Levetiracetam - instructions for use, dose, side effects, contraindications

		For dosage:
Active substance:	250 mg		500 mg	1000 mg
Levetiracetam	250.0 mg		500.0 mg	1000.0 mg
Excipients:
Corn starch	52.0 mg		104.0 mg	208.0 mg
Povidone K30 (Kollidone 30)	13.0 mg		26.0 mg	52.0 mg
Talc	4.8 mg		9.6 mg	19.2 mg
Silica colloidal dioxide	3.25 mg		6.5 mg	13.0 mg
Magnesium stearate	1.95 mg		3.9 mg	7.8 mg
Film sheath:
Opadry II (white) [polyvinyl alcohol - 46.9%, macrogol 4000 - 23.6%, talc - 17.4%, titanium dioxide - 12.1%]	10.0 mg		20.0 mg	30.0 mg

Description:

For a dosage of 250 mg: tablets are round, biconvex, covered with a film shell of white color. The core of the tablet is white or almost white.

For dosages of 500 mg and 1000 mg: tablets are oval, biconcave, covered with a film shell of white color. The core of the tablet is white or almost 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-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 clear that it differs from the mechanism of action of known antiepileptic drugs.

Based on the research conducted in vitro and in vivo suggest that levetiracetam does not change the basic characteristics of nerve cells and normal neurotransmission.

Research in vitro showed that levetiracetam reduces the content Ca²⁺ in the neuron due to the weakening of the ion current through Ca²⁺ channels N-type and reduce the release of Ca²⁺ from the intra-neuronal depot. Levetiracetam also partially neutralizes the decrease in ion currents caused by low and beta-carbolines through channels conjugated to gamma-aminobutyric acid (GABA) and glycine receptors.

One of the proposed mechanisms is based on proven binding to a protein 2A membranes of synaptic vesicles of brain neurons. It is believed that this way the anticonvulsant effect of this drug is realized.

Fermodynamic effects: levetiracetam prevents the development of seizures 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 inter- and intra-individual variability. The clearance of the drug does not change after repeated injections. There is no dependence of pharmacokinetics on sex, ethnicity or time of day.

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. Bioavailability is approximately 100%. The maximum concentration in plasma (C_mOh) is achieved 3.3 hours after oral administration of levetiracetam at 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. The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg / kg / day, C_max is achieved after 0.5-1 h.

Distribution. The binding of levetiracetam and its main metabolite plasma protein is less than 10%. Volume of distribution (V_d) is about 0.5-0.7 l / kg.

Metabolism. Levetiracetam is poorly metabolized in the human body. The main pathway of metabolism (24% dose) is the enzymatic hydrolysis of the acetamide group. Isoforms of 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. The main metabolite ucb L057 is pharmacologically inactive. Two secondary metabolites were also detected. The first is formed as a result of hydroxylation of the pyrrolidone ring (1.6% of the dose), the other by the opening of the pyrrolidone ring (0,9% dose). Optical isomerization of levetiracetam and its main metabolite under conditions in vivo not found. Levetiracetam and its main metabolite does not inhibit the main isoenzymes of human cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxy hydroxylase in vitro. In human hepatocyte culture levetiracetam has little or no effect on the activity of isoenzymes CYP1A2, SULT1E1 and UGT1A1. Levetiracetam weakly induces the activity of isoenzymes CYP2B6 and CYP3A4. Data on drug interaction with oral contraceptives, digoxin and warfarin in vitro and in vivo show that significant induction of enzymes in vivo Mr.e is 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. The total excretion of levetiracetam and its main metabolite is 66% and 24%, respectively, of the dose taken during the first 48 hours. The renal clearance of levetiracetam and its metabolite ucb L057 is 0.6 and 4.2 ml / min / kg, respectively.

Elderly patients

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

Patients with renal insufficiency

In patients with impaired renal function, the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance (CC). 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_1/2is 25 h in the period between dialysis sessions and 3.1 h 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, significant changes in the clearance of levetiracetam do not 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 T_1/2 in children 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, absorption of levetiracetam in children is rapid. FROM_max is achieved within 0.5-1 h.

C_max and the area under the pharmacokinetic curve "concentration-time" (AUC) are linear in nature and are proportional to the dose. Terminal T_1/2 is 5 hours. The apparent clearance is 1.1 ml / min / kg.

Indications:

As a monotherapy in the treatment of:

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:

partial seizures with secondary generalization or without it in adults and children older than 4 years with epilepsy;
myoclonic seizures in adults and adolescents over 12 years with juvenile myoclonic epilepsy;
primary-generalized convulsive tonic-clonic seizures in adults and adolescents over 12 years of idiopathic generalized epilepsy.

Contraindications:

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

- children under 4 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:

In post-marketing data obtained from several prospective pregnancy registries, more than 1,000 cases of monotherapy with levetiracetam in the first trimester of pregnancy have been recorded.

In general, these data do not indicate a significant increase in the risk of serious congenital malformations, although teratogenic risk can not be completely ruled out. Therapy with several antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, which is why monotherapy in pregnant women is more appropriate. 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, as well as in fertile women who do not use reliable contraceptive methods, except in cases of extreme necessity.

Physiological changes in the body of a woman during pregnancy can affect the concentration of levetiracetam in plasma, as well as other antiepileptic drugs. During pregnancy, there was a decrease in the concentration of levetiracetam in plasma. Treatment of pregnant women with levetiracetam should be carried out under special supervision. Interruptions in antiepileptic therapy may lead to a worsening of the course of the disease, which can harm the health of both the mother and the fetus.

Levetiracetam is excreted in breast milk, so breastfeeding with treatment with the drug is not recommended.

Dosing and Administration:

Inside, regardless of food intake, with enough liquid. The daily dose of the drug is divided into two doses in the same dose.

Monotherapy

Adults and teenagers over 16 years of age treatment should start with daily dose 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 maximum daily dose is 3000 mg (but 1500 mg twice a day).

As part of complex therapy

Children older than 4 years and adolescents (12 to 17 years) 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 divided doses (10 mg / kg body weight 2 times a day). A dose change of 20 mg / kg body weight can be performed every 2 weeks until the recommended daily dose is 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 more than 50 kg dosing is carried out according to the scheme given for adults.

Adults and adolescents (12 to 17 years) with a body weight of more than 50 kg treatment should be started 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.

Because the levetiracetam is excreted from the body by the kidneys, when the drug is administered patients with renal insufficiency and elderly patients dose should be adjusted depending on the magnitude of the SC.

QC for men can be calculated based on the serum creatinine concentration, according to the following formula:

CK (ml / min) = [140 - age (years)] х body weight (kg) / 72 х КК_serum (mg / dL)

QC for women can be calculated by multiplying the obtained value by a factor of 0.85.

Then the QC is adjusted taking into account the body surface area (PPT) according to the following formula:

KK (ml / min / 1.73 m²) = KK (ml / min) / PPT of the facility (m²) x 1.73

Adult Dose Adjustment

Renal insufficiency	CK (ml / min)	Dosing regimen
Norm	>80	from 500 to 1500 mg twice a day
Lightweight	50-79	from 500 to 1000 mg twice a day
Moderate	30-49	from 250 to 750 mg twice a day
Heavy	<30	from 250 to 500 mg twice a day
Terminal stage (patients on dialysis *)	-	from 500 to 1000 mg once a day **

* The first day of treatment is recommended to take a saturating dose of 750 mg.

** After dialysis, an additional 250-500 mg dose is recommended.

Children with kidney failure correction of the dose of levetiracetam should be made taking into account the degree of renal failure using recommendations given for adults.

For young adolescents and children apply the following formula (Schwarz form):

KK (ml / min / 1.73 m²) = Height (cm) x ks/ QC_serum (mg / dL)

in children under the age of 13 and adolescent girls ks = 0,55;

in adolescent boys ks = 0,7.

Recommendations for dose adjustment for children and adolescents impaired renal function with a body weight of less than 50 kg

Degree of severity of renal failure	KK (ml / min / 1, 73 m ²)	Children and adolescents with a body weight of less than 50 kg
Norm	>80	10-30 mg / kg 2 times a day
Lightweight	50-79	10-20 mg / kg 2 times a day
Moderate	30-49	5-15 mg / kg 2 times per day
Heavy	<30	5-10 mg / kg 2 times a day
Terminal stage (patients on dialysis)	-	10-20 mg / kg once a day , *

* On the first day of treatment it is recommended to use a loading dose of levetiracetam 15 mg / kg.

** After dialysis, an additional dose of 5-10 mg / kg is recommended.

Patients with impaired liver function of mild to moderate severity correction of the dosing regimen is not required.

In patients with decompensated impairment of liver function and renal insufficiency The level of decrease in QC may not be complete measure the severity of renal failure. In such cases, with KK <60 ml / min / 1.73 m² it is recommended to reduce the daily dose by 50%.

Side effects:

Based on clinical trials and post-marketing experience with levetiracetam, the most frequent adverse reactions were nasopharyngitis, drowsiness, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar for different age groups of adults and children.

Frequency of side effects: very often (≥1 / 10), often (≥1 / 100 to <1/10), infrequently (≥1 / 1000 to <1/100), rarely (≥1 / 10000 to <1/1000 ), very rarely (<1/10000), the frequency is not established (there is currently no data on the prevalence of adverse reactions).

On the part of the blood and lymphatic system

Infrequently: thrombocytopenia, and leukopenia.

Rarely: agranulocytosis, pancytopenia (in some cases with oppression of bone marrow function), neutropenia.

From the immune system

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

From the side of metabolism

Often: anorexia.

Infrequently: weight gain, weight loss.

Rarely: hyponatremia.

From the side of the psyche

Often: depression, mood changes, hostility, aggressiveness, insomnia, nervousness, irritability, anxiety.

Infrequently: confusion, agitation, hallucinations, emotional instability, psychotic disorders, suicide attempts and suicidal thoughts, behavioral disorders, anger, panic attacks, mood swings.

Rarely: completed suicide, personality disorder, impaired thinking.

From the nervous system

Often: drowsiness, headache.

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

Infrequently: paresthesia, amnesia, impaired coordination / ataxia, memory impairment, decreased concentration of attention.

Rarely: hyperkinesia, choreoathetosis, dyskinesia.

From the side of the organ of vision

Infrequently: diplopia, violation of accommodation.

From the side of the hearing organ

Often: Vertigo.

From the respiratory system

Often: cough.

From the digestive system

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

Infrequently: pancreatitis, changes in functional liver samples.

Rarely: hepatic insufficiency, hepatitis, weight loss.

From the skin

Often: skin rash.

Infrequently: eczema, pruritus, 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.

From the musculoskeletal system

Infrequently: muscle weakness, myalgia.

Infections and invasions

Often: nasopharyngitis.

Rarely: infection.

General disorders

Infrequently: asthenia, fatigue, accidental injuries.

The risk of anorexia is higher with the conscientious use of levetiracetam with topiramate.

In placebo-controlled studies safety profile of levetiracetam in children (patients aged 4-16 years) was comparable to that in adults, with the exception of behavioral and psychiatric adverse reactions that occurred in children more often than adults. In children and adolescents aged 4-16 years, such adverse reactions as vomiting (very often 11.2%), agitation (often 3.4%), mood changes (often 2.1%), emotional lability (often - 1.7%), aggression (often - 8.2%), behavioral disorders (often 5.6%) and lethargy (often 3.9%) were more frequent than in other age ranges.

Evaluation of cognitive and neuropsychological effects of levetiracetam in children aged 4-16 with partial seizures (according to double-blind placebo-controlled studies of the safety profile) showed that levetiracetam is not different (no less safe) from placebo on changes from the initial values on the scale "Attention and memory of Leiter-R" (Leiter-R Attention and Memory), the scale "Comprehensive monitoring of memory" (Memory Screen Composite). The results of a study of behavioral and emotional functions, confirming that, against the background of the application levetiracetam but there is an aggressive behavior, obtained with the help of a standardized method using a validated tool- "Achenbach's Children's Behavior Questionnaire" (Achenbach Child Behavior Checklist). However, in patients who took levetiracetam long-term, in the framework of open studies, there were no disturbances in behavioral and emotional functions, in particular, the level of aggressive behavior did not differ from the initial one.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

Symptoms: drowsiness, agitation, anxiety, aggressiveness, oppression 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. Specific antidote for levaThiracetam not.If necessary, symptomatic treatment in a hospital using hemodialysis (dialysis efficiency for levetiracetam is 60%, for its primary metabolite - 74%).

Interaction:

Anticonvulsants

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

Similar to adults, in children at doses up to 60 mg / kg / day levetiracetam does not interact with other medications. A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4-16 years) confirms that levetiracetam as an auxiliary therapy does not affect serum C_ss simultaneously used carbamazepine and valproic acid. However, there is evidence that the clearance of levetiracetam in children taking anticonvulsant drugs - inducers of microsomal liver enzymes - is increased by 20%.Correction of the dose is not required.

Probenecid

Probenecid (500 mg 4 times a day) is a blocker of tubular secretion in the nights, it is shown that it inhibits renal clearance of the main metabolite, but not levetiracetam. Nevertheless, the concentration of the main metabolite remains low. It is expected that other drugs excreted through active tubular secretion can 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, sulfanilamide and methotrexate, is unknown.

Oral contraceptives and other pharmacokinetic interactions

Levetiracetam at a dose of 1000 mg / day does not affect the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); The hormonal status (the content of luteinizing hormone and progesterone) does not change. Levetiracetam in a dose of 2000 mg / day had no effect on the pharmacokinetics of digoxin and warfarin.The simultaneous use of digoxin, oral contraceptives and warfarin does not affect the pharmacokinetics of levetiracetam.

Antacids

Data on the effect of antacids on the absorption of levetiracetam are absent.

Food and alcohol

Food does not affect the degree of absorption of levetiracetam, but somewhat reduces its rate. Data on the interaction of levetiracetam with ethanol are absent. There are isolated reports of a decrease in the efficacy of levetiracetam when administered topically to osmotic laxatives, and therefore it is not recommended to take osmotic laxatives at the same time for one hour before and within one hour after taking levetiracetam.

Special instructions:

No therapy

It is recommended to cancel the drug gradually. For example, in adults and adolescents with a body weight of more than 50 kg: dose reduction should be carried out at a step of 500 mg 2 times a day, not more often than every 2-4 weeks; in children from 6 years of age with a body weight of less than 50 kg: dose reduction should be carried out in steps of not more than 10 mg / kg 2 times a day, not more often than every 2 weeks.

Renal insufficiency

The use of levetiracetam in patients with renal insufficiency may require dose adjustment.In patients with severe hepatic impairment, it is recommended that the kidney function be evaluated before starting the dose selection (see "Method of administration and dose"),

Suicide

In patients taking anticonvulsants (including levetiracetam), there was suicide, suicide attempts, suicidal thoughts and behavior.

A meta-analysis of randomized placebo-controlled trials of anticonvulsant drugs showed a slight increase in the risk of suicidal thoughts and behavior. The mechanism of its implementation is unknown.

In connection with the foregoing, it is necessary to monitor patients with symptoms of depression or suicidal thoughts and / or behavior and prescribe appropriate therapy. Patients (and caregivers) should be informed of the need to seek medical help if they develop symptoms of depression and / or suicidal thoughts and behavior.

Children

The dosage form of the tablet has age limits for use in childhood (see "Indications"). According to available data levetiracetam does not affect growth and puberty.However, the long-term impact on learning, intelligence, growth, endocrine function, puberty and child fertility is unknown.

Concomitant antiepileptic drugs (during the transfer of patients to receive levetiracetam) should be gradually phased out.

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

Studies on the impact on the ability to drive vehicles and work with mechanisms have not been conducted. Due to individual differences in susceptibility, some patients may experience drowsiness and other disorders from the central nervous system, especially at the beginning of therapy and after increasing the dose. Therefore, it is recommended to use caution when driving vehicles and engaging in other activities that require an increased concentration of attention and speed of psychomotor reactions. If these symptoms occur, patients should abandon such activities until they are convinced that these symptoms do not have a significant effect on them.

Form release / dosage:

Film coated tablets, 250 mg, 500 mg and 1000 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30 tablets in a jar (bottle) polymer for medicines with a lid or jar (bottle) for medicines made of plastic with a lid.

Free space in the jar (bottle) is filled with cotton absorbent medical cotton.

Each jar (bottle) or 3 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003042

Date of registration:18.06.2015

Expiration Date:18.06.2020

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp11.03.2018

Illustrated instructions

Instructions

Levetiracetam (Levetiracetam)