Levicetam

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVICITAM (LEVICITAM)

Composition:

Active substance: levetiracetam;

1 ml of solution contains levetiracetam 100 mg;

Excipients: glycerol, propyl parahydroxybenzoate (E 216), methyl parahydroxybenzoate (E 218), ammonium glycyrrhizinate, citric acid monohydrate, sodium citrate dihydrate, potassium acesulfame (E 950), maltitol (E 965), grapefruit flavor, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antiepileptic agents. Levetiracetam.

ATC code N03A X14.

Pharmacological Properties.

Pharmacodynamics.

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

Mechanism of Action

The mechanism of action of levetiracetam is not fully understood. Based on in vitro and in vivo studies, it is presumed that levetiracetam does not alter the basic characteristics of nerve cells or normal neurotransmission. In vitro studies have shown that levetiracetam affects intraneuronal Ca²⁺ levels by partially inhibiting Ca²⁺ influx through N-type calcium channels and reducing Ca²⁺ release from intraneuronal stores. It also partially counteracts the inhibition of GABA- and glycine-regulated currents induced by zinc and β-carbolines. Furthermore, in vitro studies demonstrated that levetiracetam binds to specific sites in rodent brain tissues. The binding site is synaptic vesicle protein 2A (SV2A), which is involved in vesicle fusion and neurotransmitter release. The affinity of levetiracetam and its analogs for synaptic vesicle protein 2A correlates with their anticonvulsant potency in animal models of audiogenic epilepsy. These findings suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the drug’s antiepileptic mechanism.

Pharmacodynamic Effects

Levetiracetam prevents the occurrence of seizures in a broad range of animal models of partial and primarily generalized seizures, without causing proconvulsant effects.

Its main metabolite is inactive.

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

Pharmacokinetics.

Levetiracetam is characterized by high solubility and permeability. Its pharmacokinetics are linear and exhibit low inter- and intra-subject variability. After repeated administration, clearance does not change. No influence of gender, race, or circadian rhythm on pharmacokinetics has been observed. The pharmacokinetic profile is similar in healthy volunteers and patients with epilepsy.

Due to complete and linear absorption, plasma concentrations of the drug can be predicted based on the oral dose of levetiracetam expressed in milligrams per kilogram of body weight. Therefore, monitoring plasma levels of levetiracetam is not necessary.

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

Adults and Adolescents

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

Distribution. There are no data on tissue distribution in humans. Neither levetiracetam nor its main metabolite bind significantly to plasma proteins (< 10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg, which is close to the total body water.

Metabolism. Metabolism of levetiracetam in humans is minimal. The main metabolic pathway (24% of dose) is enzymatic hydrolysis of the acetamide group. Hepatic cytochrome P450 isoenzymes are not involved in the formation of the main metabolite – ucb L057. Hydrolysis of the acetamide group occurs in a wide range of tissues, including blood cells. The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites have also been identified. One is formed by hydroxylation of the pyrrolidone ring (1.6% of dose), the other by opening of the pyrrolidone ring (0.9% of dose). Other unidentified components accounted for only 0.6% of the dose.

No interconversion of enantiomers of levetiracetam or its main metabolite was observed under in vivo conditions.

In vitro studies showed that levetiracetam and its main metabolite do not inhibit the activity of major cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, and 1A2), glucuronosyltransferases (UGT1A1 and UGT1A6), or epoxide hydrolase. Levetiracetam also does not inhibit glucuronidation of valproic acid in vitro.

In human hepatocyte cultures, levetiracetam showed weak or no effect on CYP1A1/2, SULT1E1, or UGT1A1. Levetiracetam caused weak induction of CYP2B6 and CYP3A4. In vitro and in vivo data on interactions with oral contraceptives, digoxin, and warfarin suggest that clinically significant enzyme induction is not expected in vivo. Therefore, interactions between levetiracetam and other substances are unlikely.

Elimination. The elimination half-life of the drug in plasma in adults is 7±1 hours and does not depend on dose, route of administration, or repeated administration. Mean total clearance is 0.96 mL/min/kg.

Approximately 95% of the dose is excreted renally (about 93% of the dose within 48 hours). Only 0.3% of the dose is excreted in feces.

Cumulative urinary excretion of levetiracetam and its main metabolite was 66% and 24% of the dose, respectively, within the first 48 hours. Renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 mL/min/kg, respectively, indicating glomerular filtration of levetiracetam followed by tubular reabsorption, and that the main metabolite is also eliminated via active tubular secretion in addition to glomerular filtration. Elimination of levetiracetam correlates with creatinine clearance.

Elderly Patients.

In elderly patients, elimination half-life increases by approximately 40% (10–11 hours), which is related to reduced renal function in this population (see section "Dosage and Administration").

Renal Impairment.

The apparent total clearance of levetiracetam and its main metabolite correlates with creatinine clearance. Therefore, patients with moderate to severe renal impairment require dose adjustment of the maintenance daily dose of levetiracetam according to creatinine clearance (see section "Dosage and Administration").

In patients with end-stage renal disease and anuria, elimination half-life is approximately 25 hours between dialysis sessions and 3.1 hours during dialysis. During a 4-hour fractionated dialysis session, 51% of levetiracetam is removed.

Hepatic Impairment.

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

Pediatric Population

Children aged 4–12 years.

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

Infants and Children (1 month to 4 years of age).

After a single dose (20 mg/kg) of oral solution 100 mg/mL in children with epilepsy (1 month to 4 years), levetiracetam was rapidly absorbed, with peak plasma concentrations observed approximately 1 hour after dosing. Pharmacokinetic parameters indicated a shorter elimination half-life (5.3 hours) compared to adults (7.2 hours), and faster apparent clearance (1.5 mL/min/kg) compared to adults (0.96 mL/min/kg).

Results from another population pharmacokinetic analysis in patients aged 1 month to 16 years indicated a strong correlation between body weight and apparent clearance (clearance increased with increasing body weight) and apparent volume of distribution. Age also influenced both parameters. This effect was more pronounced in infants, decreased with age, and was negligible in children around 4 years of age.

Data from both population pharmacokinetic analyses indicated an approximately 20% increase in apparent clearance of levetiracetam when co-administered with enzyme-inducing antiepileptic drugs.

Clinical characteristics.

Indications.

Monotherapy (first-line treatment) for the treatment of:

• Partial-onset seizures with or without secondary generalization in adults and adolescents aged 16 years and older who have newly diagnosed epilepsy.

As adjunctive therapy in the treatment of:

• Partial-onset seizures with or without secondary generalization in adults and children aged 1 month and older with epilepsy;
• Myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy;
• Primary generalized tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.

Contraindications.

Hypersensitivity to levetiracetam or to other derivatives of pyrrolidone, as well as to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs.

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

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (aged 4 to 17 years) confirmed that adjunctive therapy with oral levetiracetam did not affect the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data indicate that the clearance of levetiracetam is 20% higher in children receiving enzyme-inducing antiepileptic drugs. Dose adjustment is not required.

Probenecid.

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

Methotrexate.

There have been reports that concomitant use of levetiracetam and methotrexate reduces methotrexate clearance, leading to increased/prolonged methotrexate blood concentrations reaching potentially toxic levels. Methotrexate and levetiracetam blood levels should be closely monitored in patients receiving both drugs simultaneously.

Oral contraceptives and pharmacokinetic interactions with other drugs.

Levetiracetam at a daily dose of 1000 mg does not alter the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (levels of luteinizing hormone (LH) and progesterone) were unchanged. Levetiracetam at a daily dose of 2000 mg does not alter 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 co-administered.

Laxatives.

In isolated cases, reduced effectiveness of levetiracetam has been reported when co-administered with the osmotic laxative macrogol and oral levetiracetam. Therefore, macrogol should not be taken orally within one hour before or one hour after taking levetiracetam.

Food and alcohol.

The extent of levetiracetam absorption is not affected by food intake, but the rate of absorption is slightly reduced when taken with food. There are no data on the interaction between levetiracetam and alcohol.

Special precautions for use.

Renal impairment.

Patients with renal impairment may require dose adjustment of levetiracetam. In patients with severe hepatic dysfunction, renal function should be assessed before initiating treatment (see section "Dosage and administration").

Acute kidney injury.

Very rare cases of acute kidney injury have been reported with levetiracetam use, with onset ranging from several days to several months.

Blood count.

Rare cases of blood cell count reduction (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have been reported in association with levetiracetam use, typically at the beginning of treatment. Complete blood count monitoring is recommended in patients presenting with marked weakness, fever, recurrent infections, or coagulation disorders (see section "Adverse reactions").

Suicidal behavior.

Cases of suicide, suicide attempts, suicidal ideation, and suicidal behavior have been reported in patients treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomized, placebo-controlled trials showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is not understood. Due to this risk, patients should be monitored for signs of depression and/or suicidal ideation, and treatment adjustments should be considered if needed. Patients (or their caregivers) should be advised to promptly report any symptoms of depression and/or suicidal thoughts to their physician.

Unusual and aggressive behavior.

Levetiracetam may cause psychotic symptoms and behavioral disturbances, including irritability and aggression. Patients receiving levetiracetam should be monitored for the emergence of psychiatric signs indicating significant mood and/or personality changes. If such behavior occurs, consideration should be given to adjusting treatment or gradually discontinuing the drug. For discontinuation, see section "Dosage and administration".

Exacerbation of seizures.

As with other antiepileptic drugs, levetiracetam may increase the frequency and severity of seizures. This paradoxical effect has mostly been reported within the first month after initiating levetiracetam or increasing the dose, and is usually reversible upon discontinuation or dose reduction. Patients should be advised to contact their physician immediately if seizures worsen. For example, insufficient efficacy or seizure exacerbation has been reported in patients with epilepsy associated with mutations in the alpha subunit of voltage-gated sodium channels.

Prolongation of QT interval on ECG.

Rare cases of QT interval prolongation on ECG have been reported during post-marketing surveillance. Levetiracetam should be used with caution in patients with known QTc prolongation, in patients taking concomitant medications affecting the QTc interval, or in patients with pre-existing cardiac conditions or electrolyte imbalances.

Children.

Available data in pediatric patients do not indicate effects on growth or sexual maturation. However, long-term effects on learning ability, intelligence, growth, endocrine functions, sexual maturation, and reproductive potential in children have not been studied.

Excipients.

The medicine contains propylparahydroxybenzoate (E 216) and methylparahydroxybenzoate (E 218), which may cause allergic reactions (possibly delayed). The medicine also contains maltitol (E 965); therefore, patients with known intolerance to certain sugars should consult their physician before using this medicine.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Specific recommendations should be provided to women of childbearing potential. Levetiracetam treatment should be reviewed if a woman plans pregnancy. As with all antiepileptic drugs, abrupt discontinuation of levetiracetam should be avoided, as this may provoke seizures, which could have serious consequences for both the woman and the unborn child. Whenever possible, monotherapy should be preferred, as treatment with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the drug combination.

Pregnancy.

Extensive post-marketing data from pregnant women who used levetiracetam (over 1800 women, including 1500 exposed during the first trimester) do not indicate an increased risk of major congenital malformations. There is only limited information on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. However, existing epidemiological studies (approximately 100 children) do not suggest an increased risk of neurodevelopmental disorders or delays. Levetiracetam may be used during pregnancy if, after careful evaluation, it is considered clinically necessary. In such cases, the lowest effective dose should be used.

Physiological changes during pregnancy may alter levetiracetam concentrations. Decreased plasma concentrations of levetiracetam have been observed during pregnancy, most pronounced in the third trimester (up to 60% reduction compared to pre-pregnancy levels). Adequate clinical monitoring of pregnant women receiving levetiracetam is essential.

Breastfeeding period.

Levetiracetam passes into breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam is required during breastfeeding, the benefits and risks of treatment should be weighed against the importance of breastfeeding.

Effect on fertility.

No effect on fertility was observed in animal studies. The potential risk in humans is unknown due to lack of available clinical data.

Ability to affect reaction speed when driving or operating machinery.

Levetiracetam has a minor to moderate effect on the ability to drive or operate machinery. Due to possible individual sensitivity, some patients may experience somnolence and other central nervous system-related symptoms, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should refrain from activities requiring rapid psychomotor responses, such as driving or operating machinery. Patients are advised to avoid driving and operating machinery until it is established that their ability to perform such activities is not impaired.

Dosage and Administration

The medication is taken orally, regardless of food intake. The oral solution can be taken after dilution in a glass of water or a feeding bottle.

Partial Seizures

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

All Indications

Adults (≥18 years) and adolescents (12–17 years) with body weight ≥50 kg

The initial therapeutic dose is 500 mg twice daily. Treatment may be initiated at this dose on the first day. However, a lower initial dose of 250 mg twice daily may be prescribed by the physician based on an assessment of seizure frequency reduction versus potential adverse effects. This dose may be increased to 500 mg twice daily after 2 weeks.

Depending on clinical response and tolerability, the daily dose may be increased up to 1500 mg twice daily. The dose may be increased or decreased by 500 mg twice daily every 2–4 weeks.

Adolescents (12 to 17 years) with body weight less than 50 kg and children from 1 month of age

The physician should select the most appropriate dosage form, dosage strength, and formulation based on body weight, age, and required dose. For information on dose adjustment according to body weight, see the section "Children".

Discontinuation of Treatment

If discontinuation of treatment is necessary, levetiracetam should be withdrawn gradually (e.g., for adults and adolescents with body weight ≥50 kg, reduce the dose by 500 mg twice daily every 2–4 weeks; for infants aged 6 months and older, children, and adolescents with body weight <50 kg, reduce the dose by no more than 10 mg/kg twice daily every two weeks; for infants under 6 months of age, reduce the dose by no more than 7 mg/kg twice daily every two weeks).

Special Patient Groups

Elderly Patients (≥65 years)

Dose adjustment in elderly patients is required only in case of renal impairment (see section "Patients with Renal Impairment").

Patients with Renal Impairment

The daily dose of levetiracetam should be individually adjusted.

For adult patients, the dose should be adjusted as shown in Table 1. To adjust the dose, the patient's creatinine clearance (CrCl) in mL/min must be determined.

In adults and adolescents with body weight ≥50 kg, CrCl in mL/min can be calculated from serum creatinine level (mg/dL) using the following formula:

[140 ─ age (years)] × body weight (kg)
CrCl (mL/min) = -------------------------------------------------------------- × 0.85 (for women).
72 × serum creatinine (mg/dL)

Then, correct CrCl according to body surface area (BSA) as follows:

CrCl (mL/min)
CrCl (mL/min/1.73m²) = --------------------------- × 1.73.
Patient's BSA (m²)

Table 1

Dosage adjustment recommendations for adult patients and adolescents with body weight ≥50 kg and renal impairment.

(1) On the first day of treatment, a loading dose of levetiracetam 750 mg is recommended.

(2) After dialysis, an additional dose of 250–500 mg is recommended.

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

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

(1) For doses up to 250 mg, for doses not divisible by 250 mg when the recommended dose cannot be achieved by taking several tablets, and for patients unable to swallow tablets, levetiracetam oral solution should be used.

(2) On the first day of treatment, a loading dose of levetiracetam 10.5 mg/kg (0.105 mL/kg) is recommended.

(3) On the first day of treatment, a loading dose of levetiracetam 15 mg/kg (0.15 mL/kg) is recommended.

(4) After dialysis, an additional dose of 3.5–7 mg/kg (0.035–0.07 mL/kg) is recommended.

(5) After dialysis, an additional dose of 5–10 mg/kg (0.05–0.1 mL/kg) is recommended.

Patients with hepatic impairment

Dose adjustment is not required in 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, in patients with creatinine clearance < 60 mL/min/1.73 m², the recommended daily maintenance dose should be reduced by 50%.

Children

The physician should select the most appropriate pharmaceutical form, strength, and dosage form based on age, body weight, and required dose.

Levetiracetam oral solution is preferred for infants and children under 6 years of age. Additionally, the available tablet strengths are not suitable for initial treatment of children weighing less than 25 kg, for patients unable to swallow tablets, or for doses below 250 mg. In these cases, levetiracetam oral solution should be used.

Monotherapy

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

Data are lacking.

Adolescents (16–17 years of age) weighing ≥50 kg with partial-onset seizures with or without secondary generalization, newly diagnosed with epilepsy

See section above titled "Adults (≥ 18 years) and adolescents (12–17 years) weighing ≥50 kg".

Adjunctive therapy in infants 6–23 months, children (2–11 years), and adolescents (12–17 years) weighing less than 50 kg

The initial therapeutic dose is 10 mg/kg twice daily.

Depending on clinical response and tolerability, the dose may be increased up to 30 mg/kg twice daily. Dose increases or decreases should not exceed 10 mg/kg twice daily every two weeks. The lowest effective dose should be used for all indications.

Children weighing 50 kg or more should receive the same doses as adults for all indications.

For information on use across all indications, see the section above titled "Adults (≥ 18 years) and adolescents (12–17 years) weighing ≥50 kg".

Table 3

Recommended doses for infants from 6 months of age, children, and adolescents:

(1) For children with a body weight of 25 kg or less, treatment should be initiated with levetiracetam 100 mg/ml oral solution.

(2) For children with a body weight of 50 kg and above, the same doses as for adults should be used.

Infants aged 1 to < 6 months

The initial therapeutic dose is 7 mg/kg twice daily.

Depending on the clinical response and tolerability, the dose may be increased up to 21 mg/kg twice daily. The dose should not be increased or decreased by more than 7 mg/kg twice daily every two weeks. The lowest effective dose should be used.

For infants, treatment should be initiated with Leviceptam 100 mg/ml oral solution.

Table 4

Recommended doses for infants aged 1 to 6 months:

Oral solution administration method

Dosing is performed using the measuring syringe provided in the package.

The syringe has a nominal capacity of 10 mL (corresponding to 1000 mg of levetiracetam) with 0.25 mL graduations (corresponding to 25 mg). The measured dose should be diluted in a glass of water (200 mL) or in a feeding bottle.

Instructions for dosing the solution using the measuring syringe:

• Open the bottle by pressing down on the cap and turning it counterclockwise (Fig. 1).
• Insert the syringe adapter into the neck of the bottle. Ensure it is securely attached, then insert the syringe into the adapter (Fig. 2).
• Turn the bottle upside down (Fig. 3).
• Draw a small amount of solution into the syringe by pulling the plunger down (Fig. 4), then press the plunger to expel any air bubbles (Fig. 5).
• Fill the syringe with solution by pulling the plunger to the graduation mark corresponding to the amount prescribed by the physician (Fig. 6).
• Turn the bottle right side up. Remove the syringe from the adapter.
• Expel the syringe contents into a glass of water or feeding bottle by fully depressing the plunger (Fig. 7).
• Drink the entire contents of the glass.
• Close the bottle with the plastic cap.
• Rinse the syringe with water (Fig. 8).

Children.

This pharmaceutical form of the drug is intended for use in children aged 1 month and older. The physician selects the optimal pharmaceutical form and dosage based on age, body weight, and required dose. The drug is not recommended for use in children under 1 month of age due to lack of safety and efficacy data. It should be noted that tablet formulation should not be used for initial treatment in children with body weight below 25 kg when high doses are required; in patients unable to swallow tablets; or for doses below 250 mg. In such cases, the oral solution formulation should be used.

The safety and efficacy of the drug as monotherapy in children under 16 years of age have not been studied.

Overdose.

Symptoms. In cases of levetiracetam overdose, symptoms such as somnolence, agitation, aggression, respiratory depression, confusion, and coma have been observed.

Treatment. In case of acute overdose, gastric lavage should be performed or vomiting induced. There is no specific antidote. If necessary, symptomatic treatment should be administered in a hospital setting, with hemodialysis used if needed (up to 60% of levetiracetam and 74% of the main metabolite are removed).

Adverse reactions

The most common adverse reactions associated with the use of levetiracetam are nasopharyngitis, somnolence, headache, increased fatigue, and dizziness. The adverse reaction profile provided is based on a pooled analysis of data from placebo-controlled clinical trials involving a total of 3416 patients who received levetiracetam. These data are supplemented by the use of levetiracetam in appropriate open-label extension studies and post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adults and children) for the approved epilepsy indications.

Adverse reactions reported in clinical studies (in adults, adolescents, children, and infants from 1 month of age) and during the post-marketing period are listed below by system organ class, with frequencies specified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000).

Infections and infestations: very common – nasopharyngitis; rare – infections.

Blood and lymphatic system disorders: uncommon – thrombocytopenia, leukopenia; rare – neutropenia, pancytopenia, agranulocytosis.

Immune system disorders: rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), hypersensitivity (including angioedema and anaphylaxis).

Metabolism and nutrition disorders: common – anorexia; uncommon – weight increased, weight decreased; rare – hyponatremia.

Psychiatric disorders: common – depression, hostility, aggression, anxiety, insomnia, irritability, nervousness; uncommon – suicide attempts and suicidal ideation, psychotic disorders, abnormal behavior, hallucinations, anger, confusion, panic attacks, emotional lability/mood changes, agitation; rare – suicide, personality disorders, abnormal thoughts, delirium; very rare – obsessive-compulsive disorder**.

Nervous system disorders: very common – somnolence, headache; common – convulsion, impaired balance, dizziness, lethargy, tremor; uncommon – amnesia, memory impairment, ataxia, coordination disorder, paresthesia, attention disturbance; rare – hyperkinesia, choreoathetosis, dyskinesia, gait disturbance, encephalopathy, seizure aggravation, neuroleptic malignant syndrome.

Eye disorders: uncommon – diplopia, blurred vision.

Ear and labyrinth disorders: common – vertigo.

Cardiac disorders: rare – QT interval prolongation on ECG.

Respiratory, thoracic and mediastinal disorders: common – cough.

Gastrointestinal disorders: common – abdominal pain, diarrhea, dyspepsia, nausea, vomiting; rare – pancreatitis.

Hepatobiliary disorders: uncommon – liver function test abnormalities; rare – hepatitis, hepatic failure.

Renal and urinary disorders: rare – acute kidney injury.

Skin and subcutaneous tissue disorders: common – rash; uncommon – eczema, pruritus, alopecia; rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal and connective tissue disorders: uncommon – myalgia, muscle weakness; rare – rhabdomyolysis and elevated blood creatine phosphokinase levels*.

General disorders and administration site conditions: common – asthenia, fatigue.

Injury, poisoning and procedural complications: uncommon – injuries.

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

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

Description of selected adverse reactions.

The risk of anorexia increases when levetiracetam is used concomitantly with topiramate.
In cases of alopecia, hair regrowth has been observed in some instances after discontinuation of levetiracetam.

In cases of pancytopenia, bone marrow suppression has been observed in some instances.

Cases of encephalopathy typically occurred early in treatment (within days to months) and were reversible upon discontinuation of therapy.

Children.

A total of 190 patients aged 1 month to 4 years received levetiracetam treatment in placebo-controlled and open-label add-on studies, with 60 of these patients participating in placebo-controlled trials. A total of 645 patients aged 4–16 years received levetiracetam in placebo-controlled and open-label add-on studies, of whom 233 participated in placebo-controlled trials. For both age groups, these data are supplemented by post-marketing safety data.

Post-marketing safety studies have included infants up to 12 months of age. No new safety data have been obtained regarding the use of levetiracetam in infants under 12 months of age with epilepsy.

The adverse reaction profile of levetiracetam is generally similar across different age groups and for all approved epilepsy indications. Safety data from placebo-controlled clinical trials in children are consistent with the safety profile in adults, except for behavioral and psychiatric adverse reactions, which are more frequent in children than in adults. In children and adolescents aged 4–16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood alteration (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behavior (common, 5.6%), and lethargy (common, 3.9%) were observed more frequently 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 coordination disorder (common, 3.3%) occurred more frequently than in other age groups or in the overall safety profile.

In a double-blind, placebo-controlled safety study in children conducted to demonstrate non-inferiority of the drug compared to active control, the impact of levetiracetam on cognitive and neuropsychological parameters was evaluated in children aged 4–16 years with partial seizures. Levetiracetam did not differ from placebo in terms of change from baseline in attention and memory. However, results related to behavioral and emotional functions indicated worsening in patients treated with levetiracetam, particularly in aggressive behavior, as assessed systematically and standardized using validated tools (CBCL – Achenbach Child Behavior Checklist). Nevertheless, in patients receiving levetiracetam during a long-term open-label follow-up study, no overall worsening of behavioral and emotional functions was observed on average; specifically, aggressive behavior scores did not deteriorate compared to baseline.

Shelf life. 3 years.

Shelf life after first opening of the bottle – 7 months.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 300 ml in a bottle No. 1, supplied with a plastic measuring syringe, in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Bluepharma – Indústria Farmacêutica, S.A.

Manufacturer's address. S. Martinho do Bispo, Coimbra, 3045-016, Portugal.

Marketing Authorization Holder. LLC "Asino Ukraine".

Address of the Marketing Authorization Holder. 8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse reactions or questions regarding the safety and efficacy of the medicinal product, please contact the pharmacovigilance department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.