought out of an organism by kidneys, at purpose of drug patients with a renal failure and to patients of advanced age should adjust a dose depending on the level of clearance of creatinine.

Ability to influence speed of reactions at control of motor transport or work with other mechanisms.
Researches on studying of influence of drug on ability to control of motor transport and work with mechanisms were not conducted. Because of possible individual sensitivity some patients can note the drowsiness and other symptoms connected with influence on the central nervous system, especially in an initiation of treatment or in the course of increase in a dose.

Side effects:

Treat the most frequent side reactions:
disturbance of the general character: very often – an adynamy, fatigue;
from the central nervous system: very often – drowsiness; often – a headache, amnesia, an ataxy, spasms, a hyperkinesia, a tremor, balance disturbance, confusion of consciousness, a memory impairment, paresthesia;
from mentality: excitement, depression, emotional instability, changes of mood, hostility, aggression, sleeplessness, nervousness, irritability, hallucinations, psychotic frustration, suicide, attempts of suicide and thought of a suicide;
from the alimentary system: often – abdominal pain, diarrhea, dyspepsia, nausea, vomiting; sometimes – pancreatitis;
from a liver and biliary tract: liver failure, hepatitises. Drug influences results of hepatic tests;
from a metabolism: often – anorexia (the risk increases at simultaneous use with topiramaty), loss of body weight;
from acoustic organs and vestibular mechanism: dizziness;
from organs of sight: diplopia, loss of clearness of sight;
from skeletal muscles and connecting fabric: mialgiya;
wounds, intoxications and complications: accidental injuries;
infections and invasions: infectious diseases, nasopharyngitis;
from respiratory system: often – cough;
from integuments and their derivatives: often – skin rash; separate messages – an allopecia (in many cases recovery of a pilar cover was observed after drug withdrawal);
from blood: thrombocytopenia; sometimes – a leukopenia, a neutropenia, a pancytopenia.

Interaction with other medicines:

Drug does not interact with other antiepileptic drugs (Phenytoinum, carbamazepine, valproic acid, phenobarbital, lamotridzhiny, gabapentiny, Primidonum). It is necessary to consider that the clearance of a levetiratsetam is 22% higher at children who accept fermentosoderzhashchy anticonvulsants.

Levetiratsetam in a daily dose of 1000 mg does not change pharmacokinetics of peroral contraceptives (ethinylestradiol and levonorgestrel). Levetiratsetam in a daily dose of 2000 mg does not change pharmacokinetics of digoxin and warfarin. Digoxin, peroral contraceptives and warfarin, in turn, do not influence pharmacokinetics of a levetiratsetam.

There are data on what пробеницид (500 mg 4 times a day), blocking secretion of renal tubules, suppresses renal clearance of primary metabolite of a levetiratsetam. It is assumed that also some other medicines, for example non-steroidal anti-inflammatory drugs, streptocides, a methotrexate in the same way interact. There are no data on influence of antiacid drugs on absorption of a levetiratsetam. Extent of absorption of a levetiratsetam does not depend on meal, but the speed of absorption decreased. Data relatively of interaction of a levetiratsetam with alcohol are absent.

Contraindications:

Hypersensitivity to a levetiratsetam or other derivatives of a pirrolidon, and also to any components of drug; children's age up to 4 years (safety and efficiency of drug are not established); patients advanced age (of 65 years); heavy abnormal liver functions; renal failure.

Overdose:

Symptoms: drowsiness, excitement, aggression, respiratory depression, confusion of consciousness, lump.

Treatment: reception of absorbent carbon and gastric lavage. There is no special antidote. If necessary the symptomatic treatment in the conditions of a hospital with use of a hemodialysis is carried out ( about 60% are removed).

Storage conditions:

To store in the place, unavailable to children, in original packaging at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister; on 3 or 6 blisters in a cardboard pack.