Thirapol - instructions for use, doses, side effects, contraindications

Sheath: Opaprai II blue (85F20694) [polyvinyl alcohol-4.00 mg; macrogol-3350 - 2.02 mg; titanium dioxide (H171) 2.23 mg; indigo carmine (E132) 0.27 mg; talc - 1.48 mg].

1 tablet (500 mg) contains:

Active substance: levetiracetam - 500.00 mg.

Excipients: Macrogol-4000 - 16.12 mg; croscarmellose sodium - 3.64 mg; talcum - 16.12 mg: magnesium stearate - 1.62 mg.

Sheath: Opadry II yellow (85F32004) [polyvinyl alcohol - 8.00 mg; macrogol-3350 - 4.04 mg; titanium dioxide (E1 71) - 4.78 mg; ferric iron oxide yellow (E172) - 0.22 mg; talc - 2.96 mg].

1 tablet (750 mg) contains:

Active substance: levetiracetam - 750,00 mg.

Excipients: Macrogol-4000 - 24.18 mg; croscarmellose sodium - 5.46 mg; talc-24.18 mg; magnesium stearate-2.43 mg.

Sheath: Opapray II orange (85F23452) [polyvinyl alcohol - 12.00 mg; macrogol 3350-6.06 mg; titanium dioxide (E171) -7.20 mg; iron dye red oxide (E172) - 0.06 mg; dye sunset yellow (El 10) 0.24 mg; talc - 4.44 mg].

1 tablet (1000 mg) contains:

Active substance: levetirabetam - 1000,00 mg.

Excipients: Macrogol-4000 - 32,24 mg; croscarmellose sodium - 7.28 mg; talc - 32.24 mg; magnesium stearate - 3.24 mg.

Sheath: Opadry II white (85F18422) [polyvinyl alcohol - 16.00 mg; Macrogol-3350 - 8.08 mg; titanium dioxide (E171) - 10.00 mg; talc - 5.92 mg].

Description:

For tablets 250 mg:

Oblong, biconvex tablets with a risk on one side, covered with a film coating of blue color, on a broken white color, it is allowed to have a bluish background.

For tablets 500 mg:

Oblong, biconvex tablets with a risk on one side, covered with a film coating of yellow color, on a broken white color, yellowish color is allowed.

For tablets 750 mg:

Oblong, biconvex tablets with a risk on one side, covered with a filmy coat of pink-orange color, on a broken white color, pink-orange shade is allowed.

For tablets 1000 mg:

Oblong, biconvex tablets with a risk on one side, covered with a film coating of white, on a broken white 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 of α-ethyl-2-oxo-1-pyrrolidine-acetamide) differing in chemical structure from known antiepileptic drugs.The mechanism of action of levetiracetam is not fully understood, but it differs from the mechanism of action of known antiepileptic drugs.

Experiments in vitro and in vivo showed that levetiracetam does not affect the basic characteristics of cells and neurotransmission.

Research in vitro showed that levetiracetam affects the intra-neuronal concentration of calcium priests (Ca²⁺), partially inhibiting the current Sa²⁺ through the channels Ntype and reducing the release of Ca²⁺ from intra-neural depots. Besides, levetiracetam partially restores currents through GABA and glycine-dependent channels, reduced by zinc and β-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. The activity of the drug was confirmed with respect to both focal and generalized epileptic seizures (epileptiform manifestation / photoparoxysmal reaction).

Pharmacokinetics:

Suction

After oral administration levetiracetam quickly and almost completely absorbed from the gastrointestinal tract. Absorption is linear in nature, so the concentration of levetiracetam in the blood plasma is predictable, based on the accepted dose of the drug, expressed in mg / kg body weight. The degree of absorption does not depend on the dose and time of food intake. Bioavailability is about 100%. Maximum concentration in blood plasma (FROM_max), equal to 31 μg / ml, is achieved after 1.3 hours after a single dose of levetiracetam in a dose of 1000 mg, 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, FROM_m_Oh is achieved after 0.5-1 h.

Distribution

The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%, the volume of distribution (V_d) is about 0.5-0.7 l / kg.

Metabolism

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.

In conditions in vitro levetiracetam and its main metabolite did not inhibit the main isoenzymes of cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), as well as the activity of glucuronyl transferase (UGT1A1 and UGT1 A6) and epoxy hydroxylase.

Levetiracetam also did not affect the glucuronation of valproic acid in vitro.

Excretion

The half-life (T_1/2) from the blood plasma of an adult 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. 95% of the drug is excreted by the kidneys. The renal clearance of levetiracetam and its metabolite is 0.6 ml / min / kg and 4.2 ml / min / kg, respectively.

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.

In patients with impaired renal function the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, patients with renal failure are recommended to select a dose depending on the creatinine clearance. 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.

In patients with impaired liver function of mild and moderate severity there are no significant changes 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%.

T_1/2 in children after a single oral administration of the drug at a dose of 20 mg / kg body weight is 5-6 hours. The total clearance of levetiracetam in children is approximately 40% higher than in adults and is directly dependent on body weight.

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 6 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 with idiopathic generalized epilepsy.

Contraindications:

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

- children under 6 years of age (safety and efficacy not established);

- children with a body weight of less than 25 kg (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:

Adequate and strictly controlled studies on the safety of levetiracetam in pregnant women have not been conducted. Studies in animals have revealed reproductive toxicity. Women with a preserved reproductive function during treatment with levetiracetam should take contraceptive measures. The drug should be administered during pregnancy only in case of emergency. Physiological changes in the body of a woman during pregnancy can affect the plasma concentration of levetiracetam, as well as other antiepileptic 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 observed before pregnancy).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.

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 breastfeeding.

Dosing and Administration:

Inside, regardless of food intake.

The daily dose of the drug is divided into two doses in the same dose.

Tablets are taken with a sufficient amount of liquid.

Monotherapy

Adults and teenagers over 16 years of age treatment should begin with a daily dose of 500 mg. divided into 2 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 (1500 mg twice a day).

As part of complex therapy

Adults and adolescents 12-17 years of age with a body weight of more than 50 kg 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 twice a day can be carried out every 2-4 weeks.

Children over 6 years and adolescents 12-17 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).

Body mass	Initial dose 10 mg / kg twice daily	The maximum dose of 30 mg / kg 2 times a day
25-50 kg	250 mg twice a day	750 mg twice a day
more than 50 kg	500 mg twice a day	1500 mg twice a day

Children with a body weight of 25 kg and less it is recommended to begin 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 but the scheme given for adults.

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.

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).

Creatinine clearance for men can be calculated from the serum creatinine concentration using the following formula:

CK (ml / min) = [14 - age (years)] х body weight (kg) / 72 x QC_serum(mg / dL)

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

Renal insufficiency	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	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 levetiranetam should be performed 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):

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

ks = 0.55 for children under 13 and females;

ks = 0.7 for adolescent males.

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

Renal insufficiency	QC (ml / min / 1.73 m²)	Dosing regimen
Renal insufficiency	QC (ml / min / 1.73 m²)	Children over 6 years of age and adolescents with a body weight of less than 50 kg
Norm	>80	10-30 mg / kg (0.10-0.30 ml / kg) twice daily
Lightweight	50-79	10-20 mg / kg (0.10-0.20 ml / kg) twice daily
Moderate	30-49	5-15 mg / kg (0.05-0.15 ml / kg) twice daily
Heavy	<30	5-10 mg / kg (0.05-0.10 ml / kg) twice daily
Terminal stage (patients on dialysis)		10-20 mg / kg (0.10-0.20 ml / kg) once a day (1) (2)

(1) - 15 mg / kg (0.15 ml / kg) the recommended loading dose on the first day of treatment;

(2) - the recommended maintenance dose after dialysis is 5-10 mg / kg (0.05-0.10 ml / 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 level 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%.

The duration of the course of treatment is determined by the doctor.

Side effects:

The most frequently reported adverse reactions are nasopharyngitis, drowsiness, headache, weakness, dizziness. The safety profile of levetiracetam is generally similar for different age groups of adults and children.

The incidence of side effects is classified according to the recommendations of the World Health Organization: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely > 1/10 000, <1/1000), very rarely (<1/10 000, including individual reports), the frequency is unknown - insufficient data to estimate the frequency of development.

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

Violations from the blood and lymphatic system: infrequently - thrombocytopenia, leukopenia; rarely - neutropenia, pancytopenia (in some cases, bone marrow depression was recorded).

Immune system disorders: rarely - a drug allergy with eosinophilia and systemic manifestations (DRESS-syndrome).

Disorders from the metabolism and nutrition: often - anorexia; infrequently - weight loss, weight gain; rarely - hyponatremia.

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

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

Disturbances on the part of the organ of sight: infrequently - diplopia, blurred vision.

Hearing disorders and labyrinthine disorders: often - vertigo.

Disturbances from the respiratory system, chest and mediastinal organs: often - a cough.

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

Disturbances from the liver and bile ducts: infrequent - deviation of laboratory parameters of liver function from the norm; rarely - hepatic insufficiency, hepatitis.

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

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

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

Trauma, intoxication and complications of manipulation: infrequent - accidental damage. With the simultaneous administration of levetiracetam and topiramate, the likelihood of developing anorexia increases.

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

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 more frequently in children than in adults, the safety profile of children is comparable to the safety profile of levetiracetam in adults.

Children and adolescents aged 4 to 16 years The following undesirable reactions were more often recorded: 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%).

Children aged from 1 month to 4 years more often recorded the following adverse reactions: irritability (very often, 11.7%) and violation coordination (often, 3.3%).

Overdose:

Symptoms: drowsiness, agitation, aggression, oppression of consciousness, oppression breathing, coma.

Treatment: in the acute period - artificial vomiting and gastric lavage followed by the appointment 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:

Antiepileptic agents

Levetiracetam does not affect the plasma concentration of antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidon), which in turn do not affect the concentration of levetiracetam. Similar to adults, in children at doses up to 60 mg / kg / day levetiracetam does not interact with other drugs.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4-17 years) levetiracetam as an auxiliary therapy does not affect the equilibrium serum concentrations of simultaneously used carbamazepine and valproic acid. However, there is evidence that the clearance of levetiracetam is 20% higher in children taking anticonvulsants - inducers of microsomal liver enzymes compared to children who do not take them. Correction of the dose is not required.

Probenecid

Probenecid is a blocker of tubular secretion in the kidneys. It is shown that when probenecid is administered at a dose of 500 mg 4 times a day, it inhibits renal clearance of the main metabolite, but not levetiracetam. Nevertheless, the concentration of the main metabolite remains low.It is assumed that other drugs excreted through active tubular secretion, can reduce the renal clearance of the main metabolite. The effect of levetiracetam with simultaneous administration with probenecid fie was also studied, it is also unknown when taken with other drugs excreted by active tubular secretion, including non-steroidal anti-inflammatory drugs, sulfonamides and methotrexate.

Oral contraceptives and other pharmacokinetic interactions

Levetiracetam in a daily dose of 1000 mg does not change 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 daily dose of 2000 mg does not change the pharmacokinetics of digoxin and warfarin; prothrombin time does not change.

The simultaneous use of digoxin, oral contraceptives and warfarin does not affect the pharmacokinetics of levetiracetam.

Antacids

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

Laxatives

There are some reports of a decrease in the efficacy of levetiracetam when administered concurrently with a laxative macrogol. Macrogol Do not use 1 hour before and 1 hour after taking levetiracetam.

Food and alcohol

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

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

Special instructions:

Abolition of therapy

If it is necessary to stop taking the drug, the abolition of treatment in adults and adolescents with a body weight of more than 50 kg is recommended to be carried out gradually, reducing the single dose by 500 mg every 2-4 weeks. In children, the dose reduction should not exceed 10 mg / kg of body weight 2 times a day every 2 weeks.

During the transfer of patients to the administration of levetiracetam, the antiepileptic drugs previously used should be gradually phased out.

Children

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.

Renal insufficiency

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.

Suicide

In patients taking anticonvulsants (including levetiracetam) there were cases of suicide, suicide attempts, suicidal thoughts and behavior. 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 not known.

It is necessary to monitor patients with symptoms of depression or suicidal thoughts and behavior and prescribe appropriate therapy. Patients (as well as carers) should be informed of the need to seek medical help if they develop symptoms of depression and / or suicidal thoughts and behavior.

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

The effect of the drug on the ability to drive vehicles and control mechanisms is not specifically studied.However, due to different individual sensitivity to the drug, from the side of the central nervous system during the treatment period (some patients may experience drowsiness), it is necessary to refrain from driving vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Film-coated tablets, 250 mg, 500 mg, 750 mg and 1000 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and fouls and aluminum.

Tablets of 250 mg and 1000 mg: 1, 2, 3, 5, 6, 10 or 20 contour mesh packages together with the instructions for use are placed in a pack of cardboard.

Tablets 500 mg: 1, 2, 3, 5, 6, 10, 12 or 20 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Tablets 750 mg: 1, 2, 3, 5, 6, 8, 10 or 20 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002875

Date of registration:24.02.2015

Expiration Date:24.02.2020

The owner of the registration certificate:Pharmaceutical factory "POLFARMA" JSCPharmaceutical factory "POLFARMA" JSC Poland

Manufacturer: & nbsp

Pharmaceutical Works POLPHARMA, S.A. Poland

Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia

Information update date: & nbsp20.10.2016

Illustrated instructions

Instructions

Thirapol (Thyrapol)