Levicitam 250 film-coated tablets 250 mg blister No. 60

Instructions Levicitam 250 film-coated tablets 250 mg blister No. 60

Composition

active ingredient: levetiracetam;

1 tablet contains levetiracetam 250 mg or 500 mg;

excipients: microcrystalline cellulose, copovidone, crospovidone, pregelatinized corn starch, magnesium stearate, coating for applying the shell Opadry II White (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171)).

Dosage form

Film-coated tablets.

Main physicochemical properties: white film-coated tablets with a biconvex surface, round shape.

Pharmacotherapeutic group

Antiepileptic drugs. Levetiracetam. ATX code N03A X14.

Pharmacological properties

Pharmacodynamics.

Levetiracetam is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide), and its chemical structure differs from known antiepileptic drugs.

Mechanism of action.

The mechanism of action of levetiracetam is not well understood. Based on in vitro and in vivo studies, it is assumed that levetiracetam does not alter the basic characteristics of the nerve cell and normal neurotransmission. In vitro studies have shown that levetiracetam affects intracellular Ca2+ levels by partially inhibiting current through N-type Ca2+ channels and reducing the release of Ca2+ from intracellular depots. It also partially eliminates the inhibition of GABA- and glycine-gated currents caused by the action of zinc and β-carbolines. In addition, in vitro studies, levetiracetam has been shown to bind to specific sites in rodent brain tissue. The binding site is synaptic vesicle protein 2A, which is involved in vesicle fusion and neurotransmitter release. The affinity (ranked) of levetiracetam and its analogues for synaptic vesicle protein 2A correlated with their anticonvulsant potency in mouse models of audiogenic epilepsy. These results suggest that an interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the mechanism of the drug's antiepileptic action.

Pharmacodynamic effects.

Levetiracetam prevents seizures in a wide range of partial and primary generalized seizure models in animals without causing a proconvulsant effect. The main metabolite is inactive.

In humans, the drug's activity has been confirmed against both partial and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal response), indicating a broad spectrum of the pharmacological profile of levetiracetam.

Pharmacokinetics.

Levetiracetam is characterized by high solubility and permeability. The pharmacokinetics are linear, independent of time and characterized by low inter- and intra-subject variability. Clearance does not change after repeated administration of the drug. There was no evidence of an effect of gender, race or circadian rhythm on pharmacokinetics. The pharmacokinetic profile was similar in healthy volunteers and patients with epilepsy.

Due to complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed in mg/kg body weight. Therefore, monitoring of levetiracetam plasma levels is not necessary.

In adults and children, a significant correlation was observed between the drug concentration in saliva and blood plasma (the ratio of saliva/plasma concentrations ranged from 1 to 1.7 after taking the oral tablets and 4 hours after taking the oral solution).

Adults and teenagers.

Absorption.

Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is close to 100%. Peak plasma concentrations (Cmax) are reached 1.3 hours after dosing. Steady state is reached after 2 days of twice daily dosing. Peak concentrations (Cmax) are typically 31 and 43 μg/ml after a single 1000 mg dose and a repeated 1000 mg dose twice daily, respectively. The extent of absorption is independent of dose and is not affected by food.

Distribution.

There are no data on the distribution of the drug in human tissues. Neither levetiracetam nor its main metabolite is significantly bound to plasma proteins (< 10%). The volume of distribution of levetiracetam is 0.5 to 0.7 l/kg, which is approximately equal to the total body water volume.

Metabolism.

Levetiracetam metabolism in humans is negligible. The main metabolic pathway (24% of the dose) is enzymatic hydrolysis of the acetamide group. Hepatic cytochrome P450 isoforms are not involved in the formation of the main metabolite, ucb L057. Hydrolysis of the acetamide group has been observed in a large number of tissues, including blood cells. The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites were also identified. One was formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), the other by opening of the pyrrolidone ring (0.9% of the dose).

Other unidentified components accounted for only 0.6% of the dose.

In vitro studies have shown that levetiracetam and its major metabolite did not inhibit the activity of the major human hepatic cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferases (UGT1A1 and UGT1A6) and epoxide hydroxylase. Levetiracetam also does not inhibit the glucuronidation of valproic acid in vitro.

In human hepatocyte culture, levetiracetam had little or no effect on CYP1A1/2, SULT1E1 or UGT1A1 conjugation. Levetiracetam induced a weak induction of CYP2B6 and CYP3A4. In vitro and in vivo data on interactions with oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected under in vivo conditions. Therefore, interactions of levetiracetam with other substances are unlikely.

Breeding.

The plasma elimination half-life in adults was 7±1 hours and was independent of dose, route of administration, or repeated administration. The mean total clearance was 0.96 mL/min/kg.

The main amount of the drug, on average 95% of the dose, was excreted by the kidneys (approximately 93% of the dose was excreted within 48 hours). Only 0.3% of the dose was excreted in the feces.

The cumulative urinary excretion of levetiracetam and its major metabolite was 66% and 24% of the dose, respectively, in the first 48 hours. The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg, respectively, indicating that levetiracetam is eliminated by glomerular filtration followed by tubular reabsorption and that the major metabolite is also eliminated by active tubular secretion in addition to glomerular filtration. Levetiracetam excretion correlates with creatinine clearance.

Elderly patients.

In elderly patients, the elimination half-life is increased by approximately 40% (10-11 hours). This is due to the deterioration of renal function in this population (see section "Method of administration and dosage").

Kidney dysfunction.

The apparent total clearance of levetiracetam and its main metabolite correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, it is recommended to adjust the maintenance daily dose of levetiracetam according to creatinine clearance (see section 4.2).

In anuric patients with end-stage renal disease, the elimination half-life was approximately 25 and 3.1 hours, respectively, between and during dialysis. 51% of levetiracetam was removed during a 4-hour fractional dialysis session.

Liver dysfunction.

No relevant changes in levetiracetam clearance were observed in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment, levetiracetam clearance was reduced by more than 50% due to concomitant renal impairment (see section 4.2).

Pediatric population.

Children aged 4-12 years.

After a single dose (20 mg/kg) of levetiracetam to epileptic children (6 to 12 years), the elimination half-life of levetiracetam was 6 hours. The apparent clearance, adjusted for body weight, was approximately 30% higher than in adult patients with epilepsy. After repeated oral administration (20-60 mg/kg/day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentrations were reached 0.5-1 hour after dosing. Peak concentrations and the area under the concentration-time curve increased linearly and were dose-dependent. The elimination half-life was approximately 5 hours; the apparent total clearance was 1.1 ml/min/kg.

Indication

Monotherapy (first-choice drug) in the treatment of:

partial seizures with or without secondary generalization in adults and adolescents aged 16 years and older with newly diagnosed epilepsy.

As an additional therapy in the treatment of:

partial seizures with or without secondary generalization in adults, adolescents and children aged 6 years and over with epilepsy;

myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy;

primary generalized convulsive (tonic-clonic) seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.

Contraindication

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

Interaction with other medicinal products and other types of interactions

Antiepileptic drugs.

Pre-marketing data from clinical studies in adult patients indicate that levetiracetam does not affect the serum concentrations of other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone), which in turn do not affect the pharmacokinetics of levetiracetam.

There are no data on clinically significant drug interactions in pediatric patients, as well as in adults receiving up to 60 mg/kg/day of levetiracetam.

Probenecid.

Probenecid (500 mg 4 times daily), a drug that blocks renal tubular secretion, inhibits renal clearance of the major metabolite, but not levetiracetam itself. However, concentrations of this metabolite remain low.

Methotrexate.

Concomitant use of levetiracetam and methotrexate has been reported to reduce the clearance of methotrexate, leading to increased/prolonged blood concentrations of methotrexate to potentially toxic levels. Methotrexate and levetiracetam blood levels should be closely monitored in patients receiving both drugs concurrently.

Oral contraceptives and pharmacokinetic interactions with other drugs.

Levetiracetam at a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); endocrine parameters (LH and progesterone levels) did not change. Levetiracetam at a daily dose of 2000 mg does not change the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives and warfarin, in turn, do not affect the pharmacokinetics of levetiracetam when used simultaneously.

Laxatives.

In isolated cases, reduced efficacy of levetiracetam has been reported when the osmotic laxative macrogol was used concomitantly with oral levetiracetam. Therefore, oral macrogol should not be taken within 1 hour before or 1 hour after taking levetiracetam.

Food and alcohol.

The extent of absorption of levetiracetam is independent of food intake, but the rate of absorption is slightly reduced when taken with food. There are no data on the interaction of levetiracetam with alcohol.

Application features

Kidney failure.

Patients with renal impairment may require dose adjustment of levetiracetam. In patients with severe hepatic impairment, it is recommended that renal function be assessed before dose adjustment (see section 4.2).

Acute kidney injury.

The use of levetiracetam has been very rarely associated with acute kidney injury, the time to onset of which ranged from a few days to several months.

Complete blood count.

Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia and pancytopenia) have been reported in association with levetiracetam, usually at the start of treatment. A complete blood count is recommended in patients who experience significant weakness, fever, recurrent infections or coagulation disorders (see section 4.8).

Suicide.

Cases of suicide, suicide attempts, suicidal thoughts and behaviour have been reported in patients treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomised placebo-controlled trials of antiepileptic drugs has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. In view of this risk, patients should be monitored for signs of depression, suicidal thoughts and behaviour and treatment should be adjusted as necessary. Patients (or their carers) should be advised to report any symptoms of depression, suicidal thoughts and behaviour to their doctor.

Abnormal and aggressive behavior.

Levetiracetam may cause psychotic symptoms and behavioral disturbances, including irritability and aggression. Patients treated with levetiracetam should be monitored for the development of psychiatric symptoms indicative of significant changes in mood and/or personality. If such behaviour is observed, consideration should be given to adjusting the treatment or gradually withdrawing the treatment. If discontinuation is considered, see section 4.2.

Worsening of attacks.

As with other antiepileptic drugs, levetiracetam may occasionally increase the frequency or severity of seizures. This paradoxical effect has been reported mostly within the first month of levetiracetam initiation or with dose increases, and was reversible upon discontinuation or dose reduction. Patients should be advised to seek immediate medical advice if their epilepsy worsens. For example, failure to respond to treatment or exacerbation of seizures has been reported in patients with epilepsy associated with mutations in the alpha subunit of voltage-gated sodium channels.

QT prolongation on ECG.

Rare cases of QT prolongation on ECG have been reported during post-marketing surveillance. Levetiracetam should be used with caution in patients with a history of QTc prolongation, in patients receiving concomitant medications that affect the QTc interval, or in patients with pre-existing cardiac disease or electrolyte disturbances.

Children.

The drug in tablet form is not suitable for use in infants and children under 6 years of age.

Available data in children do not indicate any effects on development and puberty. However, the long-term effects on learning ability, intelligence, development, endocrine function, puberty and reproductive function in children remain unknown.

Use during pregnancy or breastfeeding

Women of reproductive age.

Special advice should be given to women of childbearing potential. Levetiracetam treatment should be reconsidered if a woman is planning to become pregnant. As with all antiepileptic drugs, abrupt withdrawal of levetiracetam should be avoided as it may lead to seizures, which may have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible, as treatment with multiple antiepileptic drugs may be associated with a higher risk of birth defects than monotherapy, depending on the combination of drugs.

Pregnancy.

It is known that a large amount of post-marketing data from pregnant women exposed to levetiracetam (more than 1800 women, of whom 1500 women used the drug during the first trimester) does not indicate an increased risk of major birth defects. There are only limited data on the development of the nervous system of children exposed to levetiracetam monotherapy in utero. However, available epidemiological studies (about 100 children) do not indicate an increased risk of disorders or delays in the development of the nervous system. Levetiracetam can be used during pregnancy if, after careful assessment, it is considered clinically necessary. In such cases, it is recommended to use the lowest effective dose.

Physiological changes during pregnancy may alter levetiracetam concentrations. Decreases in plasma levetiracetam concentrations have been observed during pregnancy. This decrease is most pronounced in the third trimester (up to 60% of the initial concentration before pregnancy). Appropriate clinical supervision should be provided for pregnant women receiving levetiracetam.

Breast-feeding.

Levetiracetam is excreted in breast milk, so breastfeeding is not recommended. If levetiracetam must be used during breastfeeding, the benefits and risks of treatment should be weighed against the importance of breastfeeding.

Impact on reproductive function.

No effects on reproductive function were found in animal studies.

The potential risk to humans is unknown because no clinical data are available.

Ability to influence reaction speed when driving vehicles or other mechanisms

Levetiracetam has minor or moderate influence on the ability to drive and use machines. Due to possible individual sensitivity, some patients may experience drowsiness, dizziness and other symptoms associated with the effects on the central nervous system, especially at the beginning of treatment or during dose increases. Therefore, such patients should be careful when performing work that requires increased concentration, such as driving a car or operating machinery. Patients are advised to refrain from driving or operating machinery until it is established that their ability to perform such activities is not impaired.

Method of administration and doses

Tablets should be taken orally, with sufficient liquid, regardless of meals. Divide the daily dose into 2 equal doses.

Partial seizures

The recommended dose for monotherapy (patients aged 16 years and over) and adjunctive therapy is the same and is listed below.

All indications

Adults (≥ 18 years) and adolescents (12 to 17 years) weighing 50 kg or more.

The initial therapeutic dose is 500 mg twice daily. This is the initial dose prescribed on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be used by the physician based on an assessment of the reduction in seizure frequency compared to potential side effects. This dose may be increased to 500 mg twice daily after 2 weeks.

Depending on the clinical picture and tolerability of the drug, the daily dose can be increased to a maximum of 1500 mg 2 times a day. The dose can be changed to 250 mg or 500 mg 2 times a day every 2-4 weeks.

Children aged 6 years and over and adolescents (aged 12 to 17 years) weighing less than 50 kg.

The physician should prescribe the most appropriate dosage form, dosage and release form based on body weight, age and dose. For information on dose adjustment based on body weight, see the Children section.

Discontinuation of treatment.

If it is necessary to discontinue the drug, it is recommended to do so gradually (for example, for adults and adolescents weighing 50 kg or more, reduce the dose by 500 mg 2 times a day every 2-4 weeks; for children and adolescents weighing less than 50 kg, reduce the single dose by no more than 10 mg/kg 2 times a day every 2 weeks).

Special patient groups.

Elderly patients (65 years and older).

Dose adjustment is recommended for elderly patients with impaired renal function (see section "Renal failure").

Kidney failure.

The daily dose should be individually adjusted according to the state of renal function.

To adjust the dose for adults, use the table below.

To adjust the dose according to the table, it is necessary to determine the level of creatinine clearance (CC) in ml/min.

The creatinine clearance for adults and adolescents weighing more than 50 kg can be calculated based on serum creatinine concentration using the formula:

CC (ml/min) = _________________________________________________________× 0.85 (for women)

72 × serum creatinine (mg/dL)

Then adjust the CK according to body surface area (BSA) as shown below:

CC (ml/min)

CC (ml/min/1.73 m2) = ___________________________ × 1.73

Patient's PPT (m2)

Table 1

Dosage regimen for adults and adolescents with renal insufficiency with a body weight of more than 50 kg.

* A loading dose of 750 mg is recommended on the first day of treatment.

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

For children with renal impairment, the dose of levetiracetam should be adjusted according to renal function, as the clearance of levetiracetam is related to renal function. This recommendation is based on a study in adult patients with renal impairment.

For adolescents, children, and infants, the creatinine clearance in mL/min/1.73 m2 can be calculated from the serum creatinine concentration (mg/dL) using the following formula (Schwarz formula):

Height (cm) × ks

CC (ml/min/1.73 m2) = ------------------------------------------ .

Serum creatinine (mg/dL)

In children under 13 years of age and adolescent girls, ks = 0.55; in adolescent boys, ks = 0.7.

Table 2

Dose adjustment recommendations for children and adolescents with renal impairment weighing less than 50 kg

(1) For dosages up to 250 mg, for doses not multiples of 250 mg, when the recommended dosage cannot be obtained by taking multiple tablets, and for patients who cannot swallow tablets, Levicitam oral solution should be used.

(2) A loading dose of 15 mg/kg (0.15 ml/kg) of levetiracetam is recommended on the first day of treatment.

(3) After dialysis, an additional dose of 5-10 mg/kg (0.05-0.10 ml/kg) is recommended.

Liver failure.

No dose adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, creatinine clearance may not fully reflect the degree of renal impairment. Therefore, a 50% reduction in the daily maintenance dose is recommended for patients with creatinine clearance < 60 ml/min/1.73 m2.

Children.

The doctor should prescribe the most appropriate dosage form, dosage and release form, depending on age, body weight and dose.

The tablet form is not recommended for use in children under 6 years of age. In this group of patients, it is preferable to use Levicytam in the form of an oral solution. In addition, the available tablet dosages are not suitable for the initial treatment of children weighing up to 25 kg, for patients who cannot swallow tablets, or for doses up to 250 mg. In all of the above cases, treatment should be started with Levicytam, oral solution.

Monotherapy.

The safety and efficacy of Levicitam in children and adolescents under 16 years of age as monotherapy have not been established.

Data is missing.

Adolescents (aged 16–17 years) weighing 50 kg or more with partial seizures with or without secondary generalization, who have been diagnosed with epilepsy for the first time

See above section “Adults (≥ 18 years) and adolescents (12–17 years) weighing 50 kg or more”.

Adjunctive therapy for children aged 6 years and older and adolescents (aged 12 to 17 years) weighing less than 50 kg.

For infants and children under 6 years of age, it is advisable to use Levicitam in the form of an oral solution.

In children aged 6 years and older, Levicitam oral solution should be used for dosages up to 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be obtained by taking several tablets, and for patients who cannot swallow tablets.

For all indications, the lowest effective dose should be used. The starting dose for a child or adolescent weighing 25 kg should be 250 mg twice daily, the maximum dose is 750 mg twice daily.

Children weighing more than 50 kg should be dosed according to the scheme given for adults.

See above section “Adults (≥ 18 years) and adolescents (12–17 years) weighing 50 kg or more” for all indications.

Adjunctive therapy for infants aged 1 to 6 months.

Children.

The tablet form is not recommended for use in children under 6 years of age. Levicitam oral solution should be used in infants from 1 month of age and children under 6 years of age.

Overdose

Symptoms.

In case of drug overdose, drowsiness, agitation, aggression, respiratory depression, confusion, and coma were observed.

Treatment.

In case of acute overdose, gastric lavage or induce vomiting is necessary. There is no specific antidote. If necessary, symptomatic treatment is carried out, including hemodialysis (up to 60% of levetiracetam and 74% of the primary metabolite are removed).

Side effects

The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse event profile presented is based on a pooled analysis of placebo-controlled clinical trials involving a total of 3416 patients treated with levetiracetam. These data are supplemented by the use of levetiracetam in relevant open-label extension studies and post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adults and children) when used in the various established indications.

Adverse reactions reported in clinical trials (in adults, adolescents, children and infants from 1 month of age) and during the post-marketing period are listed in the following table by system organ class and frequency. The frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000).

Table 3

* Prevalence is significantly higher in Japanese compared to non-Japanese patients.

** During post-marketing surveillance, very rare cases of obsessive-compulsive disorder (OCD) have been observed in patients with a history of OCD or psychiatric disorders.

Description of selected adverse reactions.

Bone marrow suppression has been observed in some cases of pancytopenia.

Cases of encephalopathy were usually observed early in treatment (from a few days to several months) and were reversible after discontinuation of treatment.

Children.

A total of 190 patients aged 1 month to 4 years were treated with levetiracetam in placebo-controlled and open-label extension studies. Of these, 60 were treated with levetiracetam in placebo-controlled studies. A total of 645 patients aged 4 to 16 years were treated with levetiracetam in placebo-controlled and open-label extension studies. Of these, 233 were treated with levetiracetam in placebo-controlled studies. In both age groups, these data are supplemented by data from post-marketing use of levetiracetam.

In addition, 101 infants under 12 months of age were treated with levetiracetam in a post-marketing safety study. No new safety data were obtained for the use of levetiracetam in infants with epilepsy under 12 months of age.

The adverse reaction profile of levetiracetam is generally similar across age groups and across all approved epilepsy indications. The safety profile of levetiracetam in children in placebo-controlled clinical trials was consistent with the safety profile of levetiracetam in adults, except for behavioural and psychiatric adverse reactions, which were more frequent in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%) and lethargy (common, 3.9%) were observed at a higher frequency than in other age groups or in the overall safety profile. In infants and children aged 1 month to 4 years, irritability (very common, 11.7%) and incoordination (common, 3.3%) were observed at a higher frequency than in other age groups or in the overall safety profile.

It is known that a pediatric safety study, conducted to demonstrate non-inferiority to an active control, evaluated the effects of levetiracetam on cognitive and neuropsychological measures in children aged 4 to 16 years with partial onset seizures. Levetiracetam was non-different (non-inferior) from placebo in terms of change from baseline in attention and memory on the Leiter-R scale, a population-based summary measure of memory testing, as per protocol. Results related to behavioral and emotional functioning indicated an increase in aggressive behavior in levetiracetam-treated patients, as measured in a standardized and systematic manner using validated measures (Achenbach Child Behavior Checklist). It was reported that patients treated with levetiracetam did not experience, on average, any deterioration in behavioral and emotional functioning during the follow-up study; in particular, indicators of aggressive behavior were not