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

Composition:1 tablet contains:
active substance: levetiracetam 250 mg / 500 mg / 1000 mg;
Excipients: cellulose microcrystalline 21.6 mg / 43.2 mg / 86.4 mg, crospovidone 47 mg / 94 mg / 188 mg, macrogol 6000 (IOLE 6000) 18 mg / 36 mg / 72 mg, silicon dioxide colloid (aerosil) 8 mg / 3.6 mg / 7.2 mg. sodium croscarmellose 18 mg / 36 mg / 72 mg, magnesium stearate 3.6 mg / 7.2 mg / 14.4 mg. excipients for the shell:
- for a dosage of 250 mg: Opadrai II 85F30695 blue [polyvinyl alcohol 4.4 mg, macrogol 2.22 mg, talc 1.63 mg, titanium dioxide 2.6 mg. aluminum lacquer based on indigo carmine dye 0.136 mg, iron oxide dye yellow 0.014 mg];
- for a dosage of 500 mg: Opadrai II 85F32577 yellow [polyvinyl alcohol 8.8 mg, macrogol 4.44 mg, talc 3.26 mg, titanium dioxide 5.01 mg, aluminum lacquer based on quinoline yellow dye 0.487 mg, aluminum lacquer based on indigo carmine dye 0.003 mg];
- for a dosage of 1000 mg: Opadrai II 85F48105 white [polyvinyl alcohol 20.63 mg, macrogol 10.39 mg, talc 7.66 mg, titanium dioxide 5.32 mg].

Description:Dosage of 250 mg: tablets covered with a film shell of light blue color, biconvex, oblong with rounded ends, with a risk.
Dosage 500 mg: tablets, covered with a film coat of light yellow color, biconvex, oblong with rounded ends, with a risk.
Dosage of 1000 mg: tablets covered with a film shell white or almost white, biconvex, oval, without risks.
On the cross section, the nucleus is white or almost white in color.

Pharmacotherapeutic group:Antiepileptic agent.

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-etil-2-oxo-1-pyrrolidine-acetamide), differs in chemical structure from known antiepileptic medicines.

The mechanism of action of levetiracetam is not fully understood, but it is clear that it differs from the mechanism of action of known anti-epileptic drugs.

Experiments in vitro and in vivo showed that levetiracetam ns affects the basic characteristics of cells and normal neurotransmission transmission. Research in vitro showed that levetiracetam affects the vitriereironal concentration of Ca²⁺, partially inhibiting the current of Ca²⁺ through the 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 β-carbolines.

One of the proposed mechanisms of action is based on proven binding to the glycoprotein of synaptic vesicles SV2A, contained in the gray matter of the brain and spinal cord. It is believed that the anticonvulsant effect is realized in this way, which is expressed in counteracting the hypersynchronization of neuronal activity. Also levetiracetam affects the receptors of GABA and glycine receptors, modulating these receptors through various endogenous agents. Does not change the normal neurotransmission, but suppresses epileptiform neuronal outbreaks induced by GABA agonist bicuculine. and excitation of glutamate receptors. The activity of levetiracetam has been confirmed with respect to both focal and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction).

Pharmacokinetics:

There was no dependence of pharmacokinetics on sex, race and time of day.

Suction

Levetiracetam is a highly soluble substance with a high penetrating ability. After oral administration levetiracetam well absorbed from the gastrointestinal tract.Absorption occurs completely and is linear in nature, due to which the concentration in the blood plasma can be predicted, based on the accepted dose of levetiracetam expressed in mg / kg of body weight. Degree of absorption levetiracetam and does not depend on the dose and time of taking the food. Bioavailability is approximately 100%. Maximum concentration (FROM_max) in the blood plasma is achieved after 1.3 hours after oral administration of levetiracetam in a dose 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 through 2 day with a two-time administration of levetiracetam. Distribution

The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%. Volume of distribution (V_d) is about 0.5-0.7 l / kg. Data on the distribution of the drug but tissues are absent.

Metabolism

The main metabolic pathway (24% of the dose) is the enzymatic hydrolysis of the acetamide group. Formation of a primary pharmacologically inactive metabolite (ucb L057) occurs without the involvement of liver cytochrome P450. Levetiracetam does not affect the enzymatic activity of hepatocytes.

Two secondary metabolites were also detected. The former is formed by hydroxylation of the pyrrolidone ring (1,6% of the dose), the second - by opening the pyrrolidone ring (0.9%). Other unidentified metabolites are only 0,6% of the dose.

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

In conditions in vitro levetiracetam and its main metabolite did not inhibit the main isoforms of cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), also the activity of glucuronyl transferase (UGT1A1 and UGT1A6) and epoxy hydroxylase. Levetiracetam It also did not affect the puncture of valproic acid in vitro.

Excretion

Half-life (T_1/2) levetiracetam from the blood plasma of an adult is 7 ± 1 hours and does not depend on the mode of administration and dosage regimen. The average overall 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.

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.

Have patients with impaired renal function the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, a patient with renal insufficiency is recommended to select a dose depending on the creatinine clearance. In the terminal stage of renal failure in adult patients T_1/2 levetiracetam 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.

Have patients with impaired liver function light and moderate severity of significant changes in the clearance of levetiracetam ns occurs. In most patients with severe impairment of liver function with concomitant renal failure, the clearance of levetiracetam declines by more than 50%.

Have children (4-12 years) after a single oral administration of levetiracetam at a dose of 20 mg / kg of body weight is 6 hours. The total clearance of levetiracetam in children 4-12 years old is approximately 30% higher than in adults and is directly related to body weight. After repeated oral administration at a dose of 20-60 mg / kg of body weight to children 4-12 years of age, the maximum plasma concentration is reached after 0.5-1.0 hours and increases linearly andPortsionflax dose.

Indications:As a monotherapy in the treatment of:
- partial seizures with secondary generalization or without it in adults and adolescents with 16 years of age with newly diagnosed epilepsy.
In the complementary therapy in the treatment:
- partial seizures with secondary generalization or without it in adults and children from the age of 6 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 other components of the drug.
Children under 6 years.
Children with a body weight of less than 25 kg (the impossibility of accurate dosing).

Carefully:Patients of advanced age (over 65 years).
Diseases of the liver in the stage of decompensation.
Renal failure.

Pregnancy and lactation:

Pregnancy

Studies in animals have revealed reproductive toxicity of the drug. 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 may not be completely eliminated. Therapy with several antiepiletsFrimeans from a higher risk of congenital malformations than monotherapy, so that 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 given during pregnancy and in women with a preserved genital function, except in cases of clinical necessity.

Physiological changes in the body of a woman during pregnancy can affect the plasma concentration of levetiracetam as well as other antiepilepticsPtical medicines. During pregnancy, there was a decrease in the concentration of levetiracetam in the blood plasma. This decrease is more pronounced in the third trimester (up to 60% of the baseline concentration during the third trimester).

Treatment with levetiracetam pregnant women should be carried out under special supervision. Breaks in the conduct of antiepileecan lead to a worsening of the course of the disease, which can harm the health of both the mother and the fetus.

Dore-feeding

Levetiracetam is excreted in breast milk, so breastfeeding during treatment with the drug is not recommended. However, if treatment with levetiracetam is necessary during breastfeeding, the risk / benefit ratio should be carefully weighed against the importance of feeding.

Fertility

In animal studies,e Influence on fertility is found. Clinical data on the effect on fertility are not available, the potential risk to humans is unknown.

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 from 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 maximum daily dose is 3000 mg (but 1500 mg twice a day).

In the complementary therapy

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 two divided doses (500 mg divided into two 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.

Children from 6 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, divided into 2 divided doses (but 10 mg / kg body weight 2 times a day). A dose change of 20 mg / kg body weight (10 mg / kg body weight 2 times a day) can be performed every 2 weeks until the recommended daily dose is 60 mg / kg body weight (30 mg / kg body weight 2 times day). With intolerance of the recommended daily dose, there may be a reduction. The minimum effective dose should be used. The doctor should prescribe the drug at the most appropriate dosage depending on the age, body weight of the patient and the required therapeutic dose. Children with a body weight of more than 50 kg are dosed according to the scheme given for adults.

Because the levetiracetam is excreted from the body by the kidneys, when the drug is administered patients with renal insufficiency and elderly patients The dose should be adjusted depending on the amount of creatinine clearance (CC).

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

CK (ml / min) =[140 years of agedu)] x is the mass of the body (kg) / 72 х КК_from_turn(mg/ dl)

The creatinine clearance 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 surface area of the body (ПPT) according to the following formula:

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

Theone-time failure	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 renal insufficiency correction of the dose of levetiracetam should be made taking into account the degree of renal failure.

Creatinine clearance (ml / min / 1,73 m²) can be assessed based on serum creatinine (mg / dl) for adolescents and children using the following formula (Schwarz formula):

KK (ml / min / 1,73 m²) = Height (cm) x ks / QC_from_turn(mg/ dl)

ks = 0.55 for children under 13 and adolescent females;

ks = 0.7 for adolescent males.

Dosing for children and adolescents weighing less than 50 kg with impaired renal function:

Renal failure	K K (ml / min / 1.73 m²)	Dosing regimen
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	-	10-20 mg / kg once a day (1). (2)
dialysis)

(1) 15 mg / kg recommended loading dose on the first day of treatment

(2) recommended maintenance dose after dialysis 5-10 mg / kg

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 degree of decrease in the clearance of creatinine may not fully reflect the severity of renal failure. In such cases, when the creatinine clearance is <60 ml / min / 1.73 m² it is recommended to reduce the daily dose by 50%.

Side effects:

Presented below, the profile of adverse events is based on the analysis of the results of placebo-controlled studies, as well as the experience of post-marketing application of levetincentnersetama. 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.

The frequency of unwanted reactions is as follows: very often (≥1/10 cases), often (≥1/100 and <1/10 cases), infrequently (≥1/1000 and <1/100 cases), rarely (≥1/10000 and <1/1000 cases) and very rarely (<1/10000 cases).

Infectious and parasitic diseases: very often - nasopharyngitis; rarely - infection.

From the side of the blood and lymphatic system: infrequently - a thrombocytopaMr.oya, leukopenia; rarely - pancytopenia, agranulocytosis, neutropeniaetion.

From the immune system: rarely - drug reaction with eosinophilia and systemic manifestations (DRESS-syndrome).

Co side of metabolism: often - anorexia; infrequently - weight gain, weight loss; rarely - hyponatremia.

Disorders of the psyche: often - depression, feudeaggression, anxiety, insomnia, nervousness, irritability; infrequently - suicide attempts, suicidal intentions,psychotic disorders, behavioral disorders, hallucinations, anger, confusion, emotional lability, mood swings, agitation, panic attacks; rarely - suicide, personality disorder, violation of thinking.

From the side nervousth system: very often - drowsiness, headache; often - convulsions, imbalance, dizziness, lethargy, tremor, infrequently - amnesia, memory impairment, coordination / ataxia disorder, paresthesia, decreased concentration of attention; rarely - choreoathetosis, dyskinesia, hyperkinesia.

From the side of the organ of vision: infrequently - diplopia, blurred vision.

From the organ of hearing: often - vertigo.

On the part of the respiratory system, the organon of the thorax and the mediastinum: often - a cough.

From the gastrointestinal tract: often - abdominal pain, diarrhea, dyspepsia, vomiting, nausea, rarely - pancreatitis.

From the liver and bile ducts: infrequently - changes in functional liver samples; rarely - hepatic insufficiency, hepatitis.

From the skin and subcutaneous tissues: often - a rash; infrequently - alopecia, eczema, itching; rarely - toxic epidermal Mr.ekroliz, Stevens-Johnson syndrome, erythema multiforme.

From the side of the musculoskeletal and connective tissue: infrequently - muscle weakness, myalgia.

General disorders and disorders at the site of administration: often - asteMr./ fatigue.

Trauma, intoxication and complications of manipulation: infrequently - accidental damage. The risk of anorexia is higher with the simultaneous use of levetiracetam and topiramate.

AT In a number of cases, hair restoration was observed after the removal of levetiracetam.

In some cases of pancytopenia, bone marrow depression was recorded.

The safety profile of levetiracetam generally does not differ depending on age (in adults and children), and also does not depend on approved indications for use (various variants of epilepsy). With the exception of behavioral and psychiatric adverse reactions that occur in children more often than in adults, the safety profile of children is comparable to the safety profileeVetiracetam in adults.

The following undesirable reactions were more often recorded in children and adolescents aged 4-16 years: vomiting (very often, 11.2%), excitation (often, 3.4%), moodiness (often 2.1%),emotional lability (often, 1.7%), aggressiveness (often, 8.2%), behavioral disorders (often, 5.6%) and lethargy (often 3,9%). In children aged 1 month to 4 years, the following adverse reactions were more often reported: irritability (very often 11.7%) and impaired coordination (often, 3.3%).

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. There is no specific antidote for levetramratsagam. If necessary, symptomatic treatment is performed in a hospital using hemodialysis (dialysis efficiency for iratcetam light is 60%, for its primary metabolite 74%).

Interaction:

Levetiratsethere ne affects the concentration in the blood plasma of antiepileptic drugs (phenytoina, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, topiramate and primidon), and these antiepileptic drugs do not affect the concentration of levetiracetam.

Similar to adults, in children at doses up to 60 mg / kg / day, the levitricanethere does not interact with other medicines.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4-17 years) confirms the lefethere as an auxiliary therapy does not affect the equilibrium serum concentrations of concomitant carbamazepine and valproic acid.

The clearance of levetiracetam was 20% higher in children taking antiepileptic drugs - inducers of microsomal liver enzymes Pcompared with children who do not accept them. Correction of the dose is not required.

Probenecid is a blocker of tubular secretion in the kidneys. Reduction of renal secretion of the primary metabolite, bute levetiracetam was observed when taking probenecid at a dose of 500 mg 4 times a day. Nevertheless, the concentration of the primary metabolite remains low. It is assumed that other drugs excreted through active tubular secretion can reduce the clearance of the primary metabolite. The effect of levetaricatama with simultaneous administration with probenecid has not been studied, nor is it known when taken with non-steroidal anti-inflammatory drugs, sulfonamides and methotrexate.

Levetiracetam in a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives (ethinyl estradiol, levonorgearrow); The hormonal status (the content of luteinizing hormone and progesterone) does not change.

Levetiracetam in a daily dose of 2000 mg does not change the pharmacokinetics of digoxsion and warfarin; Irothrombin time does not change.

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

There is no data on the effect of antacids on the absorption of levetiracetam.

There are some reports of a decrease in the efficacy of levetiracetam when administered concomitantly with a laxative macrogol. Macrogol Mr.e should be applied 1 hour before and 1 hour after taking levetiracetam.

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

There are no data on the interaction of levetiracetam with alcohol.

Special instructions:

If it is required to stop taking the drug, it is recommended to cancel the treatment gradually, reducing the single dose by 500 mg every 2-4 weeks (in adults and adolescents weighing more than 50 kg).In children, the dose reduction 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 levetiracetam) should be gradually phased out.

The available information on the use of levetiracetam in children does not indicate any of its negative effects on development and puberty. However, the long-term effects of levetiracetam therapy on children's ability to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

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

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

In connection with the available reports of cases of suicide,suicidal intentions and suicide attempts in the treatment with levetiracetam should warn patients (as well as carers) of the need to immediately notify the attending physician of any symptoms of depression or suicidal intentions. It is necessary to monitor patients with symptoms of depression or suicidal thoughts and behavior and prescribe appropriate therapy.

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. However, due to the different individual sensitivity to the drug from the central nervous system, during the treatment period (some patients may experience drowsiness), it is necessary to refrain from managing vehicles, mechanisms and occupations of potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

For 10, 15, 25, 30 tablets in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

1, 2, 3, 4, 5, 6 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

At a temperature not exceeding 25 ° FROM.

Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003089

Date of registration:14.07.2015

Expiration Date:14.07.2020

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Information update date: & nbsp2016-10-27

Illustrated instructions

Instructions

Epitropyl (Epitropil)