Levetiracetam pills 1000mg, 30pcs

Composition

Per one film-coated tablet: Active ingredient: Levetiracetam-1000.00 mg, Excipients: Corn starch-208.0 mg, Povidone K 30 (collidone 30) – 52.0 mg, Talc-19.2 mg, colloidal silicon dioxide-13.0 mg, Magnesium stearate-7.8 mgfilm shell: Opadray II (white) [polyvinyl alcohol-46.9%, macrogol 4000-23.6%, talc-17.4%, titanium dioxide-12.1%] – 30.0 mg

Pharmacological action

Pharmacotherapy group: Antiepileptic agent

ATX Code: N03AX

Pharmacodynamics :

Levetiracetam is a derivative of pyrrolidone (S-enantiomer-ethyl-2-oxo-1-pyrrolidine-acetamide) and differs in chemical structure from known antiepileptic drugs. The mechanism of action of levetiracetam is not fully understood but it is obvious that it differs from the mechanism of action of known antiepileptic drugs.

Based on the conducted in vitro and in vivo studies, it is assumed that levetiracetam does not change the main characteristics of nerve cells and normal neurotransmission.

In vitro studies have shown that levetiracetam reduces the content of Ca2+ in the neuron by reducing the flow of ions through N-type Ca2+ channels and reducing the release of Ca2+ from intraneuronal depots. Levetiracetam also partially eliminates the decrease in ion currents caused by alpha and beta-carbolines through channels conjugated to the gamma-aminobutyric acid (GABA) and glycine receptors.

One of the proposed mechanisms is based on the proven binding to protein 2A of the synaptic vesicle membrane of brain neurons. It is believed that in this way the anticonvulsant effect of this drug is realized.

Pharmacodynamic effects:  levetiracetam prevents the development of seizures in various experimental models of partial and primary generalized seizures without a pro-convulsive effect. The main metabolite of levetiracetam is inactive. In humans, the activity of the drug against both partial and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal reaction) confirms its wide spectrum of pharmacological action.

Pharmacokinetics:

Levetiracetam is a highly soluble substance with high permeability. The pharmacokinetic profile is linear with low inter-and intra-individual variability. Clearance of the drug does not change after repeated injections. There is no dependence of pharmacokinetics on gender, ethnicity, or time of day.

Suction. After oral use, levetiracetam is well absorbed from the gastrointestinal tract (GIT). Absorption occurs completely and is linear, so that the concentration in blood plasma can be predicted based on the dose of levetiracetam taken expressed in mg/kg of body weight. The degree of absorption of levetiracetam does not depend on the dose and time of food intake. Bioavailability is approximately 100%. The maximum plasma concentration (Cmax) is reached 33 hours after oral use of levetiracetam at a dose of 1000 mg and with a single dose is 31 mcg / ml after repeated use (2 times a day) – 43 mcg/ml. The equilibrium state is reached after 2 days with a double dose of the drug. The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg / kg / day Cmax is reached in 05-1 hours.

Distribution. The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%. The volume of distribution (Vd) is approximately 05-07 l/kg.

Metabolism. Levetiracetam is poorly metabolized in the human body. The main route of metabolism (24% of the dose) is the enzymatic hydrolysis of the acetamide group. Cytochrome P 450 isoforms are not involved in the formation of the main metabolite (ucb L057). Hydrolysis of the acetamide group occurs in many tissues, including blood cells. The main metabolite of ucb L057 is pharmacologically inactive. Two minor metabolites were also detected. The first is formed as a result of hydroxylation of the pyrrolidone ring (16% of the dose), the other is formed by opening the pyrrolidone ring (09% of the dose). No optical isomerization of levetiracetam and its main metabolite was detected in vivo. Levetiracetam and its main metabolite do not inhibit the main human liver cytochrome P 450 isoenzymes (CYP3A4 2 A 6 2 C 9 2 C 19 2D6 2 E 1 and 1 A 2) glucuronyl transferase (UGT1 A 1 and UGT1A6) and epoxidohydroxylase in vitro. In human hepatocyte culture, levetiracetam has little or no effect on the activity of CYP1A2 SULT1E1 and UGT1A1 isoenzymes. Levetiracetam weakly induces the activity of CYP2B6 and CYP3A4 isoenzymes. Data on drug interactions with the oral contraceptives digoxin and warfarin in vitro and in vivo indicate that no significant enzyme induction is expected in vivo. Therefore, interaction of levetiracetam with other substances or interaction of other substances with levetiracetam is unlikely.

Output. The half-life (T 1/2) from adult blood plasma is 7 ± 1 h and does not depend on the dose route of use and duration of use. The average total clearance is 096 ml / min / kg. 95% of the drug is excreted by the kidneys. The total amount of excretion of levetiracetam and its main metabolite is 66% and 24% of the dose taken during the first 48 hours, respectively. The renal clearance of levetiracetam and its metabolite ucb L057 is 06 and 42 ml / min / kg, respectively.

Elderly patients

In elderly patients, T 1/2 increases by 40% and is 10-11 hours, which is associated with impaired renal function in this category of people.

Patients with renal insufficiency

In patients with impaired renal function, the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance (CC). Therefore, patients with renal insufficiency are recommended to adjust the dose depending on the creatinine clearance.

In end-stage renal failure in adult patients, T 1/2 is 25 hours between dialysis sessions and 31 hours during dialysis. During a 4-hour dialysis session, up to 51% of levetiracetam is removed.

Patients with impaired liver function

No significant changes in levetiracetam clearance occur in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment and concomitant renal insufficiency, the clearance of levetiracetam decreases by more than 50%.

Children aged 4-12 years

The pharmacokinetics of levetiracetam in children are linear. After a single dose of 20 mg/kg, the T 1/2 in children is 6 hours. Body weight-adjusted apparent clearance is 30% higher than that of adults with epilepsy. After long-term use of the drug at a dose of 20 to 60 mg/kg/day, the absorption of levetiracetam in children is rapid. Cmax is reached within 05-1 h

. Cmax and the area under the concentration-time pharmacokinetic curve (AUC) are linear and proportional to the dose. The terminal T 1/2 is 5 h. The apparent clearance is 11 ml / min / kg.

Indications

As monotherapy in the treatment of:

• partial seizures with or without secondary generalization in adults and adolescents over 16 years of age with newly diagnosed epilepsy.

As part of complex therapy in the treatment of:

• partial seizures with or without secondary generalization in adults and children over 4 years of age with epilepsy;
• myoclonic seizures in adults and adolescents over 12 years of age with juvenile myoclonic epilepsy;
• primary generalized convulsive tonic-clonic seizures in adults and adolescents over 12 years of age with idiopathic generalized epilepsy.

Use during pregnancy and lactation

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

In general, these data do not indicate a significant increase in the risk of serious congenital malformations, although teratogenic risk cannot be completely excluded. Treatment with multiple antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, and therefore monotherapy in pregnant women is more appropriate. Adequate and strictly controlled clinical studies on the safety of levetiracetam in pregnant women have not been conducted so the drug should not be prescribed during pregnancy or in fertile women who do not use reliable methods of contraception except in cases of extreme necessity.

Physiological changes in a woman’s body during pregnancy can affect the concentration of levetiracetam in plasma as well as other antiepileptic drugs. During pregnancy, a decrease in the concentration of levetiracetam in plasma was noted. Treatment of pregnant women with levetiracetam should be carried out under special supervision. Interruptions in antiepileptic therapy can 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 breast-feeding during treatment with the drug is not recommended.

Contraindications

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

– children under 4 years of age (safety and efficacy have not been established).

With caution:

– Elderly patients (over 65 years of age);

– liver diseases in the stage of decompensation;

– renal failure.

Side effects

Based on clinical trials and post marketing experience with levetiracetam, the most common 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.

Frequency of side effects: very common (≥1/10) common (≥1/100 to< 1/10) uncommon (≥1/1000 to <1/100) rare (≥1/10000 to <1/1000) very rare (

Blood and lymphatic system disorders

Infrequently: thrombocytopenia leukopenia.

Rare: agranulocytosis pancytopenia (in some cases with bone marrow suppression) neutropenia.

From the immune system

Rare: drug reaction with eosinophilia and systemic manifestations (DRESS-syndrome).

From the side of metabolism

Often: anorexia nervosa.

Infrequently: weight gain weight loss.

Rare: hyponatremia.

From the side of the psyche

Often: depression mood changes hostility aggressiveness insomnia nervousness irritability anxiety.

Infrequently: confusion agitation hallucinations emotional instability psychotic disorders suicide attempts and suicidal thoughts behavioral disorders anger disorder panic attacks mood swings.

Rare: completed suicide personality disorder thinking disorder.

Nervous system disorders

Very common: drowsiness, headache.

Common: convulsions dizziness tremors balance disorders lethargy.

Infrequently: paresthesia amnesia impaired coordination/ataxia memory impairment decreased concentration.

Rarely: hyperkinesia choreoathetosis dyskinesia.

From the side of the visual organ

Infrequently: diplopia accommodation disorder.

From the side of the organ of hearing

Often: vertigo.

From the respiratory system

Often: cough.

From the digestive system

Often: abdominal pain diarrhea dyspepsia nausea vomiting.

Infrequently: pancreatitis changes in functional liver tests.

Rare: liver failure hepatitis weight loss.

From the skin

Often: skin rash.

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

Rare: toxic epidermal necrolysis Stevens-Johnson syndrome erythema multiforme.

Musculoskeletal disorders

Infrequently: muscle weakness and myalgia.

Infections and infestations

Very common: nasopharyngitis.

Rare: infections.

Common disorders

Infrequently: asthenia fatigue accidental injuries.

The risk of anorexia is higher when levetiracetam is co-administered with topiramate.

In placebo-controlled studies, the safety profile of levetiracetam in children (patients aged 4-16 years) It was comparable to that in adults with the exception of behavioral and psychiatric adverse reactions that occurred more frequently in children than in adults. In children and adolescents aged 4-16 years, adverse reactions such as vomiting (very common-112%) agitation (often-34%) mood changes (often-21%) emotional lability (often-17%) aggression (often-82%) behavioral disorders (often – 56%) and lethargy (often – 39%) were observed more often than in other age ranges.

Assessment of the cognitive and neuropsychological effects of levetiracetam in children aged 4-16 years with partial seizures (according to double-blind placebo-controlled safety profile studies) showed that levetiracetam is no different (no less safe) from placebo by changes from baseline values on the Leiter-R Attention and Memory scale (Leiter-R Attention and Memory) on the Memory Screen Composite scale. The results of a study of behavioral and emotional functions confirming that aggressive behavior occurs during the use of levetiracetam a were obtained using a standardized method using a validated tool-the Achenbach Child Behavior Checklist. However, patients who took levetiracetam long-term in open-label studies did not experience behavioral and emotional disorders, in particular, the level of aggressive behavior did not differ from the baseline.

If any of the side effects listed in the instructions get worse or you notice any other side effects not listed in the instructions, tell your doctor.

Interaction

Anticonvulsants

According to pre-marketing clinical studies, levetiracetam does not affect the serum concentrations of other anticonvulsants: phenytoin carbamazepine valproic acid phenobarbital lamotrigine gabapentin topiramate and primidone A. These anticonvulsants do not affect the pharmacokinetics of levetiracetam.

Similarly to adults, levetiracetam does not interact with other medications in children at doses up to 60 mg/kg/day. A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4-16 years) confirms that levetiracetam as adjunctive therapy does not affect the serum Css of concomitantly administered carbamazepine and valproic acid. However, there is evidence that the clearance of levetiracetam in children taking anticonvulsants – inducers of microsomal liver enzymes – increases by 20%. No dose adjustment is required.

Probenecid

Probenecid (500 mg 4 times a day) is a tubular secretion blocker at night it has been shown to inhibit the renal clearance of the main metabolite but not levetiracetam. However, the concentration of the main metabolite remains low. It is expected that other drugs excreted through active tubular secretion may reduce the renal clearance of the main metabolite. The effect of levetiracetam on probenecid has not been studied; the effect of levetiracetam on other drugs excreted by active tubular secretion including the nonsteroidal anti-inflammatory drugs sulfonamide and methotrexate is unknown.

Oral contraceptives and other pharmacokinetic interactions

Levetiracetam at a dose of 1000 mg / day does not affect the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); the hormonal status (content of luteinizing hormone and progesterone) does not change. Levetiracetam at a dose of 2000 mg / day had no effect on the pharmacokinetics of digoxin and warfarin. Concomitant use of digoxin, an oral contraceptive, and warfarin does not affect the pharmacokinetics of levetiracetam.

Antacids

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

Food and alcohol

Food does not affect the degree of absorption of levetiracetam, but slightly reduces its rate. There are no data on the interaction of levetiracetam with ethanol. There are isolated reports of a decrease in the effectiveness of levetiracetam when it is applied topically with osmotic laxatives, and therefore it is not recommended to simultaneously take osmotic laxatives for one hour before and for one hour after taking levetiracetam.

How to take, course of use and dosage

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

Monotherapy

Adults and adolescents over 16 years of age should start treatment with a daily dose of 500 mg divided into 2 doses (250 mg 2 times a day). After 2 weeks, the dose can be increased to the initial therapeutic dose of 1000 mg (500 mg 2 times a day). The maximum daily dose is 3000 mg (but 1500 mg 2 times a day).

As part of complex therapy

Children over 4 years of age and adolescents (12 to 17 years of age) with a body weight of less than 50 kg should start treatment with a daily dose of 20 mg/kg of body weight divided into 2 doses (10 mg/kg of body weight 2 times a day). The dose can be changed by 20 mg/kg of body weight every 2 weeks until the recommended daily dose is 60 mg/kg of body weight (30 mg/kg of body weight 2 times a day). If you are intolerant to the recommended daily dose, it may be reduced. The minimum effective dose should be used.

The doctor should prescribe the drug in the most appropriate dosage form and dosage, depending on the patient’s body weight and the required therapeutic dose.

Children with a body weight of more than 50 kg are dosed according to the scheme given for adults.

Adults and adolescents (from 12 to 17 years) with a body weight of more than 50 kg should start treatment with a daily dose of 1000 mg divided into 2 doses (500 mg 2 times a day). Depending on the clinical response and tolerability of the drug, the daily dose can be increased to a maximum of 3000 mg (1500 mg 2 times a day). Changing the dose to 500 mg 2 times a day can be carried out every 2-4 weeks.

Since levetiracetam is eliminated from the body by the kidneys, when prescribing the drug to patients with renal insufficiency and elderly patients, the dose should be adjusted depending on the value of creatinine clearance.

CC for men can be calculated based on the concentration of serum creatinine using the following formula:

CC (ml / min) = [140 – age (years)] x body weight (kg)/ 72 x Creatinine clearance (mg / dl)

CC for women can be calculated by multiplying the obtained value by a factor of 085.

Then the CC is adjusted for the body surface area (BTA) using the following formula::

CC (ml / min/173 m%^%2) = KK (ml / min)/ Item’s BCP (m%^%2) x 173

Adult dose adjustment

* On the first day of treatment, a saturating dose of 750 mg is recommended

. * * After dialysis, an additional dose of 250-500 mg is recommended.

In children with renal insufficiency, dose adjustment of levetiracetam should be made taking into account the degree of renal insufficiency using the recommendations given for adults.

For young adolescents and children, the following formula (Schwartz form)is used:

CC (ml / min/173 m2) = Height (cm) x ks/ kxerum (mg / dl)

in children under 13 years of age and adolescent girls, ks = 055;

in adolescent boys, ks = 07.

Recommendations for dose adjustment in children and adolescents with impaired renal function with a body weight of less than 50 kg

*On the first day of treatment, a loading dose of levetiracetam of 15 mg/kg

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

Patients with mild to moderate hepatic impairment do not need to adjust the dosage regimen.

In patients with decompensated hepatic impairment and renal insufficiency, the level of decrease in creatinine clearance may not fully reflect the severity of renal insufficiency. In such cases, with CC

Overdose

Symptoms: drowsiness agitation anxiety aggressiveness depression of consciousness respiratory depression 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 is performed in a hospital setting using hemodialysis (the effectiveness of dialysis for levetiracetam is 60% for its primary metabolite-74%).

Special instructions

Discontinuation of therapy

Discontinuation of the drug is recommended gradually. For example, in adults and adolescents with a body weight of more than 50 kg: dose reduction should be carried out in increments of 500 mg 2 times a day no more than every 2-4 weeks; in children from 6 years of age with a body weight of less than 50 kg: dose reduction should be carried out in increments of no more than 10 mg/kg 2 times a day no more than every 2 weeks.

Kidney failure

The use of levetiracetam in patients with renal insufficiency may require dose adjustment. In patients with severe hepatic insufficiency, it is recommended to evaluate renal function before starting dose selection (see “Dosage and use”).

Suicide

Patients taking anticonvulsants (including levetiracetam) have been reported to have suicidal thoughts and behaviors.

A meta-analysis of randomized placebo-controlled trials of anticonvulsant medications showed a small increase in the risk of suicidal thoughts and behavior. The mechanism of its implementation is unknown.

Therefore, patients with depressive symptoms or suicidal thoughts and/or behaviors should be monitored and given appropriate therapy. Patients (and their caregivers) should be informed about the need to seek medical attention if they experience symptoms of depression and/or suicidal thoughts and behaviors.

Children

The dosage form of the tablet has age restrictions for use in children (see “Indications”). According to available data, levetiracetam does not affect growth and puberty. However the long term effects on learning intelligence growth endocrine function puberty and child fertility are unknown.

Concomitant antiepileptic drugs (during the transfer of patients to levetiracetam) should be discontinued gradually.

Influence on the ability to drive vehicles and mechanisms:

Studies on the effect on the ability to drive vehicles and work with mechanisms have not been conducted. Due to individual differences in susceptibility, some patients may experience drowsiness and other central nervous system disorders, especially at the beginning of therapy and after increasing the dose. Therefore, it is recommended to use caution when driving vehicles and engaging in other activities that require increased concentration of attention and speed of psychomotor reactions. If these symptoms occur, patients should refrain from such activities until they are satisfied that these symptoms do not have a significant effect on them.

Storage conditions

Store in a dry place protected from light at a temperature not exceeding 25 °C.

Keep out of reach of children.

Shelf

life is 2 years.

Do not use after the expiration date.

Active ingredient

Levetiracetam

Conditions of release from pharmacies

By prescription

Dosage form

Tablets