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

Excipients: corn starch - 48,00 / 96,00 / 192,00 mg, povidone K30 - 5,00 / 10,00 / 20,00 mg, silicon dioxide colloid - 4,00 / 8,00 / 16,00 mg, talc - 2.00 / 4.00 / 8.00 mg, magnesium stearate - 1.00 / 2.00 / 4.00 mg; tablet shell: Opadney 85F20694 (polyvinyl alcohol partially hydrolyzed - 3,600 mg, titanium dioxide - 2,006 mg, macrogol / PEG 3350 - 1,818 mg, talc - 1,332 mg, aluminum lacquer indigo carmine - 0.244 mg) - 9.00 mg (for tablets 250 mg), Opadrai 85F32004 (polyvinyl alcohol partially hydrolyzed - 7,200 mg, titanium dioxide - 4,306 mg, macrogol / PEG 3350 - 3,636 mg, talc - 2,664 mg, iron oxide oxide yellow - 0.194 mg) - 18.00 mg (for tablets 500 mg), Opadrai 85F18422 (polyvinyl alcohol partially hydrolyzed - 14,400 mg, titanium dioxide - 9,000 mg, macrogol / PEG 3350 - 7,272 mg, talc - 5.328 mg) - 36.00 mg (for tablets 1000 mg).

Description:

250 mg: Oblong film-coated tablets, blue, with a risk and engraved "250" on one side of the tablet.

500 mg: Oblong film-coated tablets are yellow, with a risk and engraving "500" on one side of the tablet.

1000 mg: Oblong film-coated tablets are white, with a risk and engraved "1000" on one side of the tablet.

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 of α-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.

Experiments in vivo and in vitro showed that levetiracetam does not change the basic characteristics of cells and the normal transmission of nerve impulses.

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 currents through gammaaminobutyric 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. 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 neural flares 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:

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

Suction. Levetiracetam is a highly soluble substance with a high penetrating power. After oral administration levetiracetam well absorbed from 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. Absolute bioavailability is approximately 100%. The maximum concentration of the drug in the blood plasma (C_m_Oh) is achieved 1.3 hours after oral administration of levetiracetam in 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.

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

Data on the distribution of the drug on the tissues are absent.

Metabolism. The main metabolic pathway (24% dose) is the enzymatic hydrolysis of the acetamide group. Isozymes of liver cytochrome P450 do not participate in the formation of a primary pharmacologically inactive metabolite (ucb L057).

Levetiracetam does not affect the enzymatic activity of hepatocytes.

Levetiracetam and its main metabolite do not inhibit the main cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxy hydroxylase in vitro. Levetiracetam also does not affect the glucuronation of valproic acid in vitro.

Excretion. The half-life period (T1 / 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 administration. 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.

Elderly patients

In elderly patients, T1 / 2 increases by 40% and is 10-11 hours, which is associated with a decrease in kidney function in this category of patients.

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, T1 / 2 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.

Patients with impaired hepatic function

In patients with impaired liver function of mild to moderate severity, significant there is no change in the clearance of levetiracetam. 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

After a single oral intake of 20 μg / kg of body weight, T1 / 2 in children aged 4-12 years is 6 hours. The total clearance of levetiracetam in children 4-12 years old is approximately 30% higher and is directly related to body weight .

After repeated intake of the drug in a dose of 20 to 60 mg / kg in children 4-12 years of age C_m_Oh is achieved within 0.5-1.0 h and increases linearly and proportionally to the dose.

Indications:

As a monotherapy (the drug of the first choice) in the treatment:

- 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 the following conditions:

- partial seizures with or without secondary generalization, in adults and children older than 6 years 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 derivatives of pyrrolidone and other components of the drug. Children under 6 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:

Pregnancy. 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 are 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 well-controlled clinical safety trials of levetiracetam in pregnant women has not been, so the drug should not be administered during pregnancy except in cases of clinical need.

Physiological changes in the body during pregnancy may affect levetiracetam concentration in plasma, as well as other anti-epileptic drugs. During pregnancy, there was a decrease in the concentration of levetiracetam in 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. 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.

To monitor the effects of the use of levetiracetam in pregnant women doctors recommend patients to register data in the European and the International Register of Antiepileptic Drugs (EURAP).

Breast-feeding. Levetiracetam is excreted in breast milk, therefore, if it is necessary to use it during lactation, breast-feeding for the time of taking the drug is not recommended. However, if treatment with levetiracetam is necessary during the feeding period, the risk / benefit ratio of treatment should be carefully weighted relative to the importance of feeding.

Fertility. In animal studies, levetiracetam has not been shown to influence fertility. Clinical data are not available, a possible risk in humans is unknown.

Dosing and Administration:

Inside, squeezed enough water, regardless of food intake. The daily dose is divided into 2 doses in the same dose.

As a monotherapy

Adults and teenagers over 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). Dose can be increased in steps of 250 mg 2 times a day every two weeks, depending on the clinical response. The maximum daily dose is 3000 mg (1500 mg twice a day).

As part of complex therapy

Children older than 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 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 (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, it is possible to reduce it. The minimum effective dose should be used. The doctor should prescribe the drug in the most suitable dosage form and dosage, depending on the age, body weight of the patient and the required therapeutic dose.

Due to the lack of dosage, the tablets are not intended for treatment of children weighing less than 25 kg, with a dose of less than 250 mg, as well as for patients who have difficulty swallowing. In these cases, it is recommended to start treatment with taking the drug in the form of a solution for oral administration.

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 old) with a body weight of 50 kg and more treatment should begin 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.

Special patient groups

Because the levetiracetam is excreted from the body by the kidneys, when the drug is prescribed for patients with renal insufficiency and elderly patients (65 years and older), the dose should be adjusted depending on the amount of CC, daily dose is selected individually. KK (in ml / min) can be calculated from the serum creatinine (CS) concentration (in mg / dL).

KK for men can be calculated by the formula:

CK (ml / min) = [140 - age (years)] x body weight (kg) / 72 x CS (mg / dl)

KK 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 (PPT) according to the formula:

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

Table 1. Dosage regimen in adults and adolescents with impaired renal function, body weight of more than 50 kg

Group	KK (ml / min / 1,73 m²)	Dosing regimen
Norm	>80	From 500 to 1500 mg twice a day
Lightweight	50-79	From 500 to 1000 mg twice a day
Moderate Gravity	30-49	From 250 to 750 mg twice a day
Heavy	<30	From 250 to 500 mg twice a day
Terminal stage (patients on hemodialysis *)	-	From 500 to 1000 mg once a day **

* On the first day of treatment, a loading dose of 750 mg

** after completion of hemodialysis, an additional dose of 250-500 mg is recommended. For children with renal insufficiency, correction of the dose of levetiracetam should be made with taking into account the degree of renal failure.

Creatinine clearance (ml / min / 1.73 m²) can be estimated 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 / CS (ml / dl)

ks=0,55 for children under 13 years of age and adolescents for females; ks=0,7 for teenagers male.

Table 2. Dosage regimen for children and adolescents with impaired function kidneys whose body weight is less than 50 kg

Group	KK (ml / min / 1,73 m²)	Dosing regimen
Group	KK (ml / min / 1,73 m²)	Children older than 4 years 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 Gravity	30-49	5-15 mg / kg 2 times per day
Heavy	<30	5-10 mg / kg 2 times a day
Terminal stage (patients on hemodialysis)	-	10-20 mg / kg once a day^1,2

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

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

Impaired liver function

Patients with a mild or moderate liver function disorder are not required to adjust the dosing regimen. In patients with decompensated violation liver function and renal insufficiency, a decrease in QC may not fully reflect the severity of renal failure. In such cases, when KK <60 ml / min / 1.73 m² it is recommended to reduce the daily dose by 50%.

Side effects:

The following profile of adverse events is based on an analysis of the results of placebo-controlled studies, as well as the experience of post-marketing use of 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.

To indicate the frequency of side effects, the following classification is used: Often (≥1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and <1/1000) and rarely (< 1/10000).

Infections and invasions: Often - nasopharyngitis; rarely - infection.

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

Mental disorders: often - Depression, hostility / aggressiveness, 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 nervous system: 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 - cough.

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

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

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

Disturbances from musculoskeletal system and connective tissue: infrequently - Muscular weakness, myalgia.

General disorders: often - asthenia / fatigue.

Injuries, complications of procedures: infrequently - accidental damage.

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

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

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

The safety profile of children in placebo-controlled clinical trials was comparable to the safety profile of levetiracetam in adults.In children and adolescents aged 4 to 16 years, the following undesirable reactions were more frequent: 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%).

In a double-blind, placebo-controlled study whose goal was to show that the drug was as good as a placebo, the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial seizures were evaluated. According to the results of the study, it was concluded that levetiracetam did not differ from placebo (did not concede to him) with respect to changes in the sum of points in the sections "Attention and Memory" and "Combined Memory Screening" of the Leiter-R scale (Leiter-R) in patients who underwent a protocol study compared with the initial visit.

As a result of the analysis of the behavioral and emotional status with the help of a validated tool - the Achenbach questionnaire (Achenbach) aggressive behavior in the group of patients receiving levetiracetam. However, patients who took levetiracetam during long-term follow-up in the open phase of the study, did not demonstrate a worsening of the behavioral and emotional status, in In particular, the indicators of aggressive behavior did not deteriorate in comparison with the baseline.

Overdose:

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

Treatment: after acute overdose, it is necessary to induce vomiting and rinse the stomach with the subsequent administration of activated charcoal. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment in a hospital using hemodialysis (dialysis efficiency for levetiracetam is 60%, for its primary metabolite - 74%).

Interaction:

The drug does not interact with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, topiramate, primidon).

The clearance of levetiracetam was 22% higher in children taking enzyme-induced antiepileptic drugs than children who did not take them.Reduction of renal secretion of the primary metabolite was observed with the administration of probenecid in a dose of 500 mg 4 times a day. The effect of levetiracetam when concomitantly with probenecid has not been studied, and it is unknown when taken with NSAIDs, sulfonamides and methotrexate.

Levetiracetam in a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives (ethinyl estradiol, levonorgestrel).

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

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

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

With joint admission with topiramate, the probability of anorexia is higher.

There are no data on clinically significant drug interactions in children who received levetiracetam in a dose up to 60 mg / kg / day.

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

Data on the interaction of levetiracetam with alcohol is not available.

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 the patient to receive levetiracetam) should be gradually phased out.

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 on children's ability to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

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

The risk of anorexia increases with simultaneous use with topiramate.

In connection with the available reports of cases of suicide,suicidal intentions and suicide attempts in the treatment with levetiracetam should alert patients to the need to immediately notify the attending physician of any symptoms of depression or suicidal intentions.

For children younger than 6 years, the recommended dosage form is oral solution.

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

The effect of levetiracetam on the ability to drive vehicles and 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, it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions .

Form release / dosage:

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

Packaging:

250 mg: For 15 tablets, coated with a film sheath, in PVC / Al blister. 2 or 4 blisters together with instructions for use are placed in a cardboard box.

500 mg: 10 tablets, film-coated, in PVC / Al blister. 3 or 6 blisters together with instructions for use are placed in a cardboard box.

1000 mg: For 6 tablets, film-coated, in PVC / Al blister. 5 or 10 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C. Keep out of the reach of children!

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004250

Date of registration:18.04.2017

Expiration Date:18.04.2022

The owner of the registration certificate:Beluga, medicines and cosmetics.Beluga, medicines and cosmetics. Croatia

Manufacturer: & nbsp

BELUPO, Pharmaceuticals & Cosmetics, d.d. Croatia

RIVOPHARM, S.A. Switzerland

Representation: & nbspBeluga, medicines and cosmetics. Beluga, medicines and cosmetics. Croatia

Information update date: & nbsp03.02.2018

Illustrated instructions

Instructions

Convilept® (Konvilept)