Epitera Long - instructions for use, dose, side effects, contraindications

Excipients: povidone-K30 12.0 mg / 18.0 mg, povidone-K90 13.0 mg / 19.5 mg, ethylcellulose 100.0 mg / 150.0 mg, dibutyl sebacate 15.0 mg / 22.5 mg, cellulose microcrystalline 80.0 mg / 120.0 mg, castor oil hydrogenated 40.0 mg / 60.0 mg, magnesium stearate 6.0 mg / 9.0 mg;

film sheath Opadray 03F18435 white 16.0 mg / 24.0 mg: hypromellose 9.80 mg / 14.69 mg, macrogol-3350 3.26 mg / 4.90 mg, titanium dioxide 2.94 mg / 4.41 mg;

ink Opacode S-1-17823 black: pharmaceutical glaze [shellac solution in ethanol] 44.467%, isopropanol 26.882%, iron dye black oxide (E172) 23.409%, butanol 2.242%, Propylene glycol 2,000%, ammonia water is 1,000%.

Description:

Dosage 500 mg: oblong, biconvex tablets, covered with a film shell of white color, with the inscription of black "TV/ 7795 "on one side.

Dosage of 750 mg: oblong, biconvex tablets, covered with a film shell of white color, with the inscription of black "TV/ 7796 "on one side.

At the break of the tablet, the nucleus is visible white or almost white (all dosages).

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.14 Levetiracetam

Pharmacodynamics:

An antiepileptic drug, a pyrrolidone derivative (S-enantiomer of alpha-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.

Research in vitro showed that levetiracetam affects the intra-neuronal 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 ion currents through gamma-aminobutyric acid (GABA) - and glycine-dependent channels reduced by zinc and carbolines.

One of the proposed mechanisms 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.Does not change the normal neurotransmission, but suppresses epileptiform neuronal outbreaks induced by GABA agonist bicuculine, and the excitation of glutamate receptors. The activity of the drug has been confirmed with respect to both focal and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction).

Pharmacokinetics:

The bioavailability of levetiracetam in the sustained-release tablet dosage form is similar to the bioavailability of levetiracetam in the immediate-release tablet dosage form. The pharmacokinetic parameters of levetiracetam are linear and have low intra- and intergroup variability. Pharmacokinetic parameters such as the area under the "concentration-time" curve (AUC) and the maximum concentration in the blood plasma (C_mOh), are proportional to a single oral dose of 1000 mg, 2000 mg and 3000 mg. The half-life (T_1/2) levetiracetam - 7 hours.

Suction and distribution

After oral administration levetiracetam almost completely absorbed in the gastrointestinal tract (GIT). Levetiracetam slightly binds to blood plasma proteins (less than 10%).The volume of distribution is close to the volume of intracellular and extracellular water.

FROM_mOhlevetiracetam in blood plasma is reached approximately 4 hours after ingestion of long-acting tablets, which is about 3 hours longer than when taking an immediate-release tablet.

AUC and C_max levetiracetam at a single ingestion of two tablets of prolonged action at a dose of 500 mg once a day are comparable with the intake of tablets with immediate release at a dose of 500 mg 2 times a day.

Degree of influence (AUC_0-24) levetiracetam with repeated administration of long-acting tablets is close to AUC_0-24 with repeated use of immediate-release tablets. C_max and C_min levetiracetam were lower by 17% and 26%, respectively, with repeated use of long-acting tablets compared with repeated use of immediate-release tablets.

When taking levetiracetam after a high-fat meal, after a high-calorie breakfast C_mOh and the average time to reach C_mOh (T_mOh) are increasing. T_mOh increases by 2 hours after ingestion.

The intake of 2 tablets of prolonged action in a dose of 750 mg levetiracetam bioequivalent to the simultaneous use of 3 tablets prolonged action at a dose of 500 mg.

Metabolism

Levetiracetam does not undergo significant metabolism in the human body. The main pathway of metabolism is the enzymatic hydrolysis of the acetamide group, with the help of which the carboxylic acids of metabolites are synthesized, the primary metabolite USB L057 (24% of the dose), which does not depend on the activity of cytochrome P450 isoenzymes of the liver. Metabolite USB L057 does not have pharmacological activity. Two secondary metabolites were also identified. One is formed as a result of hydroxylation of the 2-oxo-pyrrolidone ring (2% dose), and the other is due to the opening of the 2-oxo-pyrrolidone ring at position 5 (1% of the dose). There is no enantiomeric interconversion of levetiracetam or its main metabolite.

In vitro, as well as in natural conditions levetiracetam and its primary metabolite did not suppress the activity of the cytochrome P450 isoenzyme systems (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferase (UGT1A1 and UGT1A6), and epoxy hydroxylase. Besides, in vitro levetiracetam does not affect the glucuronidation of valproic acid.

In human hepatocyte culture levetiracetam had little or no effect on the activity of the isoenzymes CYP1A2, SULT1E1 and UGT1A1. Levetiracetam slightly induces the activity of the isoenzymes 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

T_1/2 levetiracetam in adults is 7 ± 1 h and does not depend on the mode of administration and dosing regimen. The average overall clearance is 0.96 ml / min / kg, and the renal clearance is 0.6 ml / min / kg. Levetiracetam is excreted by the kidneys through glomerular filtration followed by partial tubular reabsorption. Metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with renal clearance of 4 ml / min / kg. The removal of levetiracetam correlates with the clearance of creatinine (CC). The clearance of levetiracetam declines in patients with impaired renal function.

Pharmacokinetics in special clinical cases

In elderly patients insufficient pharmacokinetic data on the use of levetiracetam in the dosage form of a sustained-release tablet.

In elderly patients (61-88 years) with QC of 30-74 ml / min compared to healthy volunteers with a daily dose of 2 doses for 10 days, the overall clearance was reduced by 38%, the duration of T_1/2 levetiracetam increased by 2.5 h.

In patients with impaired hepatic and mild liver function no significant changes in the clearance of levetiracetam have been detected. In severe violations of liver function the clearance of levetiracetam declines by more than 50% due to concomitant renal failure.

Among women compared with men above AUC (18 and 8%, respectively) and C_mOh (30% and 21%, respectively). Nevertheless, the clearance of the drug, corrected for body weight, was comparable.

In patients with mild renal impairment (CK 50-80 ml / min), the clearance of levetiracetam is reduced by 40%, with an average severity disorder (CK 30-50 ml / min) - by 50%, with severe severity (KC less than 30 ml / min) - by 60 %. With anuria (terminal stage of renal failure), the total clearance was reduced by 70% compared to healthy patients (CC greater than 80 ml / min).Approximately 50% of levetiracetam is removed from the body during a standard 4-hour hemodialysis procedure.

In patients with hepatic insufficiency light (class A, 5-6 points on the Child-Pugh scale) and secondary (class B, 7-9 on the Child-Pugh scale) severity the pharmacokinetics of levetiracetam did not change. In patients with severe hepatic insufficiency (class C, more than 10 points on the Child-Pugh scale), the total clearance is 50% of the norm due to a decrease in renal clearance. Dose adjustment is not required for patients with hepatic impairment.

Indications:

Additional therapy of partial seizures in adults and children over 16 years of age with epilepsy.

Contraindications:

Hypersensitivity to levetiracetam, to derivatives of pyrrolidone or other components of the drug, children under 16 years of age.

Carefully:

Renal failure, severe hepatic failure, elderly age 65 years.

Pregnancy and lactation:

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

In general, these data do not indicate a significant increase in the risk of serious congenital malformations. Teratogenic damage can not be completely ruled out. Therapy with several antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, so monotherapy in pregnant women is more appropriate.

Adequate and strictly controlled clinical trials on the safety of levetiracetam in pregnant women have not been carried out, therefore Epiterra Long is used during pregnancy only if the expected benefit to the mother exceeds the possible risk to the fetus.

Physiological changes in the body of a woman during pregnancy can affect the concentration of levetiracetam, like other antiepileptic drugs, in blood plasma. During pregnancy, there was a decrease in the concentration of levetiracetam in the blood plasma. This decrease was expressed in the third trimester of pregnancy (up to 60% of the baseline concentration during the third trimester). The use of levetiracetam in pregnant women should be carried out under special supervision.It should be borne in mind that 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.

Levegiracetam is excreted in breast milk, so the use of the drug Epiterra Long in the period of breastfeeding Not recommended. However, when levetiracetam is needed during breastfeeding, the benefit / risk ratio of treatment should be evaluated in view of the importance of breastfeeding.

In animal studies, no effect of levetiracetam on fertility. Clinical evidence of the effect of levetiracetam on fertility is not available, the possible risk to humans is unknown.

Dosing and Administration:

Inside, squeezed enough fluids, regardless of food intake.

Adults and children over 16 years of age

The initial dose is 1000 mg once a day. The dose can be adjusted by an increase of 1000 mg every 2 weeks.

The maximum daily dose is 3000 mg.

In elderly patients and patients with renal insufficiency dose should be adjusted depending on the QC.

QC can be calculated from the serum creatinine concentration by the following formula.

For men:

CK (ml / min) = [140-yr (years)] x body weight (kg) / 72 x creatinine concentration (mg / dl)

For women: multiply that value by 0.85.

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

KK (ml / min / 1.73 m²) = KK (ml / min) / PPT (m²) X 1.73

Kidney function status	KK (ml / min / 1.73 m²)	Dose and multiplicity of admission
Norm	more than 80	1000-3000 mg every 24 hours
Easy degree of violation	50-79	1000-2000 mg every 24 hours
The average degree of violation	30-49	500-1500 mg every 24 hours
Severe degree of violation	less than 30	500-1000 mg every 24 hours

In patients with hepatic insufficiency correction of the dose is not required.

Side effects:

The safety profile presented below is based on an analysis of the results of clinical trials and the experience of post-marketing use. The most frequent adverse reactions were nasopharyngitis, drowsiness, headache, fatigue and dizziness. The profile of levetiracsegam is generally similar for different age groups of adults and children.

Side effects are classified according to the following frequency: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000).

Infections and invasions: very often - nasopharyngitis; rarely - infection.

On the part of the blood and lymphatic system: infrequently - leukopenia, thrombocytopenia; rarely - pancytopenia, neutropenia, agranulocytosis.

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

From the side of metabolism and nutrition: often - anorexia; infrequently - weight gain, weight loss; rarely - hyponatremia.

Mental disturbance: often - depression, hostility / aggressiveness, anxiety, insomnia, nervousness / irritability; infrequently - suicidal attempts, suicidal thoughts, psychotic disorders, behavioral disorders, hallucinations, anger, confusion, emotional lability / mood swings, agitation, panic attack; rarely - suicide, personality disorder, violation of thinking.

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

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

From the side of the hearing organ: often - vertigo.

From the respiratory system: often - a cough.

From the gastrointestinal tract: often - abdominal pain, diarrhea, indigestion, vomiting, nausea; pancreatitis.

From the liver and biliary tract: infrequently - change of functional samples; rarely - hepatic insufficiency, hepatitis.

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

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

Other: often - asthenia / fatigue; infrequently - accidental damage.

The risk of anorexia is higher with the simultaneous use of levetiracetam and topiramate. There are reports of the restoration of the hair follicle after the cancellation of levetiracetam. Some cases of pancytopenia were accompanied by oppression of bone marrow function.

Safety profile of levetiracetam in children withWe will be identified with the safety profile of adults.

Overdose:

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

Treatment: in the acute period - induction of vomiting, gastric lavage, reception of activated charcoal. There is no specific antidote for levetiracetam.If necessary, symptomatic treatment in a hospital using hemodialysis (dialysis efficiency for levetiracetam - 60%, for the primary metabolite - 74%).

Interaction:

Levetiracetam does not affect the concentration of antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidon) in the blood plasma. In turn, these antiepileptic drugs do not affect the concentration of levetiracetam in the blood plasma.

There are no data on clinically significant drug interactions in children who received levetiracetam in a dose of 60 mg / kg / day. A retrospective analysis of pharmacokinetic interactions in children aged 4-17 years with epilepsy confirmed that additional intake of levetiracetam does not affect the equilibrium plasma concentrations of concurrently taken carbamazepine and valproic acid. Nevertheless, the data indicate that the clearance of levetiracetam is 20% higher in children taking enzyme-induced antiepileptic drugs. Correction of the dose in these cases is not required.

Levetiracetam in a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives of ethinylestradiol and levonorgestrel.

Levetiracetam in a daily dose of 2000 mg does not change the pharmacokinetics of warfarin and digoxin.

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

Probenecid (500 mg 4 times a day) reduces the renal clearance of the primary metabolite of levetiracetam. It is assumed that drugs that are excreted from the body due to active renal secretion, are also able to reduce the clearance of the metabolite. The effect of levetiracetam on probenecid and other drugs with a similar mechanism of elimination (nonsteroidal anti-inflammatory drugs, sulfonamides, methotrexate etc.) remains unclear.

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

Single reports were received on the reduction in the efficacy of levetiracetam when used simultaneously with osmotic laxatives macrogol. Macrogol should not be taken within 1 hour before and within 1 hour after taking levetiracetam.

The degree of absorption of levetiracetam does not change under the influence of food,while the suction speed is somewhat reduced.

Data on the interaction of levetiracetam with alcohol are absent.

Special instructions:

If it is necessary to discontinue therapy, it is recommended that epiterra Long be discontinued gradually, reducing the single dose by 500 mg every 2-4 weeks. In adults weighing less than 50 kg, it is recommended to reduce the dose by 20 mg / kg every 2 weeks. In children with a body weight of 25-50 kg, it is recommended to reduce the dose by 10 mg / kg every 2 weeks.

The use of Epiterra Long in patients with impaired renal function may require dose adjustment (see section "Method of administration and dose").

During the reception of the drug Epiterra Long, there may be abnormalities in the central nervous system, including drowsiness, weakness, fatigue, psychotic and nonpsychotic behavior changes, especially in the first month of therapy, so at the beginning of the treatment, patients should be carefully monitored.

Patients should be regularly monitored for signs of depression, suicidal and obsessive ideas, due to the increased risk of suicide attempts in patients taking antiepileptic drugs, including. preparation Epitera Long.

If there are signs of depression and suicide attempts, patients and caregivers should consult a specialist.

It is recommended to gradually phase out concomitant anticonvulsants during the period of transfer of the patient to the drug Epiterra Long.

In patients with partial seizures during treatment with the drug, there was a slight but statistically significant decrease in red blood counts, which does not require active clinical intervention.

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 of treatment on the ability of children to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

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

There have been no studies on the impact on the ability to drive vehicles and work with mechanisms.

Due to the possible varying individual sensitivity, some patients may experience drowsiness or other symptoms from the central nervous system, especially at the beginning of treatment or after increasing the dose.Thus, such patients need to be cautious in performing tasks such as driving a vehicle or a mechanism.

Patients are advised not to drive the vehicle and do not use the mechanisms until the absence of influence on their ability is established.

Form release / dosage:Tablets of prolonged action, film-coated, 500 mg and 750 mg.

Packaging:

For 30, 60 or 100 tablets in a bottle of HDPE with a lid, equipped with a system of protection from opening by children.

1 bottle with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature of no higher than 25 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003814

Date of registration:31.08.2016

Expiration Date:31.08.2021

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Representation: & nbspTeva Teva Israel

Information update date: & nbsp16.10.2016

Illustrated instructions

Instructions

Epiterra Long (Epiterra Long)