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

Excipients: silicon colloidal dioxide 3 mg, croscarmellose sodium 10 mg, calcium stearate 3 mg, mannitol 20.2 mg, povidone 6.3 mg, microcrystalline cellulose 17.5 mg;

composition of film shell: Opadrai II blue 10 mg, including: polyvinyl alcohol 4 mg, macrogol (polyethylene glycol) 2.02 mg, talc 1.48 mg, titanium dioxide 2.05 mg, aluminum lacquer based on indigo carmine dye 0.43 mg, aluminum lacquer based on the dye red charming 0.02 mg.

Dosage 500 mg

1 tablet, film-coated, contains:

active substance: levetiracetam 500 mg;

Excipients: silicon dioxide colloid 6 mg, croscarmellose sodium 20 mg, calcium stearate 6 mg, mannitol 40.4 mg, povidone 12.6 mg, microcrystalline cellulose 35 mg;

composition of film shell: Opadrai II blue 20 mg, including: polyvinyl alcohol 8 mg, macrogol (polyethylene glycol) 4.04 mg, talc 2.96 mg, titanium dioxide 4.1 mg, aluminum lacquer based on indigo carmine dye 0.86 mg, aluminum lacquer based on the dye red charming 0.04 mg.

Dosage of 1000 mg

1 tablet, film-coated, contains:

active substance: levetiracetam 1000 mg;

Excipients: silicon dioxide colloid 12 mg, croscarmellose sodium 40 mg, calcium stearate 12 mg, mannitol 80.8 mg, povidone 25.2 mg, cellulose microcrystalline 70 mg;

composition of film shell: Opadrai II blue 40 mg, including: polyvinyl alcohol 16 mg, macrogol 8.08 mg, talc 5.92 mg, titanium dioxide 8.2 mg, aluminum lacquer based on indigo carmine dye 1.72 mg, aluminum lacquer based on the dye red charming 0.08 mg.

Description:

Dosage of 250 mg: tablets are round, biconcave with a risk, covered with a film membrane of blue color. On the cross-section - almost white.

Dosages of 500 mg and 1000 mg: tablets are oval, biconcave with a risk, covered with a film membrane of blue color. On the cross-section - almost white.

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) 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 vitro and in vivo showed that levetiracetam does not affect the basic characteristics of cells and normal transmission. In studies in vitro It is shown that it affects the intra-neuronal concentration of Ca ions, partially inhibiting the current of calcium ions through the channels Ntype and reducing the release of calcium from intra-neural depots. In addition, it partially restores currents through GABA and glycine-dependent channels. 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. The drug does not change the normal neurotransmission, but it suppresses the 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:

Suction. After oral administration levetiracetam well absorbed from the gastrointestinal tract. Levetiracetam It is very soluble in water and has a good penetrating power. 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. The degree of absorption does not depend on the dose and time of food intake. Bioavailability is approximately 100%. The maximum concentration in plasma (C_mOh) 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.

The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg / kg / day, C_mOh is achieved after 0.5-1 h.

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

Metabolism. The main way of metabolism (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.

In vitro levetiracetam and its main metabolite did not inhibit the main forms of cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, 1A2) as well as the activity of glucuronyl transferase (UGT1A1, UGT1A6) and epoxy hydroxylase. It 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 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_1/2in children after a single oral administration of the drug at a dose of 20 mg / kg of body weight is 5-6 hours. The total clearance of levetiracetam in children is approximately 40% higher than in adults, and is in direct proportion to body weight.

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 old with newly diagnosed epilepsy.

As part of complex therapy in the treatment

partial seizures with secondary generalization or without it in adults and children over 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 to any components of the drug;

- Children under 6 years of age (in this dosage form in the treatment of partial seizures with or without secondary generalization in children suffering from epilepsy);

- children under 12 years of age (in the treatment of myoclonic seizures in children with juvenile myoclonic epilepsy and in primary generalized convulsive (tonic-clonic) seizures in children suffering from idiopathic generalized epilepsy);

- body weight less than 20 kg;

- children under 16 years of age in the treatment of partial seizures with or without secondary generalization with newly diagnosed epilepsy;

- the period of breastfeeding.

Carefully:

- Patients of advanced age (over 65 years);

- liver disease in the stage of decompensation;

- renal failure (creatinine clearance less than 50 ml / min);

- depression, suicidal behavior;

- simultaneous use with sulfonamides, probenecid, non-steroidal anti-inflammatory drugs, methotrexate.

Pregnancy and lactation:

Adequate and strictly controlled clinical studies on the safety of levetiracetam in pregnant women have not been conducted, so the drug should not be administered during pregnancy, except in cases of extreme necessity. It is necessary to observe contraception for women with preserved reproductive potential.

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 in the period preceding the 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 excreted in breast milk, so breastfeeding during treatment with a drug is contraindicated.

Dosing and Administration:

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

Monotherapy

Adults and teenagers over 16 years of age treatment should 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 (1500 mg twice a day).

As part of complex therapy

Children over 6 years treatment should begin with a daily dose of 20 mg / kg body weight divided into 2 divided doses (10 mg / kg body weight 2 times a day). A dose change of 20 mg / kg body weight can be performed every 2 weeks until the recommended daily dose is 60 mg / kg body weight (30 mg / kg body weight 2 times a day). With intolerance of the recommended daily dose, it is possible to reduce it. The minimum effective dose should be used.The doctor should prescribe the drug at the most appropriate dosage, depending on the patient's body weight and the required therapeutic dose.

Children with a body weight of more than 50 kg dosing is carried out according to the scheme given for adults.

Adults and adolescents over 16 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 2 times a day can be carried out every 2-4 weeks.

Because the levetiracetam is excreted from the body by the kidneys, when the drug is administered patients with renal insufficiency and elderly patients 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 by the following formula:

CK (ml / min) = (140 - age (years)) х body weight (kg) / 72 x KKsyvorot (mg / dL)

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

Renal insufficiency	QC (ml / min)	Dosing regimen
Easy degree	50-79	from 500 to 1000 mg twice a day
Average degree	30-49	from 250 to 750 mg twice a day
Heavy Degree	<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, using recommendations given for adults.

Renal insufficiency	QC (ml / min)	Dosing regimen
Easy degree	50-79	from 10 to 20 mg / kg per day
Average degree	30-49	from 5-15 mg / kg per day
Heavy Degree	<30	from 5-10 mg / kg per day
Terminal stage (patients on dialysis *)	---	from 10 -20 mg / kg once a day **

* On the first day of treatment, a saturating dose of 15 mg / kg is recommended.

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

Patients with impaired liver function of mild to moderate severity do not need to adjust the dosage regimen. In patients with decompensated impairment of liver function and renal insufficiency, the level of decrease in creatinine clearance may not fully reflect the severity of renal failure.In such cases, when creatinine clearance is <60 ml / min, a daily dose reduction of 50% is recommended.

Side effects:

Classification of WHO frequency of development of side effects:

very often - ≥1/10 appointments (> 10%)

often from ≥1 / 100 to <1/10 of appointments (> 1% and <10%)

infrequently - from ≥1 / 1000 to <1/100 of prescriptions (> 0.1% and <1%)

rarely from ≥1 / 10000 to <1/1000 appointments (> 0.01% and <0.1%)

very rarely - <1/10000 prescriptions (<0.01%)

From the nervous system and the psyche

Often: drowsiness, headache, asthenic syndrome.

Often: convulsions, dizziness, headache, tremor, imbalance, agitation, depression, mood swings, hostility / aggressiveness, insomnia, nervousness, irritability, personality disorders, thinking disorder, anxiety, vertigo.

Infrequently: ataxia, amnesia, decreased concentration of attention, memory impairment, suicide attempts, suicidal intentions, psychotic disorders, behavioral disorders, hallucinations, confusion, emotional lability.

Rarely: choreoathetosis, dyskinesia, hyperkinesia, suicide, personality disorder, thinking disorder.

From the side of the organs of sight

Infrequently: diplopia, violation of accommodation.

From the respiratory system

Often: increased cough.

From the digestive system

Often: abdominal pain, diarrhea, dyspepsia, nausea, vomiting, anorexia, weight gain.

Infrequently: pancreatitis, changes in functional liver samples.

Rarely: hepatic insufficiency, hepatitis, weight loss.

From the skin

Often: skin rash.

Infrequently: eczema, pruritus, alopecia (in some cases, the restoration of the hair was observed after the drug was discontinued).

Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Changes in laboratory indicators

Infrequently: thrombocytopenia, and leukopenia.

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

Other

Infections, nasopharyngitis, myalgia, muscle weakness, propensity to injury.

Children: vomiting, agitation, mood swings, emotional lability, aggressiveness, behavioral disorders, lethargy.

Overdose:

Symptoms: drowsiness, agitation, 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 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 antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and accept the don).

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

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

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

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

The clearance of levetiracetam was higher by 20% in children receiving anticonvulsants - inducers of microsomal oxidation in the liver, compared to children who do 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.

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 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 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 of treatment on the ability of children 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.

Due to reports of cases of suicide, suicidal intentions and suicide attempts in the treatment with levetiracetam, patients should be warned to immediately notify the attending physician of any symptoms of depression or suicidal intentions.

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

The effect of levetiracetam preparation on the ability to drive vehicles and control mechanisms has not been specifically studied. Nevertheless, 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 that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

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

Packaging:

Dosage of 250 mg: on 10 or 15 tablets in a contour cellular packing from a film of polyvinylchloride and a foil of the aluminum printed varnished.

According to 1, 3, 6 contour cell packs of 10 tablets or 2, 4 contour cell packs of 15 tablets together with the instructions for use are placed in a pack of cardboard.

Dosages of 500 mg and 1000 mg: on 10 tablets in a contour cellular packing from a film of polyvinylchloride and a foil of an aluminum printed varnished.

According to 1, 3, 6 contour cell packs of 10 tablets together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002135

Date of registration:11.07.2013

Expiration Date:11.07.2018

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia

Information update date: & nbsp22.10.2016

Illustrated instructions

Instructions

Levetiracetam Canon (Levetiracetam Canon)