Levebrain

INSTRUCTION for medical use of the medicinal product LEVEBRAIN (LEVEBRAIN)

Composition:

Active substance: levetiracetam;

One film-coated tablet contains levetiracetam 250 mg or 500 mg or 1000 mg;

Excipients: colloidal anhydrous silicon dioxide, talc, povidone K30, partially pregelatinized corn starch, magnesium stearate;

Film coating:

250 mg film-coated tablets (Opadry II Blue 85F20400): polyvinyl alcohol partially hydrolyzed, polyethylene glycol, titanium dioxide (E 171), talc, indigo carmine aluminum lake (E 132);

500 mg film-coated tablets (Opadry II Yellow 85F220095): polyvinyl alcohol partially hydrolyzed, polyethylene glycol, titanium dioxide (E 171), talc, iron oxide yellow (E 172), tartrazine (E 102), sunset yellow FCF (E 110);

1000 mg film-coated tablets (Opadry II White 85F18422): polyvinyl alcohol partially hydrolyzed, polyethylene glycol, titanium dioxide (E 171), talc.

Medicinal form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: blue, oval-shaped, biconvex, film-coated tablets with a dividing line on one side;

500 mg tablets: yellow, oval-shaped, biconvex, film-coated tablets with a dividing line on one side;

1000 mg tablets: white, oval-shaped, biconvex, film-coated tablets with a dividing line on one side.

Pharmacotherapeutic group.

Antiepileptic drugs. Levetiracetam. ATC code N03AX14.

Pharmacological properties.

Pharmacodynamics.

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

The mechanism of action of levetiracetam is not fully understood. Based on in vitro and in vivo studies, it is assumed 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 the influx through N-type Ca2+ 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 brain tissues of rodents. The binding site is synaptic vesicle protein 2A (SV2A), which is involved in vesicle fusion and neurotransmitter release. The affinity (in rank order) of levetiracetam and its corresponding analogs for synaptic vesicle protein 2A correlated with their anticonvulsant potency in models of audiogenic epilepsy in mice. These results suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the antiepileptic mechanism of action of levetiracetam.

Levetiracetam provides protection against seizures in a broad range of animal models of partial and primarily generalized seizures, without causing proconvulsant effects. The main metabolite is inactive.

In humans, the activity of levetiracetam has been confirmed for both focal and generalized epileptic seizures (epileptiform discharges/photo-epileptic response), indicating a broad pharmacological profile of levetiracetam.

Pharmacokinetics.

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

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

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

Adults and adolescents

Absorption

Levetiracetam is rapidly absorbed after oral administration. The absolute oral bioavailability is close to 100%. Maximum plasma concentration (Cmax) is reached within 1.3 hours after administration of levetiracetam. Steady-state levels are achieved within 2 days of twice-daily dosing. Cmax is typically 31 µg/mL and 43 µg/mL after a single 1000 mg dose and repeated 1000 mg doses twice daily, respectively. The extent of absorption is dose-independent and not affected by food.

Distribution

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

Metabolism

Metabolism of levetiracetam in humans is minimal. The main metabolic pathway (24% of the 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 formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), and the other by opening of the pyrrolidone ring (0.9% of the 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 human hepatic 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 in vivo is unlikely. Therefore, drug interactions between levetiracetam and other substances, or vice versa, are improbable.

Elimination

The elimination half-life of levetiracetam in plasma in adults is 7 ± 1 hour and does not depend on dose, route of administration, or repeated dosing. The mean total clearance is 0.96 mL/min/kg.

The majority of levetiracetam, on average 95% of the dose, is excreted by the kidneys (approximately 93% of the dose is excreted 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 mL/min/kg and 4.2 mL/min/kg, respectively, indicating that levetiracetam is eliminated by glomerular filtration with subsequent tubular reabsorption, while the main metabolite is also eliminated by active tubular secretion in addition to glomerular filtration. Elimination of levetiracetam correlates with creatinine clearance.

Elderly patients

In elderly patients, the elimination half-life (t1/2) increases by approximately 40% (10–11 hours). This is associated with impaired renal function in this population (see section "Dosage and administration").

Patients with renal impairment

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

In patients with anuria in end-stage renal disease, the elimination half-life (t1/2) 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.

Patients with hepatic impairment

The clearance of levetiracetam is not altered in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment, the clearance of levetiracetam is reduced by more than 50% due to concomitant renal impairment (see section "Dosage and administration").

Paediatric population

Children aged 4–12 years

After administration of a single dose (20 mg/kg) in children with epilepsy (aged 6 to 12 years), the t1/2 of levetiracetam was 6 hours. The 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. Cmax was reached within 0.5–1 hour after dosing. Cmax and the area under the plasma concentration-time curve increased linearly and were dose-dependent. The t1/2 was approximately 5 hours, and the apparent total clearance was 1.1 mL/min/kg.

Clinical characteristics.

Indications.

Monotherapy (first-line treatment) for:

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

As adjunctive therapy in:

• Partial-onset seizures with or without secondary generalization in adults and children aged 6 years 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, other pyrrolidone derivatives, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs

Pre-registration data and data obtained during clinical trials involving adult patients indicate that levetiracetam does not affect plasma concentrations of concomitant 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 interactions of levetiracetam in pediatric patients, as well as in adults receiving up to 60 mg/kg/day.

Pharmacokinetic interaction assessment in children and adolescents with epilepsy (aged 4 to 17 years) confirmed that adjunctive therapy with oral levetiracetam did not affect steady-state plasma concentrations of concurrently administered carbamazepine and valproate. However, data indicate that levetiracetam clearance is 20% higher in children taking enzyme-inducing antiepileptic drugs. Dose adjustment is not required.

Probenecid

Probenecid (at a dose of 500 mg four times daily)—a tubular secretion blocking agent—reduces renal clearance of the major metabolite, but not of levetiracetam itself. However, concentrations of this metabolite remain low.

Methotrexate

Concomitant use of levetiracetam and methotrexate has been reported to reduce methotrexate clearance, leading to increased/prolonged plasma methotrexate concentrations to potentially toxic levels. Methotrexate and levetiracetam plasma levels should be closely monitored in patients receiving both medicinal products concomitantly.

Oral contraceptives and pharmacokinetic interactions with other medicinal products

Levetiracetam at a daily dose of 1000 mg does not alter the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone levels) remained 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 efficacy 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 administration of levetiracetam.

Food and alcohol

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

Special precautions for use.

Patients with renal impairment

Patients with renal impairment may require dose adjustment of levetiracetam. Patients with severe hepatic dysfunction are recommended to have renal function assessed before determining the drug dosage (see section "Dosage and administration").

Acute renal injury

Very rare cases of acute renal 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, usually at the beginning of treatment. Complete blood count monitoring is recommended in patients who develop significant weakness, fever, recurrent infections, or bleeding disorders (see section "Adverse reactions").

Suicidal behavior

Suicide, suicide attempts, suicidal thoughts, and suicidal behavior have been observed in patients treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs 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, suicidal thoughts, and behavior, and treatment should be adjusted if necessary. Patients (or their caregivers) should be advised to report any symptoms of depression, suicidal thoughts, or behavior to their physician.

Unusual or aggressive behavior

Levetiracetam may cause psychiatric symptoms and behavioral disturbances, including irritability and aggression. Patients should be monitored for the emergence of psychiatric signs indicating significant mood and/or personality changes during treatment. If such behavior occurs, treatment adjustment or gradual discontinuation of the drug is recommended. For information on discontinuation, see section "Dosage and administration".

Exacerbation of seizures

As with other antiepileptic drugs, levetiracetam may rarely increase the frequency or severity of seizures. This paradoxical effect has been most frequently reported during the first month after initiation of levetiracetam or during dose escalation. This effect is reversible upon discontinuation or dose reduction of the drug. Patients should be advised to seek immediate medical advice if seizure control worsens.

For example, lack of efficacy or worsening of seizures has been reported in patients with epilepsy associated with mutations in the alpha subunit 8 of the voltage-gated sodium channel (SCN8A).

Prolongation of QT interval on electrocardiogram (ECG)

Rare cases of QT interval prolongation on ECG have been reported during post-marketing surveillance. The drug should be used with caution in patients with known QT prolongation, in patients concomitantly taking medications that affect the QT interval, and in patients with underlying cardiac conditions or electrolyte imbalances.

Children

The tablet formulation is not suitable for use in infants and children under 6 years of age. Available data in children do not indicate effects on development or sexual maturation. However, the long-term impact on learning ability, intelligence, development, endocrine functions, sexual maturation, and reproductive function in children remains unknown.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Specific recommendations should be provided to women of childbearing potential. Treatment with levetiracetam should be reviewed if a woman plans pregnancy. As with all antiepileptic drugs, abrupt discontinuation of levetiracetam should be avoided, as it 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 combination of drugs used.

Pregnancy

A large amount of post-marketing data from pregnant women using levetiracetam (more than 1800 women, including 1500 women exposed during the first trimester) does not indicate an increased risk of congenital malformations. There is only limited data on the neurodevelopmental outcomes of children exposed to levetiracetam monotherapy in utero. However, existing epidemiological studies (approximately 100 children) do not indicate an increased risk of neurodevelopmental disorders or developmental delay. The drug may be used during pregnancy if, after careful assessment, it is considered clinically necessary. In such cases, the lowest effective dose is recommended. 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 from pre-pregnancy baseline). Appropriate clinical monitoring of pregnant women taking levetiracetam is required.

Breastfeeding period

Levetiracetam passes into human breast milk; therefore, breastfeeding is not recommended. However, if levetiracetam treatment is necessary during breastfeeding, the benefits and risks of treatment and the importance of breastfeeding should be carefully weighed.

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 or moderate influence on the ability to drive or operate machinery. Due to possible individual sensitivity, some patients may experience somnolence, dizziness, and other central nervous system-related symptoms, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should exercise caution in activities requiring high concentration, such as driving 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.

Dosage and Administration

The medicinal product is intended for oral administration. Tablets should be taken with sufficient liquid, regardless of food intake. The daily dose should be divided into two equal administrations.

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 (aged 12 to 17 years) with body weight ≥ 50 kg

The initial therapeutic dose of the medicinal product is 500 mg twice daily. This is the starting dose administered on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be used at the physician’s discretion, based on a risk-benefit assessment balancing seizure frequency reduction against potential adverse reactions. This dose may be increased to 500 mg twice daily after 2 weeks. Depending on the clinical response and tolerability of levetiracetam, the daily dose may be increased up to a maximum of 1500 mg twice daily. Dose adjustments by 250 mg or 500 mg twice daily may be made every 2–4 weeks.

Children aged 6 years and older and adolescents (aged 12 to 17 years) with body weight < 50 kg

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

Discontinuation of Treatment

If discontinuation of the medicinal product is required, it is recommended to withdraw treatment 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 children and adolescents with body weight < 50 kg: reduce the single dose by no more than 10 mg/kg twice daily every 2 weeks).

Special Patient Populations

Elderly Patients (aged 65 years and older)

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

Patients with Renal Impairment

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

For dose adjustment in adults, use the table provided below.

To adjust the dose using the table, the creatinine clearance (CrCl) in mL/min must be determined.

CrCl in adults and adolescents with body weight > 50 kg can be calculated from plasma creatinine concentration using the following formula:

[140 ─ age (years)] × body weight (kg)

CrCl (mL/min) = -------------------------------------------------------------- × 0.85 (for females)

72 × plasma creatinine (mg/dL)

Then, CrCl should be corrected for body surface area (BSA) as follows:

CrCl (mL/min)

CrCl (mL/min/1.73 m²) = --------------------------- × 1.73

Patient's BSA (m²)

Table 1

Dosing regimen for adults and adolescents with impaired renal function and body weight > 50 kg

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

(2) An additional dose of 250–500 mg is recommended after dialysis.

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

For adolescents and children, creatinine clearance (CCl) in ml/min/1.73 m² can be calculated based on plasma creatinine concentration (mg/dl) using the following formula (Schwartz formula):

Height (cm) × ks
CCl (ml/min/1.73 m²) = ---------------------------------
Plasma creatinine (mg/dl)

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

Table 2

Dosing regimen for children and adolescents with impaired renal function and body weight less than 50 kg

(1) For doses up to 250 mg, for doses not multiples of 250 mg when the recommended dosage 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 15 mg/kg (0.15 mL/kg) is recommended.

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

Patients with hepatic impairment

Dosage adjustment of levetiracetam 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 daily maintenance dose of levetiracetam should be reduced by 50%.

Paediatric population

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

The tablet formulation is not recommended for children under 6 years of age. This patient group should be treated with levetiracetam oral solution. Furthermore, 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 all the above cases, treatment should be initiated with levetiracetam oral solution.

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 epilepsy

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

Adjunctive therapy in children aged 6 years and older and adolescents (12–17 years) weighing less than 50 kg

Levetiracetam oral solution is preferred for infants and children under 6 years of age.

For children aged 6 years and older, the oral solution should be used for dosing up to 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be achieved by taking several tablets, and for patients unable to swallow tablets.

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

For children weighing more than 50 kg, dosing for all indications should follow the regimen described for adults (see section above "Adults (≥ 18 years) and adolescents (12–17 years) weighing ≥ 50 kg" for all indications).

Adjunctive therapy in infants aged 1 to 6 months

Levetiracetam oral solution should be used in infants.

Children.

The tablet formulation is not recommended for children under 6 years of age. Levetiracetam oral solution should be used in infants aged 1 month and children under 6 years of age.

Overdose.

Symptoms

Symptoms observed in cases of levetiracetam overdose include somnolence, agitation, aggression, respiratory depression, impaired consciousness, and coma.

Treatment

In case of acute overdose, gastric lavage or induction of emesis should be performed. There is no specific antidote. Symptomatic treatment should be administered as needed, including hemodialysis (up to 60% of levetiracetam and 74% of the primary metabolite can be removed).

Adverse Reactions

The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue, and dizziness. The safety profile of levetiracetam is generally similar across different age groups (adults and children) when used according to 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 by system organ class, with frequencies 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); very rare (< 1/10,000).

Infections and infestations:

very common – nasopharyngitis; rare – infection.

Blood and lymphatic system disorders:

uncommon – thrombocytopenia, leukopenia; rare – neutropenia, pancytopenia, agranulocytosis.

Immune system disorders:

rare – drug reaction with eosinophilia and systemic symptoms (DRESS)1, hypersensitivity (including angioedema and anaphylaxis).

Metabolism and nutrition disorders:

common – anorexia; uncommon – weight increase or decrease; rare – hyponatremia.

Psychiatric disorders:

common – depression, hostility/aggression, anxiety, insomnia, nervousness/irritability; uncommon – suicide attempts, suicidal ideation, psychotic disorders, abnormal behavior, hallucinations, anger, confusion, panic attacks, affective lability/mood changes, agitation; rare – suicide, personality disorders, thought disorders, delirium; very rare – obsessive-compulsive disorders2.

Nervous system disorders:

very common – somnolence, headache; common – convulsions, balance disorder, dizziness, lethargy, tremor; uncommon – amnesia, memory impairment, ataxia/coordination disorder, paresthesia, attention disorders; rare – hyperkinesia, dyskinesia, choreoathetosis, gait disturbance, encephalopathy, seizure exacerbation, neuroleptic malignant syndrome3.

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 – diarrhea, dyspepsia, nausea, vomiting, abdominal pain; 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 plasma creatine phosphokinase3.

General disorders and administration site conditions:

common – asthenia/fatigue.

Injury, poisoning and procedural complications:

uncommon – injuries.

1See description of individual adverse reactions below.

2During post-marketing surveillance, very rare cases of development of obsessive-compulsive disorders (OCD) have been reported in patients with a history of OCD or psychiatric disorders.

3The incidence is significantly higher in Japanese patients compared to non-Japanese patients.

Available data also suggest a possible predisposition of the Japanese population to neuroleptic malignant syndrome (NMS).

Description of selected adverse reactions

Multi-organ hypersensitivity reactions

Rare cases of multi-organ hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported in patients receiving levetiracetam. Clinical manifestations may develop 2–8 weeks after initiation of treatment. This condition is associated with various systemic symptoms, including fever, rash, facial swelling, lymphadenopathy, hematological abnormalities, and may involve multiple organ systems, primarily the liver. If a multi-organ hypersensitivity reaction is suspected, the drug should be discontinued.

The risk of anorexia increases when levetiracetam is used concomitantly with topiramate.

In some cases, hair regrowth was observed after discontinuation of levetiracetam in patients who developed alopecia.

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

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

Children.

Among patients aged 1 month to 4 years, a total of 190 patients received levetiracetam treatment in placebo-controlled and open-label add-on studies. Of these, 60 patients received levetiracetam in placebo-controlled trials. Among patients aged 4–16 years, a total of 645 patients received levetiracetam treatment in placebo-controlled and open-label add-on studies. Of these, 233 patients received levetiracetam in placebo-controlled trials. Data for both age groups were supplemented with post-marketing safety data.

Additionally, 101 infants under 12 months of age received the drug in a post-marketing safety study. No new safety data were obtained regarding the use of levetiracetam in infants under 12 months with epilepsy.

The adverse reaction profile of levetiracetam is generally similar across age groups and all approved epilepsy indications. Safety results in children from placebo-controlled clinical trials were consistent with the safety profile in adults, except for behavioral and psychiatric adverse reactions, which were 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 change (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behavior (common, 5.6%), and lethargy (common, 3.9%) occurred more frequently than in other age groups or 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 the overall safety profile.

In a double-blind, placebo-controlled safety study in children designed to demonstrate non-inferiority of the drug compared to active control, the effect 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 scores on the Leiter-R scale or total memory score in the per-protocol population. Behavioral and emotional function outcomes indicated increased aggression in patients treated with levetiracetam, as assessed systematically and standardized using validated tools (CBCL – Achenbach Child Behavior Checklist). However, 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, aggression scores did not worsen compared to baseline.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 ºC, in a place inaccessible to children.

Packaging.

Date of last review.