Levetinol

General characteristics. Structure:

Pharmacological properties:

Active ingredient of drug, to levetiratseta, is derivative a pirrolidona (S-enantiomer α-etil-2-okso-1-pirrolidinatsetamid), on chemical structure different from other anticonvulsants.

The mechanism of action of a levetiratsetam is up to the end not found out, but it differs from the mechanism of action of other anticonvulsants. In experiments of in vitro and in vivo it is shown what to levetiratseta does not influence the main properties of a cell and normal nervous transfer.

In the researches in vitro it is shown that, partially reducing calcic currents of N-type and reducing release of calcium ions from intracellular depots of neurons, changes levetiratseta concentration of calcium ions in neurons. In addition to it it partially eliminates reduction of currents of GAMK-and the glycine channels caused by zinc and β-Carbolenums. Moreover, in the researches in vitro it is shown what to levetiratseta contacts special sites of a brain of rats. This site is protein 2A of synoptic bubbles which as it is supposed, is involved in process of merge of bubbles and an exocytosis of neurotransmitters. Levetiratsetam and his analogs contacting protein 2A of synoptic bubbles show anticonvulsant activity on audiogene model of epilepsy at mice, and, the communication is stronger, the activity is higher. These data mean that linkng of a levetiratsetam with protein 2A of synoptic bubbles realizes its anticonvulsant action.

Levetiratsetam has anticonvulsant effect on many models of partial and initially generalized spasms at animals without the accompanying pro-convulsive effect. The main metabolite of a levetiratsetam is inactive.

Levetiratsetam shows anticonvulsant activity at partial and generalized epilepsy at the person (epileptiform splash / the photoparoxysmal answer) that confirms its wide range of pharmacological action.

Levetiratsetam is well soluble and permeable compound. The pharmacokinetic profile has linear character with low inside - and an interindividual variation. After prolonged use of change of clearance does not occur. Certificates on existence of sexual, racial or daily differences are absent. Pharmacokinetic properties of a levetiratsetam at patients to epilepsy and healthy volunteers are comparable.

Owing to full and linear absorption plasma concentration gives in to forecasting in size of the dose of a levetiratsetam expressed in body weight mg/kg. Therefore it is not required to control plasma concentration of a levetiratsetam.

At adults and children high correlation between concentration of a levetiratsetam in plasma and saliva is shown (the relation saliva/plasma fluctuate within 1–1,7 for tablets for intake and for solution for intake in four hours after reception of the last).

Adults and teenagers.

Absorption. After intake to levetiratseta it is quickly soaked up. Absolute bioavailability after intake is close to 100%.

The maximum concentration in plasma (Cmax) is reached in 1,3 h. The equilibrium state is reached in two days at administration of drug two times in sutki.cmax usually makes 31 and 43 mkg/ml later according to a single dose of 1000 mg and reception of 1000 mg of drug two times a day.

The size of absorption does not depend on a dose and on meal.

Distribution. Data on distribution at the person are absent. Levetiratsetam and his main metabolite poorly contact proteins of plasma (<10%).

The volume of distribution of a levetiratsetam makes about 0,5-0,7 l/kg that approximately corresponds to water volume in an organism.

Biotransformation. Levetiratsetam is poorly metabolized in a human body. The main metabolic way (24% of a dose) is enzymic hydrolysis of atsetamidny group. Isoenzymes of P450 cytochrome of a liver do not participate in formation of the main metabolite (ucb L057). Hydrolysis of atsetamidny group happens in many fabrics, including blood cells. ucb L057 metabolite pharmacological is inactive.

Two minor metabolites are also found. The first is formed at the expense of a hydroxylation of a pyrrolidonic ring (1,6% of a dose), the second — by disclosure of a pyrrolidonic ring (0,9% of a dose).

The other not identified metabolites make only 0,6% of a dose.

The optical isomerization of a levetiratsetam and its main metabolite of in vivo is not revealed.

Levetiratsetam and his main metabolite do not inhibit the main isoenzymes of P450 cytochrome of a liver of the person (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), a glyukuroniltransferaza (UGT1A1 and UGT1A6) and an epoksidgidroksilaza of in vitro. Levetiratsetam also does not influence a glyukuronirovaniye of in vitro valproic acid.

In culture of hepatocytes of the person exerted levetiratseta weak impact or did not influence activity of isoenzymes of CYP1A2, SULT1E1 and UGT1A1 at all. Levetiratsetam poorly induced activity of isoenzymes of CYP2B6 and CYP3A4. Data on in vitro and data on medicinal interaction with oral contraceptives, digoxin and in vivo warfarin show that significant induction of in vivo enzymes is not expected. Therefore interaction of a levetiratsetam with other substances is improbable.

Removal. The elimination half-life at adults makes 7±1 and does not depend on a dose, a way of introduction or duration of use. The average general clearance makes 0,96 ml/min.

The main way of elimination is removal with urine (about 95% of a dose, 93% are brought out of them during 48 h). Removal with excrements makes only 0,3% of a dose.

The total value of excretion of a levetiratsetam and its main metabolite makes respectively 66 and 24% of the accepted dose during the first 48 h. The renal clearance of a levetiratsetam and ucb L057 makes 0,6 and 4,2 ml/min. respectively that testifies to excretion of a levetiratsetam by means of glomerular filtering with the subsequent canalicular reabsorption, and the main metabolite in the way along with glomerular filtering — active canalicular secretion.

Elimination of a levetiratsetam correlates with clearance of creatinine.

Elderly. The elimination half-life at elderly increases by 40% (to 10–11 h) that is caused by depression of function of kidneys at this group of the population.

Renal failure. The seeming clearance of a levetiratsetam and its main metabolite depends on clearance of creatinine. In this regard at patients from average degree and a heavy renal failure it is recommended to adjust a maintenance dose of drug depending on clearance of creatinine.

At adult patients with a terminal renal failure the elimination half-life makes 25 h in intervals between sessions of a hemodialysis and 3,1 h during the procedure.

During the ordinary four-hour session of a hemodialysis about 51% of a levetiratsetam are removed.

Abnormal liver function. At patients from easy and average degree a liver failure the clearance of a levetiratsetam changes slightly. At most of patients with a heavy liver failure the clearance of a levetiratsetam decreases more than by 50% that is caused by the accompanying renal failure.

Children are younger than 12 years.

Children at the age of 4–12 years. After a single dose of drug in a dose of 20 mg/kg the elimination half-life at children of 6-12 years makes 6 h. The seeming clearance corrected on body weight for 30% exceeds that at adults with epilepsy. After long administration of drug in a dose of 20-60 mg/kg/days absorption of a levetiratsetam at children of 4-12 years bystry. Cmax is reached during 0,5–1 h Cmax and the area under a curve "concentration time" have linear character and are proportional to a dose. The terminal elimination half-life makes 5 h. The seeming clearance — 1,1 ml/min.

Indications to use:

Levetiratsetam is shown as monotherapy for treatment of partial spasms with secondary generalization or without it at patients from 16 years with for the first time the established diagnosis epilepsy.

As auxiliary therapy to levetiratseta it is shown for treatment:

- partial spasms with secondary generalization or without it at patients with epilepsy since 6 years.

- myoclonic spasms at patients with juvenile myoclonic epilepsy since 12 years.

- initially generalized toniko-clonic spasms at patients with idiopathic generalized epilepsy since 12 years.

Route of administration and doses:

Dosing mode. Monotherapy at adults and teenagers since 16 years. The recommended initial dose makes 250 mg two times a day which needs to be raised in two weeks to initial therapeutic 500 mg two times a day. A dose two times a day each two weeks depending on the clinical answer are allowed to increase with a step 250 mg. The maximum dose — 1500 mg two times a day. Auxiliary therapy at adults (≥18 years) and teenagers (12–17 years) with the body weight of 50 kg and more. The initial therapeutic dose makes 500 mg two times a day. Such dose is allowed to be applied from the first day of treatment. Depending on the clinical answer and portability about 1500 mg two times a day are allowed to raise a daily dose. Two times a day each 2–4 weeks are allowed to raise or lower a dose by 500 mg. Special groups of patients. Elderly (65 years are also more senior). At elderly patients with an impaired renal function it is recommended to adjust a dose (see below "Renal failure"). Renal failure. Depending on degree of a renal failure the daily dose is selected individually. To use the table of dose adjustment it is necessary to calculate the clearance of creatinine (CC) of the patient in KK ml/min. in ml/min. it is possible to define, using the size of serumal concentration of creatinine (mg/dl) on the following formula (for adults and teenagers with the body weight of 50 kg and more):

Then the amendment on the body surface area (BSA) as follows is entered:

Dose adjustment at adults and teenagers with a renal failure, which body weight> 50 kg

                           Clearance of Creatinine group (ml/min. / 1,73 sq.m)           Dose and frequency of reception

 Norm                             >                                   80 500-1500  mg 2 times a day

 Easy                                                             50-79 500-1000 mg 2 times a day

 Average degree                                                      of 30-49 250-750 mg 2 times a day

Heavy                            <                                   30 250-500 mg 2 times a day

End-stage

renal failure —

the patients who are on a hemodialysis (1)    –                                500–1000 mg of 1 times a day ⁽²⁾

(2) Upon completion of a hemodialysis reception of an additional dose of 250 or 500 mg is recommended.

Because the clearance of a levetiratsetam depends on function of kidneys, to children with a renal failure its dose is selected depending on KK. The present recommendations are based on researches at adult patients.

KK at ml/min. / 1,73 sq.m at children and teenagers can be estimated on plasma concentration of creatinine (at mg/dl) on the following formula (Schwartz's formula):

 

where ks=0,45 for children up to 1st year; 0,55 — for children of 1-13 years and female teenagers; 0,7 — male teenagers.

Dose adjustment at children and teenagers with a renal failure, which body weight <50 kg

Group	KK (ml/min. / 1,73 sq.m)	Dose and frequency of reception
		Since 6 years
Norm	> 80	10–30 mg/kg 2 times a day
Easy	50–79	10–20 mg/kg 2 times a day
Average degree	30–49	5–15 mg/kg 2 times a day
Heavy	<30	5–10 mg/kg 2 times a day
End-stage of a renal failure — the patients who are on a hemodialysis (1)	–	10–20 mg/kg of 1 times a day (2) (3)

(1) Solution for intake is applied to doses <250 mg and at the patients not capable to swallow tablets.

(2) In the first day reception of a load dose of 15 mg/kg (0,15 ml/kg) is recommended.

(3) Upon completion of a hemodialysis reception of an additional dose of 5-10 mg/kg (0,05–0,1 ml/kg) is recommended.

Abnormal liver function. From easy and average degree the liver failure of dose adjustment does not require from patients. At patients with a heavy liver failure size KK can mislead about degree of a renal failure. Therefore at KK <60 ml/min. / 1,73 sq.m it is necessary to lower a maintenance dose of drug by 50%. 

 Children. Drug is appointed in the most convenient dosage form and a dosage depending on age, body weight and a necessary dose. Tablets are not intended for use for children aged 6 years are younger. To such patients drug is recommended to appoint in a dosage form solution for intake. Besides the available dosages of tablets are not intended for initial selection of a dose at children with body weight less than 25 kg, to the patients not capable to swallow tablets, and also in need of reception of a dose <250 mg. In all specified cases it is recommended to apply solution to intake. 

 Monotherapy. Efficiency and safety of a levetiratsetam at children and teenagers are younger than 16 years as monotherapy is not established. Data are absent. Auxiliary therapy at children of 6-17 years and with body weight less than 50 kg. The initial dose makes 10 mg/kg 2 times a day. Depending on the clinical answer and portability about 30 mg/kg 2 times a day are allowed to raise a dose. A dose two times a day each two weeks are allowed to raise or reduce with a step 10 mg/kg. It is necessary to apply the smallest effective dose. The dosing mode at children with the body weight of 50 kg and does not differ from adults any more.

The recommended doses at children since 6 years.

Body weight	Initial dose: 10 mg/kg 2 times a day	Maximum dose: 30 mg/kg 2 times a day
25 kg (1)	250 mg 2 times a day	750 mg 2 times a day
From 50 kg (2)	500 mg 2 times a day	1500 mg 2 times a day

(1) Children with the body weight of 25 kg are also less recommended to appoint drug in a dosage form solution for intake, 100 mg/ml

(2) The dosing mode at children with the body weight of 50 kg and does not differ from adults any more.

Route of administration. Inside, washing down with enough water, irrespective of meal. The daily dose is divided into two equal receptions.

 

Features of use:

Therapy cancellation. Drug withdrawal is recommended to be carried out gradually. For example, adults and teenagers with body weight have more than 50 kg: the dose decline has to be carried out with a step of 500 mg 2 times a day not more often than each 2–4 weeks; children from 6 years with body weight have less than 50 kg: the dose decline has to be carried out with a step no more than 10 mg/kg 2 times a day not more often than each two weeks.

Renal failure. Use of a levetiratsetam for patients with a renal failure can demand dose adjustment. At patients with a heavy liver failure it is recommended to estimate function of kidneys prior to selection of a dose (see the section "Route of Administration and Doses").

Suicide. At the patients accepting anticonvulsants (including levetiratseta), attempts of a suicide, suicide thoughts and behavior were noted a suicide. Meta-analysis of randomized placebos - controlled researches of anticonvulsant medicines showed small increase in risk of suicide thoughts and behavior. The mechanism of its implementation is not known.

Due to the above it is necessary to carry out observation of patients with symptoms of a depression or suicide thoughts and behavior and to appoint by it the corresponding therapy. Patients (and to the persons who are looking after them) should inform on need of the request for medical care at emergence of depression symptoms at them and (or) suicide thoughts and behavior.

Children. Tablets are not intended for use for children aged 6 years are younger. On the available these levetiratseta does not influence growth and puberty. However long-term influence on training, intelligence, growth, endocrine function, puberty and fertility of children is not known.

Side effects:

The profile of the undesirable phenomena given below is made by results of the analysis of placebo - controlled clinical trials of a levetiratsetam according to all indications (total quantity of patients — 3416). These data are added with data on use of a levetiratsetam within the open prolonged clinical trials, and also post-registration data. The most often reported undesirable reactions were the nasopharyngitis, drowsiness, a headache, weakness and dizziness. The profile of safety of a levetiratsetam in general does not differ depending on age (at adults and children), and also does not depend on the approved indications to use (various options of epilepsy).

Tabular data on undesirable reactions. The undesirable reactions revealed in clinical trials and within postergistratsionny monitoring (at adults, teenagers and children is more senior than the 1st month), are presented in the table on system and organ classes and frequency. Gradation of frequency: very often (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10 000 and <1/1000) and is very rare (<1/10 000).

System and organ class		Category of frequency
	Very often	Often	Infrequently	Seldom
Infections and invasions	Nasopharyngitis			Infections
From blood and lymphatic system			Thrombocytopenia, leykopeniya1	Pantsitopeniya1,2, neytropeniya1
Disturbances of metabolism and food		Anorexia	Snizheniye1 or increase in body weight
Mental disturbances		Depression, hostility or agressiya1, sleep disorder, nervousness, irritability	Suicide popytki1, suicide mysli1, psychotic rasstroystva1, disturbance povedeniya1, hallucinations, rage, confusion of consciousness, emotional lability, changes of mood, agitation	Taken place suitsid1, frustration of the personality, disturbance of thinking
From a nervous system	Drowsiness, headache	Spasms, balance disturbance, dizziness, lethargy, tremor	Amnesia, memory disturbance, lack of coordination of movements or ataxy, paresteziya1, disorder of attention	Horeoatetoz1, diskineziya1, hyperkinesia
From an organ of sight			Diplopia, vision disorder
From an acoustic organ and balance		Vertigo
From respiratory system, bodies of a thorax and a mediastinum		Cough
From digestive tract		Abdominal pains, diarrhea, dyspepsia, vomiting, nausea		Pankreatit1
From a liver and biliary tract			Disturbance of functional trials pecheni1	Hepatic nedostatochnost1, gepatit1
From skin and hypodermic fabrics		Rash	Alopetsiya1, eczema, itch	Toxic epidermal nekroliz1, Stephens-Johnson's syndrome, mnogoformny eritema1
From musculoskeletal and connecting fabrics			Muscular weakness, mialgiya
The general frustration and frustration in an injection site		Adynamy or fatigue
Injuries, poisonings and complications of procedures			Injury
1 The undesirable reactions revealed in the post-registration period 2     Oppression of a marrowy hemopoiesis is in certain cases established

Description of separate undesirable reactions. At simultaneous use of a topiramat and levetiratsetam the risk of development of anorexia increases. In certain cases alopecias it was exposed to involution after cancellation of a levetiratsetam.

Children. Within placebo - the controlled and open prolonged researches there took place treatment of 645 patients at the age of 4–16 years, 233 of which received to levetiratseta in a placebo frame - controlled researches. For both age ranges in addition there are uses of a levetiratsetam given by post-registration experience. The profile of safety of a levetiratsetam in general does not differ depending on age (at adults and children), and also does not depend on the approved indications to use (various options of epilepsy). Except for behavioural and psychiatric undesirable reactions which at children arose more often than at adults in placebo - controlled researches the profile of safety of a levetiratsetam at children was comparable to that at adults. Children at the age of 4–16 years have a vomiting (very often, 11,2%), agitation (often, 3,4%), changes of mood (often, 2,1%), emotional lability (often, 1,7%), aggression (often, 8,2%), a behavior disorder (often, 5,6%) and a lethargy (often, 3,9%) were noted more often than in other age ranges.

Cognitive and neuropsychological effects of a levetiratsetam at children of 4-16 years with partial spasms were estimated at double blind people, placebo - controlled researches of a profile of safety with use of design not of smaller safety. It was shown what to levetiratseta does not differ Leyter-R" (Leiter-R Attention and Memory), a scale "Complex Observation of Memory" (Memory Screen Composite) at the patients subjected to the analysis "under the protocol" (is not less safe) from placebo on changes from reference values on a scale "Attention and Memory. Results of a research of behavioural and emotional functions, confirmatory that against the background of use of a levetiratsetam there is an agressive behavior, are received by means of the standardized method with use of the validirovanny tool — the Questionnaire of behavior of children of Achenbach Child Behavior Checklist.

However at the patients accepting to levetiratseta dolgosrochno within the open researches, disturbances of behavioural and emotional functions did not arise, in particular the level of an agressive behavior did not differ from initial.

 

Interaction with other medicines:

Anticonvulsants. According to preregistration clinical trials to levetiratseta does not influence serumal concentration of other anticonvulsants: Phenytoinum, carbamazepine, valproic acid, phenobarbital, a lamotridzhin, a gabapentin and Primidonum — and these anticonvulsants do not influence pharmacokinetics of a levetiratsetam.

Similarly to adults, at children in doses to 60 mg/kg/days to levetiratseta does not interact with other medicines.

Retrospective assessment of pharmacokinetic interactions at children and teenagers with epilepsy (4–17 years) confirms that it to levetiratseta as auxiliary therapy does not influence equilibrium serumal concentration of at the same time applied carbamazepine and valproic acid. However there are data that the clearance of a levetiratsetam at the children accepting anticonvulsants — inductors of microsomal enzymes of a liver — increases by 20%. Dose adjustment is not required.

Probenetsid. Probenetsid (on 500 mg 4 times a day) is a blocker of canalicular secretion in kidneys, is shown that it inhibits renal clearance of the main metabolite, but not a levetiratsetam. Nevertheless, concentration of the main metabolite remains low. It is expected that other medicines which are excreted by means of active canalicular secretion can reduce renal clearance of the main metabolite. Influence of a levetiratsetam on пробенецид was not studied; influence of a levetiratsetam on other medicines which are excreted by active canalicular secretion including nonsteroid antiinflammatory drug, sulfonamide and a methotrexate, is not known.

Oral contraceptives and other pharmacokinetic interactions. Levetiratsetam in a dose of 1000 mg a day did not exert impact on pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); the hormonal status (content of luteinizing hormone and progesterone) did not change. Levetiratsetam in a dose of 2000 mg a day did not exert impact on pharmacokinetics of digoxin and warfarin, the prothrombin time did not change. Simultaneous use of digoxin, oral contraceptives and warfarin did not exert impact on pharmacokinetics of a levetiratsetam.

Antacids. Data on influence of antacids on absorption of a levetiratsetam are absent.

Food and alcohol. Food does not influence extent of absorption of a levetiratsetam, but reduces its speed a little.

Data on interaction of a levetiratsetam with ethanol are absent.

Contraindications:

— children's age up to 6 years;
— hypersensitivity to drug components;
— hypersensitivity to derivatives of a pirrolidon.

Overdose:

Symptoms. Drowsiness, agitation, aggression, consciousness oppression, respiratory depression and coma.

Treatment. After acute overdose it is necessary to wash out a stomach or to cause vomiting. The antidote of a levetiratsetam is not found. Treatment is symptomatic, can include use of a hemodialysis. The dialyzing activity concerning a levetiratsetam is equal to 60%, concerning the main metabolite — 74%.

Storage conditions:

To store in the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 250 mg, 500 mg, 750 mg, 1000 mg.